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Sample records for hepatic xenobiotic metabolizing

  1. Xenobiotic-contaminated diets affect hepatic lipid metabolism: Implications for liver steatosis in Sparus aurata juveniles

    Energy Technology Data Exchange (ETDEWEB)

    Maradonna, F.; Nozzi, V. [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); Santangeli, S. [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Traversi, I. [Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università di Genova, 16132 Genova (Italy); Gallo, P. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Dipartimento di Chimica, Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, Napoli (Italy); Fattore, E. [Dipartimento Ambiente e Salute, IRCCS–Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 Milano (Italy); Mita, D.G. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Mandich, A. [INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy); Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università di Genova, 16132 Genova (Italy); Carnevali, O., E-mail: o.carnevali@univpm.it [Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona (Italy); INBB Consorzio Interuniversitario di Biosistemi e Biostrutture, 00136 Roma (Italy)

    2015-10-15

    Highlights: • Diets contaminated with NP, BPA, or t-OP affect lipid metabolism. • Xenobiotic-contaminated diets induce metabolic disorders. • Hepatic metabolic disorders may be related to environmental pollution. - Abstract: The metabolic effects induced by feed contaminated with a lower or a higher concentration of -nonylpnenol (NP), 4-tert-octylphenol (t-OP) or bisphenol A (BPA), three environmental endocrine disruptors, were assessed in juvenile sea bream liver. Histological analysis demonstrated that all these three xenobiotics induced hepatic lipid accumulation and steatosis. These findings prompted analysis of the expression of the major molecules involved in lipid metabolism: peroxisome proliferator activated receptors (which is encoded by ppars), fatty acid synthase (encoded by fas), lipoprotein lipase (encoded by lpl) and hormone-sensitive lipase (encoded by hsl). The enzymes encoded by ppars and fas are in fact responsible for lipid accumulation, whereas lpl- and hsl- encoded proteins play a pivotal role in fat mobilization. The three xenobiotics modulated ppar mRNA expression: pparα mRNA expression was induced by the higher dose of each contaminant; pparβ mRNA expression was upregulated by the lower doses and in BPA2 fish ppary mRNA overexpression was induced by all pollutants. These data agreed with the lipid accumulation profiles documented by histology. Fas mRNA levels were modulated by the two NP doses and the higher BPA concentration. Lpl mRNA was significantly upregulated in all experimental groups except for BPA1 fish while hsl mRNA was significantly downregulated in all groups except for t-OP2 and BPA1 fish. The plasma concentrations of cortisol, the primary stress biomarker, were correlated with the levels of pepck mRNA level. This gene encodes phosphoenolpyruvate carboxykinase which is one of the key enzymes of gluconeogenesis. Pepck mRNA was significantly overexpressed in fish exposed to NP2 and both t-OP doses. Finally, the genes

  2. Xenobiotic-contaminated diets affect hepatic lipid metabolism: Implications for liver steatosis in Sparus aurata juveniles.

    Science.gov (United States)

    Maradonna, F; Nozzi, V; Santangeli, S; Traversi, I; Gallo, P; Fattore, E; Mita, D G; Mandich, A; Carnevali, O

    2015-10-01

    The metabolic effects induced by feed contaminated with a lower or a higher concentration of -nonylpnenol (NP), 4-tert-octylphenol (t-OP) or bisphenol A (BPA), three environmental endocrine disruptors, were assessed in juvenile sea bream liver. Histological analysis demonstrated that all these three xenobiotics induced hepatic lipid accumulation and steatosis. These findings prompted analysis of the expression of the major molecules involved in lipid metabolism: peroxisome proliferator activated receptors (which is encoded by ppars), fatty acid synthase (encoded by fas), lipoprotein lipase (encoded by lpl) and hormone-sensitive lipase (encoded by hsl). The enzymes encoded by ppars and fas are in fact responsible for lipid accumulation, whereas lpl- and hsl- encoded proteins play a pivotal role in fat mobilization. The three xenobiotics modulated ppar mRNA expression: pparα mRNA expression was induced by the higher dose of each contaminant; pparβ mRNA expression was upregulated by the lower doses and in BPA2 fish ppary mRNA overexpression was induced by all pollutants. These data agreed with the lipid accumulation profiles documented by histology. Fas mRNA levels were modulated by the two NP doses and the higher BPA concentration. Lpl mRNA was significantly upregulated in all experimental groups except for BPA1 fish while hsl mRNA was significantly downregulated in all groups except for t-OP2 and BPA1 fish. The plasma concentrations of cortisol, the primary stress biomarker, were correlated with the levels of pepck mRNA level. This gene encodes phosphoenolpyruvate carboxykinase which is one of the key enzymes of gluconeogenesis. Pepck mRNA was significantly overexpressed in fish exposed to NP2 and both t-OP doses. Finally, the genes encoding cyclooxygenase 2 (cox2) and 5-lipoxygenase (5 lox), the products of which are involved in the inflammatory response, transcriptions were significantly upregulated in NP and BPA fish, whereas they were unchanged in t

  3. Effect of thiabendazole on some rat hepatic xenobiotic metabolising enzymes

    NARCIS (Netherlands)

    Price, R.J.; Scott, M.P.; Walters, D.G.; Stierum, R.H.; Groten, J.P.; Meredith, C.; Lake, B.G.

    2004-01-01

    The effect of thiabendazole (TB) on some rat hepatic xenobiotic metabolising enzymes has been investigated. Male Sprague-Dawley rats were fed control diet or diets containing 102-5188 ppm TB for 28 days. As a positive control for induction of hepatic xenobiotic metabolism, rats were also fed diets c

  4. Effect of thiabendazole on some rat hepatic xenobiotic metabolising enzymes

    NARCIS (Netherlands)

    Price, R.J.; Scott, M.P.; Walters, D.G.; Stierum, R.H.; Groten, J.P.; Meredith, C.; Lake, B.G.

    2004-01-01

    The effect of thiabendazole (TB) on some rat hepatic xenobiotic metabolising enzymes has been investigated. Male Sprague-Dawley rats were fed control diet or diets containing 102-5188 ppm TB for 28 days. As a positive control for induction of hepatic xenobiotic metabolism, rats were also fed diets

  5. Xenobiotic Metabolism and Gut Microbiomes

    Science.gov (United States)

    Das, Anubhav; Srinivasan, Meenakshi; Ghosh, Tarini Shankar; Mande, Sharmila S.

    2016-01-01

    Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome) in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs) also indicate geographic as well as age specific trends. PMID:27695034

  6. Xenobiotic Exposure and Autoimmune Hepatitis

    Directory of Open Access Journals (Sweden)

    Kathleen M. Gilbert

    2010-01-01

    Full Text Available Although genetics contributes to the development of autoimmune diseases, it is clear that “environmental” factors are also required. These factors are thought to encompass exposure to certain drugs and environmental pollutants. This paper examines the mechanisms that normally maintain immune unresponsiveness in the liver and discusses how exposure to certain xenobiotics such as trichloroethylene may disrupt those mechanisms and promote autoimmune hepatitis.

  7. Hepatic xenobiotic metabolizing enzyme and transporter gene expression through the life stages of the mouse.

    Directory of Open Access Journals (Sweden)

    Janice S Lee

    Full Text Available BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs. No comprehensive analysis of the mRNA expression of XMETs has been carried out through life stages in any species. RESULTS: Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD 19, neonatal (postnatal day (PND 7, prepubescent (PND32, middle age (12 months, and old age (18 and 24 months in the C57BL/6J (C57 mouse liver and compared to adults. Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age. The total number of XMET probe sets that differed from adults was 636, 500, 84, 5, 43, and 102 for GD19, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including introduction of reactive or polar groups (Phase I, conjugation (Phase II and excretion (Phase III. In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally down-regulated. Suppression of male-specific XMETs was observed at early (GD19, PND7 and to a lesser extent, later life stages (18 and 24 months. A number of female-specific XMETs exhibited a spike in expression centered at PND7. CONCLUSIONS: The analysis revealed dramatic differences in the expression of the XMETs, especially in the fetus and neonate that are partially dependent on gender-dependent factors. XMET expression can be used to predict life stage-specific responses to environmental chemicals and drugs.

  8. Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Gueguen, Y.; Souidi, M.; Baudelin, C.; Dudoignon, N.; Grison, S.; Dublineau, I.; Marquette, C.; Voisin, P.; Gourmelon, P.; Aigueperse, J. [Direction de la RadioProtection de l' Homme, Service de Radiobiologie et d' Epidemiologie. IRSN, Institut de Radioprotection et de Surete Nucleaire, B.P. No. 17, Fontenay-aux-Roses Cedex (France)

    2006-04-15

    The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague-Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7{alpha}-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPAR{alpha} mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics. (orig.)

  9. Hepatic transcriptional analysis in rats treated with Cassia occidentalis seed: involvement of oxidative stress and impairment in xenobiotic metabolism as a putative mechanism of toxicity.

    Science.gov (United States)

    Panigrahi, Gati Krushna; Yadav, Ashish; Yadav, Anuradha; Ansari, Kausar M; Chaturvedi, Rajnish K; Vashistha, Vipin M; Raisuddin, S; Das, Mukul

    2014-08-17

    The present study was undertaken to investigate the effect of Cassia occidentalis (CO) seeds on the transcriptional expression patterns of mRNAs in rat liver by microarray analysis. The results indicated that exposure of CO (0.5%) seeds in diet to rats differentially regulated 60 transcripts belonging to various metabolic pathways including, oxidative stress, xenobiotic metabolism, carbohydrate metabolism, cell cycle, apoptosis etc. The expression of AKT1, CAT, SOD1, CYP1A1, CYP2B1, TGF-β, BAX, CREB1, JNK1 and IL-6 were validated by the qRT-PCR. In addition, involvement of oxidative stress was observed due to marked depletion of glutathione, increase in lipid peroxidation and modulation of antioxidant enzymes in hepatic tissue of rats treated with 0.5-2.0% CO in diet. Furthermore, significant decrease in the levels of Phase 1 (EROD, MROD and PROD) and Phase 2 (QR and GST) enzymes following 0.5-2.0% CO exposure indicates the impairment of xenobiotic metabolism and possible accumulation of toxic ingredients of the seeds in liver. Overall, the study predicts the involvement of multiple pathways and related biomolecules in CO induced hepatotoxicity and the data may be useful in formulating strategies for therapeutic interventions of suspected CO poisoning study cases.

  10. Developing a metagenomic view of xenobiotic metabolism

    OpenAIRE

    Haiser, Henry J.; Turnbaugh, Peter J.

    2012-01-01

    The microbes residing in and on the human body influence human physiology in many ways, particularly through their impact on the metabolism of xenobiotic compounds, including therapeutic drugs, antibiotics, and diet-derived bioactive compounds. Despite the importance of these interactions and the many possibilities for intervention, microbial xenobiotic metabolism remains a largely underexplored component of pharmacology. Here, we discuss the emerging evidence for both direct and indirect eff...

  11. Xenobiotic metabolism: a view through the metabolometer.

    Science.gov (United States)

    Patterson, Andrew D; Gonzalez, Frank J; Idle, Jeffrey R

    2010-05-17

    The combination of advanced ultraperformance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of xenobiotics. Here, a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of the experimental cancer therapeutic agent aminoflavone is presented. In all cases, the metabolic maps of the xenobiotics were considerably enlarged, providing new insights into their toxicology. The inclusion of transgenic mice permitted unequivocal attribution of individual and often novel metabolic pathways to particular enzymes. Last, a future perspective for xenobiotic metabolomics is discussed and its impact on the metabolome is described. The studies reviewed here are not specific to the mouse and can be adapted to study xenobiotic metabolism in any animal species, including humans. The view through the metabolometer is unique and visualizes a metabolic space that contains both established and unknown metabolites of a xenobiotic, thereby enhancing knowledge of their modes of toxic action.

  12. Precision-cut organ slices as a tool to study toxicity and metabolism of xenobiotics with special reference to non-hepatic tissues

    NARCIS (Netherlands)

    de Kanter, R; Monshouwer, M; Meijer, DKF; Groothuis, GMM

    2002-01-01

    Metabolism of xenobiotics is often seen as an exclusive function of the liver, but some current findings support the notion that the lungs, kidneys and intestine may contribute considerably. After the establishment of the use of liver slices as a useful in vitro model to study metabolism and toxicit

  13. Metabolic and redox barriers in the skin exposed to drugs and xenobiotics.

    Science.gov (United States)

    Korkina, Liudmila

    2016-01-01

    Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised. Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo) Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.

  14. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

    NARCIS (Netherlands)

    Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

    2016-01-01

    The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver f

  15. In silico prediction of xenobiotic metabolism in humans

    Energy Technology Data Exchange (ETDEWEB)

    Mu, Fangping [Los Alamos National Laboratory

    2009-01-01

    Xenobiotic metabolism in humans is catalyzed by a few enzymes with broad substrate specificities, which provide the overall broad chemical specificity for nearly all xenobiotics that humans encounter. Xenobiotic metabolism are classified into functional group biotransformations. Based on bona fide reactions and negative examples for each reaction class, support vector machine (SVM) classifiers are built. The input to SVM is a set of atomic and molecular features to define the electrostatic, steric, energetic, geometrical and topological environment of the atoms in the reaction center under the molecule. Results show that the overall sensitivity and specificity of classifiers is around 87%.

  16. INTERINDIVIDUAL VARIANCE OF CYTOCHROME P450 FORMS IN HUMAN HEPATIC MICROSOMES: CORRELATION OF INDIVIDUAL FORMS WITH XENOBIOTIC METABOLISM AND IMPLICATIONS IN RISK ASSESSMENT

    Science.gov (United States)

    Differences in biotransformation activities may alter the bioavailability or efficacy of drugs, provide protection from certain xenobiotic and environmental agents, or increase toxicity of others. Cytochrome P450 (CYP450) enzymes are responsible for the majority of oxidation reac...

  17. XENOBIOTIC METABOLISM – A VIEW THROUGH THE METABOLOMETER

    Science.gov (United States)

    Patterson, Andrew D.; Gonzalez, Frank J.; Idle, Jeffrey R.

    2010-01-01

    The combination of advanced ultra-performance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of xenobiotics. Here a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of the experimental cancer therapeutic agent aminoflavone is presented. In all cases, the metabolic maps of the xenobiotics were considerably enlarged, providing new insights into their toxicology. The inclusion of transgenic mice permitted unequivocal attribution of individual and often novel metabolic pathways to particular enzymes. Lastly, a future perspective for xenobiotic metabolomics is discussed and its impact on the metabolome is described. The studies reviewed here are not specific to the mouse, and can be adapted to study xenobiotic metabolism in any animal species, including Man. The view through the metabolometer is unique and visualizes a metabolic space that contains both established and unknown metabolites of a xenobiotic thereby enhancing knowledge of their modes of toxic action. PMID:20232918

  18. Characterization and profiling of hepatic cytochromes P450 and phase II xenobiotic-metabolizing enzymes in beluga whales (Delphinapterus leucas) from the St. Lawrence River Estuary and the Canadian Arctic.

    Science.gov (United States)

    McKinney, Melissa A; Arukwe, Augustine; De Guise, Sylvain; Martineau, Daniel; Béland, Pierre; Dallaire, André; Lair, Stéphane; Lebeuf, Michel; Letcher, Robert J

    2004-07-30

    Cytochromes P450 (CYP, phase I) and conjugating (phase II) enzymes can be induced by and influence the toxicokinetics (metabolism) and toxicity of xenobiotic contaminants in exposed organisms. Beluga whale (Delphinapterus leucas) from the endangered St. Lawrence (SL) River Estuary population exhibit deleterious health effects and various severe pathologies that have been associated with contaminant exposure. In contrast, such effects (e.g. reproductive and immunological impairment) are generally less frequent in less exposed populations in the Canadian Arctic (CA). In the present study, opportunistic sampling resulted in the collection immediately after death of liver tissue from a single female neonate SL beluga (SL6) and male and female CA beluga (n=10) from the Arviat region of western Hudson Bay, in addition to sampling of stranded carcasses of male and female SL beluga (n=5) at least 12 h postmortem. We immunologically characterized cross-reactive proteins of hepatic microsomal CYP1A, CYP2B, CYP3A, CYP2E, epoxide hydrolase (EH) and uridine diphosphoglucuronosyl transferase (UDPGT) isozymes. Cross-reactive proteins were found in all SL and CA beluga using anti-rat CYP1A1, anti-rainbow trout CYP3A, anti-human CYP2E1, anti-rabbit EH and anti-human UDPGT1A1 polyclonal antibodies (Abs), whereas faintly cross-reactive CYP2B proteins were only found in SL6 and the CA samples using an anti-rabbit CYP2B1 Ab. In corresponding catalytic activity assessments, only SL6 and all CA beluga microsomal samples exhibited CYP1A-mediated 7-ethoxyresorufin O-deethylase (EROD) activity (51-260 pmol/mg/min), CYP3A-mediated activity (113-899 pmol/mg/min) based on the formation of 6beta-hydroxytestosterone using a testosterone hydroxylase assay, and UDPGT activity (830-4956 pmol/mg/min) based on 1-naphthylglucuronide formation. The marginal cross-reactivity with the anti-CYP2B1 Ab and lack of catalytically measurable hydroxytestosterone isomers associated with CYP2B-type activity in

  19. The ameliorating effects of vitamin E on hepatic antioxidant system and xenobiotic-metabolizing enzymes in fenvalerate-exposed iodine-deficient rats.

    Science.gov (United States)

    Kocer-Gumusel, Belma; Erkekoglu, Pinar; Caglayan, Aydan; Hincal, Filiz

    2016-01-01

    This study investigated the effects of vitamin E (VE) on hepatic antioxidant system and drug-metabolizing enzymes in fenvalerate (FEN)-exposed iodine-deficient (ID) Wistar rats. ID was produced by perchlorate containing drinking water. VE was introduced by a loading dose of 100 mg/kg/d, i.g. for the first three days in the last week of feeding period; then with a single maintenance dose of 40 mg/kg on the 4th day. During last week, FEN groups (F) received 100 mg/kg/d, i.p. FEN. VE alone did not significantly affect thyroid hormones and antioxidant parameters; however, significantly increased total cytochrome P450 (38%) and cytochrome b5 levels (36%). In all ID groups, plasma thyroid-stimulating hormone (TSH) levels increased markedly, but remained at control level in vitamin E plus FEN receiving iodine-deficient group (IDVF) group. Glutathione peroxidase activity showed marked increases in F (19%) and FEN-exposed iodine-deficient group (IDF, 48%) groups. FEN treatment significantly increased total cytochrome P450 (28%) and thiobarbituric acid reactive substance levels (36%), as well as 7-ethoxyresorufin O-deethylase (120%), 7-penthoxyresorufin O-deethylase (139%) and glutathione S-transferase (15%) activities and decreased total glutathione concentrations (28%) versus control. Overall results suggest that vitamin E has ameliorating effects on the measured parameters in ID and/or FEN exposure.

  20. Xenobiotic metabolism in the fourth dimension: PARtners in time.

    Science.gov (United States)

    Green, Carla B; Takahashi, Joseph S

    2006-07-01

    A significant portion of the transcriptome in mammals, including the PAR bZIP transcription factors DBP, HLF, and TEF, is under circadian clock control. In this issue of Cell Metabolism, Gachon and colleagues (Gachon et al., 2006) show that disruption of these three genes in mice alters gene expression patterns of many proteins involved in drug metabolism and in liver and kidney responses to xenobiotic agents. Triple mutant mice have severe physiological deficits, including increased hypersensitivity to xenobiotic agents and premature aging, highlighting the profound effect the circadian clock has on this important response system.

  1. XENOBIOTIC METABOLISM – A VIEW THROUGH THE METABOLOMETER

    OpenAIRE

    Andrew D. Patterson; Gonzalez, Frank J.; Idle, Jeffrey R.

    2010-01-01

    The combination of advanced ultra-performance liquid chromatography coupled with mass spectrometry, chemometrics, and genetically modified mice provide an attractive raft of technologies with which to examine the metabolism of xenobiotics. Here a reexamination of the metabolism of the food mutagen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), the suspect carcinogen areca alkaloids (arecoline, arecaidine, and arecoline 1-oxide), the hormone supplement melatonin, and the metabolism of...

  2. Molecular mechanisms of metabolic resistance to synthetic and natural xenobiotics.

    Science.gov (United States)

    Li, Xianchun; Schuler, Mary A; Berenbaum, May R

    2007-01-01

    Xenobiotic resistance in insects has evolved predominantly by increasing the metabolic capability of detoxificative systems and/or reducing xenobiotic target site sensitivity. In contrast to the limited range of nucleotide changes that lead to target site insensitivity, many molecular mechanisms lead to enhancements in xenobiotic metabolism. The genomic changes that lead to amplification, overexpression, and coding sequence variation in the three major groups of genes encoding metabolic enzymes, i.e., cytochrome P450 monooxygenases (P450s), esterases, and glutathione-S-transferases (GSTs), are the focus of this review. A substantial number of the adaptive genomic changes associated with insecticide resistance that have been characterized to date are transposon mediated. Several lines of evidence suggest that P450 genes involved in insecticide resistance, and perhaps insecticide detoxification genes in general, may share an evolutionary association with genes involved in allelochemical metabolism. Differences in the selective regime imposed by allelochemicals and insecticides may account for the relative importance of regulatory or structural mutations in conferring resistance.

  3. Stimulatory effect of sesamin on hepatic cytochrome P450 activities in Atlantic salmon (Salmo salar L.) is not directly associated with expression of genes related to xenobiotic metabolism.

    Science.gov (United States)

    Zlabek, Vladimir; Vestergren, AnnaLotta Schiller; Trattner, Sofia; Wagner, Liane; Pickova, Jana; Zamaratskaia, Galia

    2015-01-01

    1. This study examined hepatic cytochrome P450 (CYP450) response to dietary sesamin in combination with different n-6/n-3 fatty acid ratios in fish diet. Over a period of 4 months, fish were fed seven different experimental diets an n-6/n-3 FA ratio of either 0.5 or 1.0 in combination with two sesamin levels: low sesamin = 1.16 g/kg feed and high sesamin = 5.8 g/kg feed. Control diets did not contain sesamin. 2. The CYP450-associated activities of ethoxyresorufin O-deethylase (EROD), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD), pentoxyresorufin O-depentylase (PROD), coumarin hydroxylase (COH), methoxyresorufin O-deethylase (MROD) and p-nitrophenol hydroxylase (PNPH) were significantly induced by dietary sesamin in a dose-related manner. 3. Expressions of the genes CYP1A1, CYP1A3, CYP3A, AhR1α, AhR2β, AhR2δ and PXR involved in the regulation of CYP450 activities, was not the primary source of this induction.

  4. Metabolic activity of gut microbiota and xenobiotics

    Directory of Open Access Journals (Sweden)

    Bojić Gordana

    2015-01-01

    Full Text Available The intestine habitat is the natural collection of symbiotic microorganisms. The bacterial population enables many permanent metabolic activities in this environment. Inside the intestine of mammals there are an extended genome of millions of bacterial genes named microbiome. In recent years, there has been an increased interest of scientists to discover the place and the role of bio-ecological content and modulation of gut microbiota in a host organism using prebiotics, probiotics and synbiotics, which may have a great benefit for human health. [Projekat Ministarstva nauke Republike Srbije, br. 46012 i br. 41012

  5. Hepatocyte-based flow analytical bioreactor for xenobiotics metabolism bioprediction

    Directory of Open Access Journals (Sweden)

    M Helvenstein

    2017-04-01

    Full Text Available The research for new in vitro screening tools for predictive metabolic profiling of drug candidates is of major interest in the pharmaceutical field. The main motivation is to avoid late rejection in drug development and to deliver safer drugs to the market. Thanks to the superparamagnetic properties of iron oxide nanoparticles, a flow bioreactor has been developed which is able to perform xenobiotic metabolism studies. The selected cell line (HepaRG maintained its metabolic competencies once iron oxide nanoparticles were internalized. Based on magnetically trapped cells in a homemade immobilization chamber, through which a flow of circulating phase was injected to transport nutrients and/or the studied xenobiotic, off-line and online (when coupled to a high-performance liquid chromatography chain metabolic assays were developed using diclofenac as a reference compound. The diclofenac demonstrated a similar metabolization profile chromatogram, both with the newly developed setup and with the control situation. Highly versatile, this pioneering and innovative instrumental design paves the way for a new approach in predictive metabolism studies.

  6. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    Directory of Open Access Journals (Sweden)

    Sathidpak Nantasanti

    Full Text Available The tumor suppressors Retinoblastoma (Rb and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC. DDC is metabolized mainly by cytochrome P450 (Cyp3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  7. Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

    Science.gov (United States)

    Merrill, A. H. Jr; Hoel, M.; Wang, E.; Mullins, R. E.; Hargrove, J. L.; Jones, D. P.; Popova, I. A.; Merrill AH, J. r. (Principal Investigator)

    1990-01-01

    To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

  8. Computer-aided prediction of xenobiotic metabolism in the human body

    Science.gov (United States)

    Bezhentsev, V. M.; Tarasova, O. A.; Dmitriev, A. V.; Rudik, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V. V.

    2016-08-01

    The review describes the major databases containing information about the metabolism of xenobiotics, including data on drug metabolism, metabolic enzymes, schemes of biotransformation and the structures of some substrates and metabolites. Computational approaches used to predict the interaction of xenobiotics with metabolic enzymes, prediction of metabolic sites in the molecule, generation of structures of potential metabolites for subsequent evaluation of their properties are considered. The advantages and limitations of various computational methods for metabolism prediction and the prospects for their applications to improve the safety and efficacy of new drugs are discussed. Bibliography — 165 references.

  9. Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities.

    Science.gov (United States)

    Omiecinski, Curtis J; Vanden Heuvel, John P; Perdew, Gary H; Peters, Jeffrey M

    2011-03-01

    To commemorate the 50th anniversary of the Society of Toxicology, this special edition article reviews the history and current scope of xenobiotic metabolism and transport, with special emphasis on the discoveries and impact of selected "xenobiotic receptors." This overall research realm has witnessed dynamic development in the past 50 years, and several of the key milestone events that mark the impressive progress in these areas of toxicological sciences are highlighted. From the initial observations regarding aspects of drug metabolism dating from the mid- to late 1800's, the area of biotransformation research witnessed seminal discoveries in the mid-1900's and onward that are remarkable in retrospect, including the discovery and characterization of the phase I monooxygenases, the cytochrome P450s. Further research uncovered many aspects of the biochemistry of xenobiotic metabolism, expanding to phase II conjugation and phase III xenobiotic transport. This led to hallmark developments involving integration of genomic technologies to elucidate the basis for interindividual differences in response to xenobiotic exposures and discovery of nuclear and soluble receptor families that selectively "sense" the chemical milieu of the mammalian cell and orchestrate compensatory changes in gene expression programming to accommodate complex xenobiotic exposures. This review will briefly summarize these developments and investigate the expanding roles of xenobiotic receptor biology in the underlying basis of toxicological response to chemical agents.

  10. Effect of dietary eugenol on xenobiotic metabolism and mediation of UDP-glucuronosyltransferase and cytochrome P450 1A1 expression in rat liver.

    Science.gov (United States)

    Iwano, Hidetomo; Ujita, Wakako; Nishikawa, Miyu; Ishii, Satomi; Inoue, Hiroki; Yokota, Hiroshi

    2014-03-01

    Xenobiotic-metabolizing enzymes (XMEs) play an important role in the elimination and detoxification of xenobiotics and drugs. A variety of natural dietary agents are known to protect against cancer by inducing XME. To elucidate the molecular mechanism of XME induction, we examined the effect of dietary eugenol (4-allyl-1-hydroxy-2-methoxybenzene) on xenobiotic metabolism. In this study, rats were administered dietary eugenol for 4 weeks to investigate the various effects of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) expression. In rats administered dietary eugenol, expression levels of hepatic CYP1A 1 were reduced to 40% than of the controls, while expression of hepatic UGT1A6, UGT1A7 and UGT2B1 increased to 2-3 times than observed in the controls. Hepatic protein levels of UGT1A6 and 2B1 were also elevated in the eugenol-treated rats. These results suggest that the natural compound eugenol improves the xenobiotic-metabolizing systems that suppress and induce the expression of CYP1A1 and UGT, respectively.

  11. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  12. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  13. Effects of the agrochemicals butachlor, pretilachlor and isoprothiolane on rat liver xenobiotic-metabolizing enzymes.

    Science.gov (United States)

    Ishizuka, M; Iwata, H; Kazusaka, A; Hatakeyama, S; Fujita, S

    1998-11-01

    1. The herbicides butachlor (2-chloro-2',6',diethyl-N-[buthoxymethyl] acetanilide) and pretilachlor (2-chloro-2',6'-diethyl-N-[2-propoxyethyl] acetanilide) are widely used in Asia, South America, Europe and Africa. Isoprothiolane (diisopropyl-1,3-dithiolan-2-ylidenemalonate) is used as a fungicide and an insecticide in rice paddies. We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver. 2. Administration of isoprothiolane, butachlor or pretilachlor to rat induced hepatic P4502B subfamily-dependent enzyme activities (pentoxyresorufin O-depentylation and testosterone 16 beta-hydroxylation) up to 271-413% of control, which coincided with the increase in expression levels of the P4502B apoprotein. 3. Activities of GST toward 1-chloro-2,4-nitrobenzene and 3,4-dichloronitrobenzene were slightly induced (127-133% of control) in the liver of the rat treated with these pesticides. On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed. NQO1-related metabolism (menadione reductase activity) was also induced (123-176% of control) in the liver of rat treated with these agrochemicals. 4. These results indicate that some of the agrochemicals currently in use are capable of inducing phase I and II xenobiotic-metabolizing enzyme activities in an isozyme selective manner. The induction of these activities may disrupt normal physiologic functions related to these enzymes in exposed animals.

  14. Interactions between Cigarette Smoking and Polymorphisms of Xenobiotic-Metabolizing Genes: The Risk of Oral Leukoplakia

    Directory of Open Access Journals (Sweden)

    Yu-Fen Li

    2013-01-01

    Full Text Available Background: This case-control study investigates the role of xenobiotic-metabolizing genes, including glutathione S-transferases (GSTs and cytochrome P450 1A1 (CYP1A1 and 2E1 (CYP2E1, in the susceptibility to oral potentially malignant disorders (OPMDs.

  15. Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism.

    Science.gov (United States)

    Döring, Barbara; Petzinger, Ernst

    2014-08-01

    The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination.

  16. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.

    Directory of Open Access Journals (Sweden)

    Sven van Eijl

    Full Text Available BACKGROUND: Human skin has the capacity to metabolise foreign chemicals (xenobiotics, but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin. METHODOLOGY/PRINCIPAL FINDINGS: Label-free proteomic analysis of whole human skin (10 donors was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin. CONCLUSIONS/SIGNIFICANCE: The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these

  17. [UDP-glucuronyltransferases in detoxification and activation metabolism of endogenous compounds and xenobiotics].

    Science.gov (United States)

    Fedejko, Barbara; Mazerska, Zofia

    2011-01-01

    Glucuronidation is a crucial pathway of metabolism and excretion of endogenous compounds and xenobiotics. UDP-glucuronyltransferases, UGT, catalyse transformations of bilirubine, steroids and thyroid hormones, bile acids as well as exogenous compounds, including drugs, carcinogens, environmental pollutants and nutrient components. From therapeutic point of view, the participation of UGTs in drug metabolism is of particular significance. Polymorphism of UGT1A and UGT2B genes resulted in various susceptibility of substrates to conjugation with glucuronic acid. Deactivation of xenobiotics and the following excretion of hydrophilic conjugates is a common task of glucuronidation, which should lead to detoxification. However, a lot of glucuronides were known, which expressed the comparable or even higher reactivity than that of the native compound. There are, among others, acyl glucuronides of carboxylic acids, morphine 6-O-glucuronide or retinoid glucuronides. They are able to bind cellular macromolecules with low or high strength and, as a consequence, their toxicity is saved or even increased, respectively.

  18. Possible contribution of GSTP1 and other xenobiotic metabolizing genes to vitiligo susceptibility.

    Science.gov (United States)

    Minashkin, Mikhail M; Salnikova, Lubov E; Lomonosov, Konstantin M; Korobko, Igor V; Tatarenko, Andrey O

    2013-04-01

    Vitiligo is an acquired pigmentary disorder with several proposed pathogenesis mechanisms and complex multifactorial genetic predisposition. We analyzed 65 polymorphisms in genes potentially relevant to vitiligo pathogenesis mechanism to reveal novel and confirm reported genetic risk factors in general Russian population. We found that polymorphism rs1138272 (TC + CC) in GSTP1 gene encoding enzyme involved in xenobiotic metabolism is associated with vitiligo (Bonferroni adjusted P value 0.0015) with extraordinary high odds ratio 13.03, and haplotype analysis confirmed association of GSTP1 gene with vitiligo risk. Moreover, analysis of variations in several genes encoding enzymes of xenobiotic metabolism showed that higher risk of vitiligo is associated with higher number of risk alleles. This finding reveals possible contribution of genetic background to observed imbalance of oxidative stress control in vitiligo through cumulative effect of multiple genetic variations in xenobiotic metabolizing genes, supporting the concept of multigenic nature of vitiligo with multiple low-risk alleles cumulatively contributing to vitiligo risk.

  19. Hepatic steatosis : metabolic consequences

    NARCIS (Netherlands)

    Boer, Adriana Maria den

    2006-01-01

    In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism

  20. Hepatic steatosis : metabolic consequences

    NARCIS (Netherlands)

    Boer, Adriana Maria den

    2006-01-01

    In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism unde

  1. The Molecular Evolution of Xenobiotic Metabolism and Resistance in Chelicerate Mites.

    Science.gov (United States)

    Van Leeuwen, Thomas; Dermauw, Wannes

    2016-01-01

    Chelicerate mites diverged from other arthropod lineages more than 400 million years ago and subsequently developed specific and remarkable xenobiotic adaptations. The study of the two-spotted spider mite, Tetranychus urticae, for which a high-quality Sanger-sequenced genome was first available, revealed expansions and radiations in all major detoxification gene families, including P450 monooxygenases, carboxyl/cholinesterases, glutathione-S-transferases, and ATP-binding cassette transporters. Novel gene families that are not well studied in other arthropods, such as major facilitator family transporters and lipocalins, also reflect the evolution of xenobiotic adaptation. The acquisition of genes by horizontal gene transfer provided new routes to handle toxins, for example, the β-cyanoalanine synthase enzyme that metabolizes cyanide. The availability of genomic resources for other mite species has allowed researchers to study the lineage specificity of these gene family expansions and the distinct evolution of genes involved in xenobiotic metabolism in mites. Genome-based tools have been crucial in supporting the idiosyncrasies of mite detoxification and will further support the expanding field of mite-plant interactions.

  2. Effects of selected xenobiotics on hepatic and plasmatic biomarkers in juveniles of Solea senegalensis.

    Science.gov (United States)

    Solé, Montserrat; Fortuny, Anna; Mañanós, Evaristo

    2014-11-01

    In recent years, Solea senegalensis has increasingly been used in pollution monitoring studies. In order to assess its response to some particular widespread pollutants, juveniles of S. senegalensis were administered an intraperitoneal injection of the model aryl hydrocarbon receptor agonist β-naphtoflavone (βNF) and chemicals of environmental concern, such as the fungicide ketoconazole (KETO), the lipid regulator gemfibrozil (GEM), the surfactant nonylphenol (NP) and the synthetic hormone ethinylestradiol (EE2). Two days after injection, the effect of these chemicals was followed up as alterations of hepatic microsomal activities of the cytochrome P450 (CYPs) and associated reductases, carboxylesterases (CbEs) and the conjugation enzyme uridine diphosphate glucuronyltransferase (UDPGT). In the cytosolic fraction of the liver, the effect on CbEs, glutathione S-transferase (GST) and antioxidant activities was also considered. Alterations on the endocrine reproductive system were evaluated by plasma levels of vitellogenin (VTG) and the sex steroids estradiol (E2), testosterone (T), 11-ketotestosterone (11KT) and the progestin 17α,20β-dihydroxy-4-pregnen-3-one (17,20β-P). Injection with the model compound βNF induced the hydrolysis rate of the seven CYP substrates assayed. The xenobiotic GEM induced three CYP-related activities (e.g. ECOD) and UDPGT, but depressed antioxidant defenses. EE2 induced four CYPs, more significantly ECOD and BFCOD activities. The xenoestrogens NP and EE2 altered the activities of CbE in microsomes and catalase, and were the only treatments that induced de novo VTG synthesis. In addition, the progestin 17,20β-P, was induced in NP-injected fish. None of the treatments caused statistically significant effects on steroid plasma levels. In conclusion, the CYP substrates assayed responded specifically to treatments and juveniles of S. senegalensis appear good candidates for assessing xenobiotics exposure.

  3. Regulation of hepatic energy metabolism by the nuclear receptor PXR.

    Science.gov (United States)

    Hakkola, Jukka; Rysä, Jaana; Hukkanen, Janne

    2016-09-01

    The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR was originally identified to regulate drug-metabolizing enzymes and transporters. During the last ten years it has become clear that PXR harbors broader functions. Evidence obtained both in experimental animals and humans indicate that ligand-activated PXR regulates hepatic glucose and lipid metabolism and affects whole body metabolic homeostasis. Currently, the consequences of PXR activation on overall metabolic health are not yet fully understood and varying results on the effect of PXR activation or knockout on metabolic disorders and weight gain have been published in mouse models. Rifampicin and St. John's wort, the prototypical human PXR agonists, impair glucose tolerance in healthy volunteers. Chronic exposure to PXR agonists could potentially represent a risk factor for diabetes and metabolic syndrome. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

  4. Effects of acetone and fasting on cytochrome P-450 and xenobiotic metabolism in intact and hypophysectomized rats

    Energy Technology Data Exchange (ETDEWEB)

    Williams, M.T.; Simonet, L.

    1987-05-01

    Hypophysectomized and intact male and female rats were fasted for 24-48 hrs or given acetone (5ml/kg body weight) in order to evaluate the effects of these treatments on hepatic microsomal cytochrome P-450 and xenobiotic metabolism. Fasting and acetone treatment resulted in a significant increase (p < 0.05) in total P-450 in intact female rats. However, there was no significant changes in P-450 in microsomes from fasted or acetone-treated hypophysectomized rats. Fasting and acetone treatment resulted in significant increases in nitrosamine metabolism in intact rats. This effect was markedly reduced in the hypophysectomized rat. When intact male rats were fasted or treated with acetone there was a significant increase in P-450 in microsomes from acetone treated rats. Aryl hydrocarbon hydroxylase activity was significantly increased in both intact and hypophysectomized male and female rats treated with acetone. These results suggest that the pituitary gland or some product markedly influences acetone-stimulated nitrosamine metabolism.

  5. Metabolism of drugs and other xenobiotics in giant liver fluke (Fascioloides magna).

    Science.gov (United States)

    Prchal, Lukáš; Vokřál, Ivan; Kašný, Martin; Rejšková, Lenka; Zajíčková, Markéta; Lamka, Jiří; Skálová, Lenka; Lecová, Lenka; Szotáková, Barbora

    2016-01-01

    1. Giant liver fluke Fascioloides magna is a dangerous parasite, which infects herbivores. It was imported to Europe from North America and started to spread. Benzimidazoles like albendazole, mebendazole, triclabendazole and salicylanilides closantel and rafoxanide are the most used anthelmintics to control fascioloidosis. However their effect might be altered via drug-metabolizing enzymes of this parasite. 2. The aim of our study was to determine the activities of drug-metabolizing enzymes in F. magna and the metabolism of above mentioned anthelmintics. 3. Activities of several oxidative, reductive and conjugative enzymes towards various model xenobiotic substrates were found in F. magna subcellular fractions. 4. Subcellular fractions from F. magna oxidized albendazole to its sulphoxide metabolite and reduced mebendazole to hydroxyl-mebendazole. Under ex vivo conditions, only very-low concentrations of these compounds were detected using high-performance liquid chromatography/mass spectrometry. 5. The results indicate that the giant liver fluke possesses the active xenobiotic-metabolizing system. The overexpression of this system may play an important role in parasite resistance against these anthelmintics.

  6. Oxidative and conjugative metabolism of xenobiotics by livers of cattle, sheep, swine and rats.

    Science.gov (United States)

    Smith, G S; Watkins, J B; Thompson, T N; Rozman, K; Klaassen, C D

    1984-02-01

    Homogenate preparations from fresh livers of cattle, sheep, swine and rats were assayed for microsomal cytochrome P-450 content, for mixed-function oxidase activities and for a wide array of conjugative activities using numerous xenobiotic substrates. Results show that hepatic enzymatic capabilities toward xenobiotics do not parallel phylogenetic classifications, thus strengthening the view that most of the comparative data available at present is more descriptive than predictive of relationships among species. Livestock species differed widely from rats in having lower activities of benzo(alpha)pyrene hydroxylase, glutathione S-transferase and acetyltransferase toward isoniazid and sulfamethazine and UDP-glucuronosyl-transferase toward bilirubin. Acetyltransferase activities toward beta-naphthylamine and 2-aminofluorene were not detected in livers of livestock species studied. Cattle livers were remarkably high in activities of styrene oxide hydrolase, ethoxyresorufin O-deethylase, 2-naphthol sulfotransferase and p-aminobenzoic acid acetyltransferase; but notably low in activity of glutathione-S-transferase toward sulfobromophthalein and 1,2-dichloro-4-nitrobenzene. Swine livers had low activity of glutathione-S-transferase toward four of six substrates and low acetyltransferase activity toward four of five substrates. Sheep livers generally were higher than cattle livers in sulfo- and UDP-glucuronsyltransferase activities and lower in acetyl- and glutathionyl-S-transferase. Findings emphasize the risk of error in extra-polations among species and in extrapolations among substrates.

  7. Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice.

    Science.gov (United States)

    Swenson, Tami L; Casida, John E

    2013-05-01

    Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general.

  8. Effects of frying oil and Houttuynia cordata thunb on xenobiotic-metabolizing enzyme system of rodents

    Institute of Scientific and Technical Information of China (English)

    Ya-Yen Chen; Chiao-Ming Chen; Pi-Yu Chao; Tsan-Ju Chang; Jen-Fang Liu

    2005-01-01

    AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents.METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO)for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase Ⅱ enzymes, the rest of the enzymes tested represented phase Ⅰ enzymes.RESULTS: The oxidized frying oil feeding produced a significant increase in phase Ⅰ and Ⅱ enzyme systems,including the content of CYP450 and microsomal protein,and the activities of NADPH reductase, EROD, PROD, ANH,AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect.CONCLUSION: The OFO diet induces phases Ⅰ and Ⅱ enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system.

  9. RNA-seq based whole transcriptome analysis of the cyclopoid copepod Paracyclopina nana focusing on xenobiotics metabolism.

    Science.gov (United States)

    Lee, Bo-Young; Kim, Hui-Su; Choi, Beom-Soon; Hwang, Dae-Sik; Choi, Ah Young; Han, Jeonghoon; Won, Eun-Ji; Choi, Ik-Young; Lee, Seung-Hwi; Om, Ae-Son; Park, Heum Gi; Lee, Jae-Seong

    2015-09-01

    Copepods are among the most abundant taxa in marine invertebrates, and cyclopoid copepods include more than 1500 species and subspecies. In marine ecosystems, planktonic copepods play a significant role as food resources in the food web and sensitively respond to environmental changes. The copepod Paracylopina nana is one of the planktonic brackish water copepods and considered as a promising model species in ecotoxicology. We sequenced the whole transcriptome of P. nana using RNA-seq technology. De novo sequence assembly by Trinity integrated with TransDecoder produced 67,179 contigs including putative alternative spliced variants. A total of 12,474 genes were identified based on BLAST analysis, and gene sequences were most similar to the sequences of the branchiopod Daphnia. Gene Ontology and KEGG pathway analysis showed that most transcripts annotated were involved in pathways of various metabolisms, immune system, signal transduction, and translation. Considering numbers of sequences and enzymes involved in the pathways, particularly attention was paid to genes potentially involved in xenobiotics biodegradation and metabolism. With regard to xenobiotics metabolism, various xenobiotic metabolizing enzymes such as oxidases, dehydrogenases, and transferases were obtained from the annotated transcripts. The whole transcriptome analysis of P. nana provides valuable resources for future studies of xenobiotics-related metabolism in this marine copepod species.

  10. Systems Approaches Evaluating the Perturbation of Xenobiotic Metabolism in Response to Cigarette Smoke Exposure in Nasal and Bronchial Tissues

    Directory of Open Access Journals (Sweden)

    Anita R. Iskandar

    2013-01-01

    Full Text Available Capturing the effects of exposure in a specific target organ is a major challenge in risk assessment. Exposure to cigarette smoke (CS implicates the field of tissue injury in the lung as well as nasal and airway epithelia. Xenobiotic metabolism in particular becomes an attractive tool for chemical risk assessment because of its responsiveness against toxic compounds, including those present in CS. This study describes an efficient integration from transcriptomic data to quantitative measures, which reflect the responses against xenobiotics that are captured in a biological network model. We show here that our novel systems approach can quantify the perturbation in the network model of xenobiotic metabolism. We further show that this approach efficiently compares the perturbation upon CS exposure in bronchial and nasal epithelial cells in vivo samples obtained from smokers. Our observation suggests the xenobiotic responses in the bronchial and nasal epithelial cells of smokers were similar to those observed in their respective organotypic models exposed to CS. Furthermore, the results suggest that nasal tissue is a reliable surrogate to measure xenobiotic responses in bronchial tissue.

  11. CHANGING METABOLIC FUNCTIONS IN EXPERIMENTAL ANIMALS AFTER INTRODUCTION OF THE XENOBIOTIC, IMMUNOTROPIC DRUG AND PROBIOTIC

    Directory of Open Access Journals (Sweden)

    Zvyagintseva O.V.

    2015-05-01

    Saccharomyces cerevisiae. The peripheral blood leukocytes were cultured according to the method of Hereford in medium 199 with the addition of fetal calf serum in the absence and in the presence of T-cell mitogen – phytohemagglutinin. Results and discussion. In all studied groups (introduction of the xenobiotic, "Fungidol", probiotic experimental animals revealed a significant increase in the concentrations of ceruloplasmin and haptoglobin on the average in 1,5 times in comparison with the control, indicating the development of the inflammatory process after the toxic action of copper sulphate. During administration of sulphate of copper, the experimental animals showed a reduction in the index of completion of phagocytosis, indicating a failure of the process of endocytosis of bacterial antigens and reduced stimulation index due to the low activity of NADPoxidase system of phagocytes. The introduction of xenobiotic animals was increased 1,2 times compared with the control (23,33±1,38 % the number of transformed cells in the background of mitogenic inducer of cell proliferation. The proliferative activity of hemolytic after the joint action of the xenobiotic and immunotropic drug in cell culture with the mitogen was the highest and exceeded 1,5 times control (23,33±1,38%. After the introduction of copper sulfate and probiotic proliferative activity of hemolytic was also significantly higher spontaneous. Introduction biologic response modifier substance to a greater extent than probiotics stimulate a protective immune processes aimed at combating the negative effect of the xenobiotic. Conclusion. Thus, the introduction of copper sulfate launches in animals a cascade of reactions aimed at the disruption of homeostasis. It is a violation of various physiological processes of digestion, respiration, cell differentiation, water-salt metabolism, metabolism of carbohydrates, proteins, lipids, detoxification of exogenous substrates and metabolites, production of biologically active

  12. ER stress and hepatic lipid metabolism

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    Huiping eZhou

    2014-05-01

    Full Text Available The endoplasmic reticulum (ER is an important player in regulating protein synthesis and lipid metabolism. Perturbation of ER homeostasis, referred as ER stress, has been linked to numerous pathological conditions, such as inflammation, cardiovascular diseases and metabolic disorders. The liver plays a central role in regulating nutrient and lipid metabolism. Accumulating evidence implicates that ER stress disrupts lipid metabolism and induces hepatic lipotoxicity. Here, we review the major ER stress signaling pathways, how ER stress contributes to the dysregulation of hepatic lipid metabolism, and the potential causative mechanisms of ER stress in hepatic lipotoxicity. Understanding the role of ER stress in hepatic metabolism may lead to the identification of new therapeutic targets for metabolic diseases.

  13. Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer

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    Rosane eVianna-Jorge

    2013-01-01

    Full Text Available Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs’ narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual’s chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet.

  14. Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

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    Van der Hauwaert, Cynthia; Savary, Grégoire [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Buob, David [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Leroy, Xavier; Aubert, Sébastien [Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); Flamand, Vincent [Service d' Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Hennino, Marie-Flore [EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille (France); Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille (France); Perrais, Michaël [Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille (France); and others

    2014-09-15

    Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

  15. Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas.

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    Haas, Susanne; Pierl, Christiane; Harth, Volker; Pesch, Beate; Rabstein, Sylvia; Brüning, Thomas; Ko, Yon; Hamann, Ute; Justenhoven, Christina; Brauch, Hiltrud; Fischer, Hans-Peter

    2006-10-15

    The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p = 0.018) and with reduced lymph node metastasis (GST pi, p = 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p CYP1B1 was associated with poor tumor differentiation (p = 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis.

  16. Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

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    DeMeo Dawn L

    2007-08-01

    Full Text Available Abstract Background In the National Emphysema Treatment Trial (NETT, marked variability in response to lung volume reduction surgery (LVRS was observed. We sought to identify genetic differences which may explain some of this variability. Methods In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV1, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution. Results A SNP upstream from glutathione S-transferase pi (GSTP1; p = 0.003 and a coding SNP in microsomal epoxide hydrolase (EPHX1; p = 0.02 were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in EPHX1 was associated with change in BODE score (p = 0.008, with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in GSTP1 and three additional SNPs in EPHX1 were associated (p Conclusion Genetic variants in GSTP1 and EPHX1, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.

  17. Odorant-binding proteins and xenobiotic metabolizing enzymes: implications in olfactory perireceptor events.

    Science.gov (United States)

    Heydel, Jean-Marie; Coelho, Alexandra; Thiebaud, Nicolas; Legendre, Arièle; Le Bon, Anne-Marie; Faure, Philippe; Neiers, Fabrice; Artur, Yves; Golebiowski, Jérôme; Briand, Loïc

    2013-09-01

    At the periphery of the olfactory system, the binding of odorants on olfactory receptors (ORs) is usually thought to be the first level of the perception of smell. However, at this stage, there is evidence that other molecular mechanisms also interfere with this chemoreception by ORs. These perireceptor events are mainly supported by two groups of proteins present in the olfactory nasal mucus or in the nasal epithelium. Odorant-binding proteins (OBPs), the first group of proteins have been investigated for many years. OBPs are small carrier proteins capable of binding odorants with affinities in the micromolar range. Although there is no absolute evidence to support their functional roles in vertebrates, OBPs are good candidates for the transport of inhaled odorants towards the ORs via the nasal mucus. The second group of proteins involves xenobiotic metabolizing enzymes, which are strongly expressed in the olfactory epithelium and supposed to be involved in odorant transformation, degradation, and/or olfactory signal termination. Following an overview of these proteins, this review explores their roles, which are still a matter of debate.

  18. Effect of a PCB-based transformer oil on testicular steroidogenesis and xenobiotic-metabolizing enzymes.

    Science.gov (United States)

    Andric, Nebojsa L; Kostic, Tatjana S; Zoric, Sonja N; Stanic, Bojana D; Andric, Silvana A; Kovacevic, Radmila Z

    2006-07-01

    Pyralene is a PCB-based transformer oil with a unique PCB congener profile when compared to other mixtures. We studied the influence of Pyralene on testicular steroidogenesis and the status of xenobiotic-metabolizing enzymes in the testis and liver of rats during oral exposure (10 and 50 mg/kg body weight, p.o. daily for 1 week) and a 3-week post-treatment recovery period. As expected, Pyralene induced a rapid and sustained increase in mRNA transcripts for CYP1A1 and CYP2B1 in hepatocytes that was associated with a dramatic increase in ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-deethylase (PROD) activities. Testicular androgenesis and the conversion of progesterone to testosterone in testicular microsomes were bidirectionally affected. An increase in these parameters was observed 24h after the initial administration of Pyralene, followed by inhibition that lasted until the fourth post-treatment day. Expression PCR analysis revealed a significant decrease in 17beta-hydroxysteroid dehydrogenase (17betaHSD) transcript abundance at 48 h after Pyralene administration. In contrast, transcripts for several other steroidogenic enzymes and for testicular CYP1A1, CYP1B1, and CYP2B1 were unaffected under the same conditions. These results in the rat indicate that a sub-chronic exposure to Pyralene disrupted testicular steroidogenesis and suggest the mechanism may involve direct action on the regulation of specific steroidogenic enzymes such as 17betaHSD.

  19. Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

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    Bhattacharya, Poulomi; Keating, Aileen F., E-mail: akeating@iastate.edu

    2012-06-15

    The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.

  20. Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

    Directory of Open Access Journals (Sweden)

    Vinay K Tripathi

    Full Text Available The expression and metabolic profile of cytochrome P450s (CYPs is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y and glial (U373-MG cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC, cyclophosphamide (CPA, ethanol and known neurotoxicant- monocrotophos (MCP, a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against

  1. Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

    Science.gov (United States)

    Tripathi, Vinay K; Kumar, Vivek; Singh, Abhishek K; Kashyap, Mahendra P; Jahan, Sadaf; Pandey, Ankita; Alam, Sarfaraz; Khan, Feroz; Khanna, Vinay K; Yadav, Sanjay; Lohani, Mohtshim; Pant, Aditya B

    2014-01-01

    The expression and metabolic profile of cytochrome P450s (CYPs) is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y) and glial (U373-MG) cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC), cyclophosphamide (CPA), ethanol and known neurotoxicant- monocrotophos (MCP), a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h) of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against xenobiotics.

  2. The roles of nuclear receptors CAR and PXR in hepatic energy metabolism.

    Science.gov (United States)

    Konno, Yoshihiro; Negishi, Masahiko; Kodama, Susumu

    2008-01-01

    Nuclear receptors constitutive active/androstane receptor (CAR) and pregnane X receptor (PXR) were originally characterized as transcription factors regulating the hepatic genes that encode drug metabolizing enzymes. Recent works have now revealed that these nuclear receptors also play the critical roles in modulating hepatic energy metabolism. While CAR and PXR directly bind to their response sequences phenobarbital-responsive enhancer module (PBREM) and xenobiotic responsive enhancer module (XREM) in the promoter of target genes to increase drug metabolism, the receptors also cross talk with various hormone responsive transcription factors such as forkhead box O1 (FoxO1), forkhead box A2 (FoxA2), cAMP-response element binding protein, and peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC 1alpha) to decrease energy metabolism through down-regulating gluconeogenesis, fatty acid oxidation and ketogenesis and up-regulating lipogenesis. In addition, CAR modulates thyroid hormone activity by regulating type 1 deiodinase in the regenerating liver. Thus, CAR and PXR are now placed at the crossroad where both xenobiotics and endogenous stimuli co-regulate liver function.

  3. Hepatic diseases related to triglyceride metabolism.

    Science.gov (United States)

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

  4. Abnormal erythrocyte metabolism in hepatic disease.

    Science.gov (United States)

    Smith, J R; Kay, N E; Gottlieb, A J; Oski, F A

    1975-12-01

    Erythrocyte (RBC) metabolic studies were done on 114 patients with severe hepatic disease. Heinz body formation after incubation of RBCs with acetyl phenylhydrazine was found to be significantly higher in patients than in controls. RBC-reduced glutathione levels were lower than those of controls both before and after incubation with acetyl phenylhydrazine, and patients with the highest Heinz body counts had the lowest reduced glutathione levels. RBC methylene blue-stimulated hexose monophosphate (HMP) shunt metabolism and glucose recycling through the shunt were significantly lower in patients with active hepatic disease than in controls. There was no difference in resting HMP shunt activity or in resting recycling of glucose. Despite impairment of shunt metabolism, total glucose consumption was greater in patients than in controls. The patients with the lowest stimulated HMP shunt metabolism and glucose recycling had the highest Heinz body counts, lowest reduced glutathione, and highest total glucose consumption. A continuum of abnormal shunt metabolism was seen, from a mild reduction of stimulated HMP shunt activity to a severe combined decrease in both the HMP shunt and glucose recycling. When measured, glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, and transketolase were normal or increased. Sequential studies were done on 11 patients who had abnormal metabolic studies. Coincident with improvement of HMP shunt metabolism, the Heinz body counts became lower, reduced glutathione higher, hematocrit higher, and liver function improved. Impaired HMP shunt metabolism appears to be a common, acquired RBC abnormality in patients with severe, active liver disease.

  5. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

    Science.gov (United States)

    Yueh, Mei-Fei; Li, Tao; Evans, Ronald M; Hammock, Bruce; Tukey, Robert H

    2012-01-01

    Triclocarban (3,4,4'-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car(-/-) mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human

  6. Transcriptional responses of xenobiotic metabolizing enzymes, HSP70 and Na+/K+ -ATPase in the liver of rabbitfish (Siganus oramin) intracoelomically injected with amnesic shellfish poisoning toxin.

    Science.gov (United States)

    Wang, Lin; Liang, Xu-Fang; Huang, Yan; Li, Shi-Ying; Ip, Kok-Chao

    2008-06-01

    Amnesic shellfish poisoning toxin domoic acid (DA) is a marine neurotoxin that accumulates in fish and shellfish, and has been implicated to be involved in human and marine wildlife mortality. The transcriptional responses of cytochrome P-450 1A (CYP1A), glutathione S-transferase alpha (GSTA), glutathione S-transferase rho (GSTR), heat shock protein 70 (HSP70), and Na(+)/K(+)-ATPase alpha 1 (ATP1A1) in the liver of rabbitfish (Siganus oramin) intracoelomically injected with DA, were investigated. Experimental fish were administered with one injection of DA (2 microg/g wet weight) or PBS as control. After 24 h, fish were killed and hepatic RNA was isolated. Partial cDNA of rabbitfish CYP1A, GSTA, GSTR, HSP70, ATP1A1, and beta-actin were obtained by PCR using degenerate primers. Using beta-actin as an external control, the relative liver CYP1A, GSTA, GSTR, HSP70, and ATP1A1 mRNA abundance of rabbitfish were determined by semi-quantitative RT-PCR within the exponential phase. The ratio CYP1A/beta-actin mRNA (%) of exposure group was determined to be 148.92+/-12.69, whereas the ratio of control group was 82.3+/-8.35, indicating that CYP1A was induced significantly in rabbitfish following DA exposure (P0.05). The induction of hepatic CYP1A in response to DA suggests a potential role for fish phase I xenobiotic metabolizing enzyme in DA metabolism.

  7. Biliary-hepatic recycling of a xenobiotic: gallbladder absorption of methyl mercury.

    Science.gov (United States)

    Dutczak, W J; Clarkson, T W; Ballatori, N

    1991-06-01

    The role of the gallbladder in the disposition of methyl mercury was investigated in guinea pig, hamster, and macaque monkey. 203Hg-labeled methyl mercury or inorganic mercury (5 microM) and [14C]inulin were instilled into the in situ guinea pig or hamster gallbladder. After 2 h, only 27.6 +/- 7.0% of the methyl mercury remained in guinea pig gallbladder fluid as compared with 85.0 +/- 3.2% of the inorganic mercury and 90.7 +/- 4.5% of the [14C]-inulin. In the hamster, 42.5 +/- 4.5% of methyl mercury and 95% +/- 0.9% of inorganic mercury remained after 2 h. When the sulfhydryl-containing compounds L-cysteine, glutathione, and bovine serum albumin (20 microM) were added to the test solution, cysteine increased and albumin decreased absorption of methyl mercury. Ligation of guinea pig cystic artery decreased gallbladder fluid absorption from 72.7 +/- 8.6 to 26.5 +/- 9.8% over 2 h but did not alter methyl mercury absorption. Bile was also sampled from gallbladders of four monkeys exposed chronically to CH3HgCl and from three control monkeys. For one of the exposed and one of the control monkeys, bile was also collected from the common hepatic duct. In both methyl mercury-exposed and control monkeys, the concentration of methyl mercury in gallbladder bile was lower than in hepatic bile. In contrast, the concentration of inorganic mercury in gallbladder bile was four to seven times that of hepatic bile, suggesting that methyl mercury but not inorganic mercury was being reabsorbed. To assess the functional significance of methyl mercury reabsorption by the gallbladder, guinea pig cystic ducts were ligated, the animals were given CH3 203HgCl (10 mumol/kg iv), and body burden of 203Hg was measured over 16 days.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. High-throughput metagenomic analysis of petroleum-contaminated soil microbiome reveals the versatility in xenobiotic aromatics metabolism.

    Science.gov (United States)

    Bao, Yun-Juan; Xu, Zixiang; Li, Yang; Yao, Zhi; Sun, Jibin; Song, Hui

    2017-06-01

    The soil with petroleum contamination is one of the most studied soil ecosystems due to its rich microorganisms for hydrocarbon degradation and broad applications in bioremediation. However, our understanding of the genomic properties and functional traits of the soil microbiome is limited. In this study, we used high-throughput metagenomic sequencing to comprehensively study the microbial community from petroleum-contaminated soils near Tianjin Dagang oilfield in eastern China. The analysis reveals that the soil metagenome is characterized by high level of community diversity and metabolic versatility. The metageome community is predominated by γ-Proteobacteria and α-Proteobacteria, which are key players for petroleum hydrocarbon degradation. The functional study demonstrates over-represented enzyme groups and pathways involved in degradation of a broad set of xenobiotic aromatic compounds, including toluene, xylene, chlorobenzoate, aminobenzoate, DDT, methylnaphthalene, and bisphenol. A composite metabolic network is proposed for the identified pathways, thus consolidating our identification of the pathways. The overall data demonstrated the great potential of the studied soil microbiome in the xenobiotic aromatics degradation. The results not only establish a rich reservoir for novel enzyme discovery but also provide putative applications in bioremediation. Copyright © 2016. Published by Elsevier B.V.

  9. Distinct rat hepatic microsomal epoxide hydrolases catalyze the hydration of cholesterol 5,6 alpha-oxide and certain xenobiotic alkene and arene oxides.

    Science.gov (United States)

    Levin, W; Michaud, D P; Thomas, P E; Jerina, D M

    1983-02-01

    Metabolism of cholesterol 5,6 alpha-oxide to the 5,6-glycol is catalyzed by a rat liver microsomal epoxide hydrolase that is distinct from the microsomal epoxide hydrolase that metabolizes a wide range of xenobiotic alkene and arene oxides. The two enzymes are antigenically distinct, and the purified microsomal epoxide hydrolase that metabolizes xenobiotic oxides does not catalyze the hydration of cholesterol 5,6 alpha-oxide. In vivo treatment of rats with inducers of microsomal epoxide hydrolase does not enhance the activity of cholesterol 5,6 alpha-oxide hydrolase and, in some cases, actually depresses enzyme activity in the resultant microsomal preparations. Octene 1,2-oxide and benz[a]anthracene 5,6-oxide, both good substrates for xenobiotic epoxide hydrolase, are not competitive inhibitors of cholesterol oxide hydration by rat liver microsomes. The above results establish the existence of a liver microsomal epoxide hydrolase that is under different regulatory control and that appears to have a different substrate specificity than the well-characterized microsomal epoxide hydrolase involved in the metabolism of a widely diverse group of alkene and arene oxides.

  10. Exercise Intensity Modulation of Hepatic Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Fábio S. Lira

    2012-01-01

    Full Text Available Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL, ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge.

  11. Phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.

  12. Shemamruthaa, herbal formulation modulates xenobiotic metabolizing enzymes and energy metabolism in 7,12-Dimethylbenz[a]anthracene-induced breast cancer in rats

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    Purushothaman Ayyakkannu

    2014-12-01

    Full Text Available There is an increasing interest in identifying naturally occurring potent preventive and therapeutic agents for cancer. Shemamruthaa, a phytochemical formulation was evaluated for the first time with a view to potentiate more intense anticancer property. Adult female Sprague-Dawley rats (8-week-old were used for the study and were divided into 4 Groups. Group I control animals received standard pellet diet and water ad libitum. Group II animals were induced for mammary carcinoma with a single oral dose of 25 mg of DMBA, whereas another set of DMBA-induced rats were treated with SM (400 mg/kg body weight/day orally by gastric intubation for 14 days after 3 months of induction period (Group III. Group IV animals served as SM-control. The status xenobiotic metabolizing enzymes, glycolytic and gluconeogenic enzymes were analysed in control and experimental rats. Our findings revealed that the SM formulation has potential to induce Phase-II enzyme activities, associated mainly with carcinogen detoxification and inhibit the Phase I enzyme activities. The activities of glycolytic and gluconeogenic enzymes were significantly brought back to near normal levels in SM treated animals. The results demonstrated unequivocally the effect of SM on inhibition of tumor progression by altering xenobiotic metabolizing enzymes and restoring energy metabolism

  13. Transposable elements are enriched within or in close proximity to xenobiotic-metabolizing cytochrome P450 genes

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    Li Xianchun

    2007-03-01

    Full Text Available Abstract Background Transposons, i.e. transposable elements (TEs, are the major internal spontaneous mutation agents for the variability of eukaryotic genomes. To address the general issue of whether transposons mediate genomic changes in environment-adaptation genes, we scanned two alleles per each of the six xenobiotic-metabolizing Helicoverpa zea cytochrome P450 loci, including CYP6B8, CYP6B27, CYP321A1, CYP321A2, CYP9A12v3 and CYP9A14, for the presence of transposon insertions by genome walking and sequence analysis. We also scanned thirteen Drosophila melanogaster P450s genes for TE insertions by in silico mapping and literature search. Results Twelve novel transposons, including LINEs (long interspersed nuclear elements, SINEs (short interspersed nuclear elements, MITEs (miniature inverted-repeat transposable elements, one full-length transib-like transposon, and one full-length Tcl-like DNA transpson, are identified from the alleles of the six H. zea P450 genes. The twelve transposons are inserted into the 5'flanking region, 3'flanking region, exon, or intron of the six environment-adaptation P450 genes. In D. melanogaster, seven out of the eight Drosophila P450s (CYP4E2, CYP6A2, CYP6A8, CYP6A9, CYP6G1, CYP6W1, CYP12A4, CYP12D1 implicated in insecticide resistance are associated with a variety of transposons. By contrast, all the five Drosophila P450s (CYP302A1, CYP306A1, CYP307A1, CYP314A1 and CYP315A1 involved in ecdysone biosynthesis and developmental regulation are free of TE insertions. Conclusion These results indicate that TEs are selectively retained within or in close proximity to xenobiotic-metabolizing P450 genes.

  14. Genome-wide transcriptional profiling and metabolic analysis uncover multiple molecular responses of the grass species Lolium perenne under low-intensity xenobiotic stress

    Directory of Open Access Journals (Sweden)

    Anne-Antonella eSerra

    2015-12-01

    Full Text Available Lolium perenne, which is a major component of pastures, lawns, and grass strips, can be exposed to xenobiotic stresses due to diffuse and residual contaminations of soil. L. perenne was recently shown to undergo metabolic adjustments in response to sub-toxic levels of xenobiotics. To gain insight in such chemical stress responses, a de novo transcriptome analysis was carried out on leaves from plants subjected at the root level to low levels of xenobiotics, glyphosate, tebuconazole, and a combination of the two, leading to no adverse physiological effect. Chemical treatments influenced significantly the relative proportions of functional categories and of transcripts related to carbohydrate processes, to signalling, to protein-kinase cascades, as Serine/Threonine-protein kinases, to transcriptional regulations, to responses to abiotic or biotic stimuli and to responses to phytohormones. Transcriptomics-based expressions of genes encoding different types of SNF1 (sucrose non-fermenting 1-related kinases involved in sugar and stress signalling or encoding key metabolic enzymes were in line with specific qRT-PCR analysis or with the important metabolic and regulatory changes revealed by metabolomic analysis. The effects of pesticide treatments on metabolites and gene expression strongly suggest that pesticides at low levels, as single molecule or as mixture, affect cell signalling and functioning even in the absence of major physiological impact. This global analysis of L. perenne therefore highlighted the interactions between molecular regulation of responses to xenobiotics, and also carbohydrate dynamics, energy dysfunction, phytohormones and calcium signalling.

  15. DDT increases hepatic testosterone metabolism in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sierra-Santoyo, Adolfo; Albores, Arnulfo; Cebrian, Mariano E. [Cinvestav-IPN, Seccion de Toxicologia, Mexico (Mexico); Hernandez, Manuel [Cinvestav-IPN, Departamento de Biologia Celular (Mexico)

    2005-01-01

    DDT and its metabolites are considered as endocrine disruptors able to promote hormone-dependent pathologies. We studied the effects of technical-grade DDT on hepatic testosterone metabolism and testosterone hydroxylase activity ratios in the rat. Male and female Wistar rats were treated by gavage with a single dose of technical-grade DDT (0, 0.1, 1, 10, and 100 mg/kg body weight) and killed 24 h later. Hepatic microsomes were incubated with [4-{sup 14}C]-testosterone and the metabolites were separated by thin-layer chromatography and quantified by radio scanning. DDT increased testosterone biotransformation and modified the profile of metabolites produced in a sex-dependent manner. Males treated with a representative dose (10 mg/kg) produced relatively less androstenedione (AD), 2{alpha}-hydroxytestosterone (OHT), and 16{alpha}-OHT but higher 6{beta}-OHT whereas treated females produced less 7{alpha}-OHT and AD but higher 6{beta}-OHT and 6{alpha}-OHT than their respective controls. In both sexes DDT decreased the relative proportion of AD and increased that of 6{beta}-OHT suggesting that the androgen-saving pathway was affected. The testosterone 6{alpha}-/15{alpha}-OHT ratio, a proposed indicator of demasculinization, was increased in treated males. This effect was in agreement with the demasculinizing ability proposed for DDT. The effects on 6{alpha}-/16{alpha}-OHT and 6-dehydrotestosterone/16{alpha}-OHT ratios followed a similar tendency, with the ratio 6{alpha}-/16{alpha}-OHT being the most sensitive marker. Interestingly, these ratios were reduced in treated females suggesting that technical-grade DDT shifted testosterone hydroxylations toward a more masculine pattern. Thus, technical-grade DDT altered the hepatic sexual dimorphism in testosterone metabolism and decreased the metabolic differences between male and female rats. (orig.)

  16. DDT increases hepatic testosterone metabolism in rats.

    Science.gov (United States)

    Sierra-Santoyo, Adolfo; Hernández, Manuel; Albores, Arnulfo; Cebrián, Mariano E

    2005-01-01

    DDT and its metabolites are considered as endocrine disruptors able to promote hormone-dependent pathologies. We studied the effects of technical-grade DDT on hepatic testosterone metabolism and testosterone hydroxylase activity ratios in the rat. Male and female Wistar rats were treated by gavage with a single dose of technical-grade DDT (0, 0.1, 1, 10, and 100 mg/kg body weight) and killed 24 h later. Hepatic microsomes were incubated with [4-14C]-testosterone and the metabolites were separated by thin-layer chromatography and quantified by radio scanning. DDT increased testosterone biotransformation and modified the profile of metabolites produced in a sex-dependent manner. Males treated with a representative dose (10 mg/kg) produced relatively less androstenedione (AD), 2alpha-hydroxytestosterone (OHT), and 16alpha-OHT but higher 6beta-OHT whereas treated females produced less 7alpha-OHT and AD but higher 6beta-OHT and 6alpha-OHT than their respective controls. In both sexes DDT decreased the relative proportion of AD and increased that of 6beta-OHT suggesting that the androgen-saving pathway was affected. The testosterone 6alpha-/15alpha-OHT ratio, a proposed indicator of demasculinization, was increased in treated males. This effect was in agreement with the demasculinizing ability proposed for DDT. The effects on 6alpha-/16alpha-OHT and 6-dehydrotestosterone/16alpha-OHT ratios followed a similar tendency, with the ratio 6alpha-/16alpha-OHT being the most sensitive marker. Interestingly, these ratios were reduced in treated females suggesting that technical-grade DDT shifted testosterone hydroxylations toward a more masculine pattern. Thus, technical-grade DDT altered the hepatic sexual dimorphism in testosterone metabolism and decreased the metabolic differences between male and female rats.

  17. Phase I and phase II reductive metabolism simulation of nitro aromatic xenobiotics with electrochemistry coupled with high resolution mass spectrometry.

    Science.gov (United States)

    Bussy, Ugo; Chung-Davidson, Yu-Wen; Li, Ke; Li, Weiming

    2014-11-01

    Electrochemistry combined with (liquid chromatography) high resolution mass spectrometry was used to simulate the general reductive metabolism of three biologically important nitro aromatic molecules: 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide, and nilutamide. TFM is a pesticide used in the Laurential Great Lakes while niclosamide and nilutamide are used in cancer therapy. At first, a flow-through electrochemical cell was directly connected to a high resolution mass spectrometer to evaluate the ability of electrochemistry to produce the main reduction metabolites of nitro aromatic, nitroso, hydroxylamine, and amine functional groups. Electrochemical experiments were then carried out at a constant potential of -2.5 V before analysis of the reduction products by LC-HRMS, which confirmed the presence of the nitroso, hydroxylamine, and amine species as well as dimers. Dimer identification illustrates the reactivity of the nitroso species with amine and hydroxylamine species. To investigate xenobiotic metabolism, the reactivity of nitroso species to biomolecules was also examined. Binding of the nitroso metabolite to glutathione was demonstrated by the observation of adducts by LC-ESI(+)-HRMS and the characteristics of their MSMS fragmentation. In conclusion, electrochemistry produces the main reductive metabolites of nitro aromatics and supports the observation of nitroso reactivity through dimer or glutathione adduct formation.

  18. Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

    Science.gov (United States)

    Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

    2016-02-01

    Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis.

  19. Metabolic Disorders and Steatosis in Patients with Chronic Hepatitis C: Metabolic Strategies for Antiviral Treatments

    Directory of Open Access Journals (Sweden)

    Munechika Enjoji

    2012-01-01

    Full Text Available It has been reported that hepatitis C virus (HCV infection is closely associated with hepatic metabolic disorders. Hepatic steatosis and insulin resistance are both relatively common in patients with chronic hepatitis C. Recent investigations suggest that HCV infection changes the expression profile of lipid-metabolism-associated factors in the liver, conferring advantages to the life cycle of HCV. Moreover, insulin resistance and steatosis are independent predictors of impaired response to antiviral treatment in chronic hepatitis C. In this paper, we summarize our current knowledge of hepatic metabolic disorders and describe how HCV leads to and exploits these hepatic disorders. We also discuss the clinical significance of insulin sensitizers used to improve insulin resistance and lipid modulators used to manage lipid metabolism as potential treatment options for chronic hepatitis C.

  20. Influences of Dietary and Other Factors on Xenobiotic Metabolism and Carcinogenesis-A Review Article in Memory of Dr. Allan H. Conney (1930-2013).

    Science.gov (United States)

    Yang, Chung S

    2015-01-01

    This article reviews our current understanding on how xenobiotic metabolism and carcinogenesis are influenced by dietary and other factors. A major contributor to this research area was Dr. Allan Conney, and his contributions are highlighted. His studies on the induction of microsomal xenobiotic-metabolizing enzymes led to the characterization of the cytochrome P450 enzymes, which catalyze the metabolism of drugs, endogenous substrates, carcinogens and many other xenobiotics. These processes are influenced by drugs, diet, and other environmental factors. These studies provided the molecular basis for drug-drug, diet-drug, and herb-drug interactions. The elucidation of the metabolic activation of chemicals to their ultimate carcinogenic forms enables us to understand the molecular basis of chemical carcinogenesis. These studies led to many subsequent investigations on dietary approaches for cancer chemoprevention, including blocking of carcinogen activation, enhancing carcinogen detoxification, and influencing oncogenic pathways, which were carried out by Dr. Conney and others. The strengths and potential for practical application of these approaches are assessed herein.

  1. Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer.

    Science.gov (United States)

    Gilsing, Anne M J; Berndt, Sonja I; Ruder, Elizabeth H; Graubard, Barry I; Ferrucci, Leah M; Burdett, Laura; Weissfeld, Joel L; Cross, Amanda J; Sinha, Rashmi

    2012-07-01

    Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

  2. Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition.

    Directory of Open Access Journals (Sweden)

    Tianyi Zhang

    Full Text Available The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn's disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD. Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3-V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions.

  3. Thyme (Thymus vulgaris L.) leaves and its constituents increase the activities of xenobiotic-metabolizing enzymes in mouse liver.

    Science.gov (United States)

    Sasaki, Keiko; Wada, Keiji; Tanaka, Yoshiko; Yoshimura, Teruki; Matuoka, Koozi; Anno, Takahiko

    2005-01-01

    The effects of thyme (Thymus vulgaris L.) leaves and its phenolic compounds, thymol and carvacrol, on the activities of xenobiotic-metabolizing enzymes, i.e., phase I enzymes such as 7-ethoxycoumarin O-deethylase (ECOD) and phase II enzymes such as glutathione S-transferase (GST) and quinone reductase (QR), were investigated. Mice were fed with a diet containing thyme (0.5% or 2.0%) or treated orally with thymol (50-200 mg/kg) or carvacrol (50-200 mg/kg) once a day for 7 successive days, and then the enzyme activities in the livers were analyzed. Dietary administration of 2% thyme caused slightly but significantly higher ECOD, GST, and QR activities by 1.1-1.4-fold. Thymol (200 mg/kg) treatment resulted in significantly higher ECOD, GST, and QR activities by 1.3-1.9-fold, and carvacrol (200 mg/kg) treatment caused significantly higher ECOD, GST, and QR activities by 1.3-1.7-fold. Thymol-treated animals had significantly higher protein levels of GST alpha and GST micro, and carvacrol-treated animals had significantly higher levels of GST micro. These results imply that thyme contains bifunctional inducers (i.e., substances capable of inducing both phase I and phase II enzymes) and that thymol and carvacrol may account for the effects of thyme.

  4. Consequences of Vitamin D and xenobiotic metabolism by cytochrome P450 in HIV infection

    NARCIS (Netherlands)

    Bout-van den Beukel, C. van den

    2009-01-01

    Antiretroviral drugs (ARVs) and medicinal herbs as well as vitamin D are metabolized by the cytochrome P450 enzyme system in the liver. This thesis focuses on the interaction between these compounds. We also explored the hypothesis that HIV-patients might develop insufficiënt vitamin D levels as a r

  5. Consequences of Vitamin D and xenobiotic metabolism by cytochrome P450 in HIV infection

    NARCIS (Netherlands)

    Bout-van den Beukel, C. van den

    2009-01-01

    Antiretroviral drugs (ARVs) and medicinal herbs as well as vitamin D are metabolized by the cytochrome P450 enzyme system in the liver. This thesis focuses on the interaction between these compounds. We also explored the hypothesis that HIV-patients might develop insufficiënt vitamin D levels as a r

  6. CHANGING METABOLIC FUNCTIONS IN EXPERIMENTAL ANIMALS AFTER INTRODUCTION OF THE XENOBIOTIC, IMMUNOTROPIC DRUG AND PROBIOTIC

    OpenAIRE

    Zvyagintseva O.V.; Klimova E.M.; Lavinska O.V.; Lenkevich A.S.

    2015-01-01

    The aim of the study was to evaluate in vivo changes in metabolic and barrier function of the resistance factors (activity of enzymes of neutrophils, the efficiency of phagocytosis), some biochemical parameters (concentration of ceruloplasmin and haptoglobin) and proliferate activity in vitro cells after introduction of copper sulfate, probiotics and immunostimulant "Fungidol" the experimental animals. Material and methods. The in vivo experiments were performed on ...

  7. Pesticide exposure and genetic variation in xenobiotic-metabolizing enzymes interact to induce biochemical liver damage.

    Science.gov (United States)

    Hernández, Antonio F; Gil, Fernando; Lacasaña, Marina; Rodríguez-Barranco, Miguel; Tsatsakis, Aristidis M; Requena, Mar; Parrón, Tesifón; Alarcón, Raquel

    2013-11-01

    Metabolic activation of pesticides in the liver may result in highly reactive intermediates capable of impairing various cellular functions. Nevertheless, the knowledge about the effect of pesticide exposure on liver function is still limited. This study assessed whether exposure to pesticides elicits early biochemical changes in biomarkers of liver function and looked for potential gene-environmental interactions between pesticide exposure and polymorphisms of pesticide-metabolizing genes. A longitudinal study was conducted in farm-workers from Andalusia (South Spain), during two periods of the same crop season with different degree of pesticide exposure. Blood samples were taken for the measurement of serum and erythrocyte cholinesterase activities as well as for determining clinical chemistry parameters as biomarkers of liver function. Serum lipid levels were also measured as they may help to monitor the progress of toxic liver damage. A reduction in serum cholinesterase was associated with decreased levels of all clinical chemistry parameters studied except HDL-cholesterol. Conversely, a decreased erythrocyte cholinesterase (indicating long-term pesticide exposure) was associated with increased levels of aspartate aminotransferase and alkaline phosphatase and increased levels of triglycerides, total cholesterol and LDL-cholesterol, but reduced levels of HDL-cholesterol. Changes in liver biomarkers were particularly associated with the PON155M/192R haplotype. The obtained results therefore support the hypothesis that pesticide exposure results in subtle biochemical liver toxicity and highlight the role of genetic polymorphisms in pesticide-metabolizing enzymes as biomarkers of susceptibility for developing adverse health effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. A catalogue of polymorphisms related to xenobiotic metabolism and cancer susceptibility.

    Science.gov (United States)

    Gemignani, Federica; Landi, Stefano; Vivant, Franck; Zienolddiny, Shanbeh; Brennan, Paul; Canzian, Federico

    2002-08-01

    High-throughput genotyping technology of multiple genes based on large samples of cases and controls are likely to be important in identifying common genes which have a moderate effect on the development of specific diseases. We present here a comprehensive list of 313 known experimentally confirmed polymorphisms in 54 genes which are particularly relevant for metabolism of drugs, alcohol, tobacco, and other potential carcinogens. We have compiled a catalog with a standardized format that summarizes the genetic and biochemical properties of the selected polymorphisms. We have also confirmed or redesigned experimental conditions for simplex or multiplex PCR amplification of a subset of 168 SNPs of particular interest, which will provide the basis for the design of assays compatible with high-throughput genotyping.

  9. Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes.

    Science.gov (United States)

    Naushad, Shaik Mohammad; Hussain, Tajamul; Al-Attas, Omar S; Prayaga, Aruna; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kutala, Vijay Kumar

    2014-07-01

    Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.

  10. Perturbation of xenobiotic metabolism in Dreissena polymorpha model exposed in situ to surface water (Lake Trasimene) purified with various disinfectants.

    Science.gov (United States)

    Sapone, Andrea; Canistro, Donatella; Vivarelli, Fabio; Paolini, Moreno

    2016-02-01

    Sanitation is of crucial importance for the microbiological safety of drinking water. However, chlorination of water rich in organic material produces disinfection by-products (DBPs), many of which have been reported to be mutagenic and/or carcinogenic compounds such as haloacetic acids and trihalomethanes. Epidemiological studies have suggested a link between drinking water consumption and cancer. We previously observed that Cyprinus carpio fish exposed to DBPs, may be subject to epigenetic effects such as those referable to the up-regulation of cytochrome P450 (CYP) superfamily (ex. co-mutagenesis/co-carcinogenesis and oxidative stress) that has been associated to non-genotoxic carcinogenesis. Our goal was to study the xenobiotic metabolism in mollusks exposed in situ to surface water of Lake Trasimene (Central Italy) treated with several disinfectants such as the traditional chlorine dioxide (ClO2), sodium hypochlorite (NaClO) or the relatively new one peracetic acid (PAA). The freshwater bivalves (Dreissena polymorpha) being selected as biomarker, have the unique ability to accumulate pollutants. Freshwater bivalves were maintained in surface water containing each disinfectant individually (1-2 mg/L). Following an exposure period up to 20 days during the fall period, microsomes were collected from the mussels, then tested for various monooxygenases. Strong CYP inductions were observed. These data indicate that drinking water disinfection generates harmful DBP mixtures capable of determining a marked perturbation of CYP-supported reactions. This phenomenon, being associated to an increased pro-carcinogen bioactivation and persistent oxidative stress, could provide an explanation for the observational studies connecting the regular consumption of drinking water to increased risk of various cancers in humans.

  11. Plant biochemistry of xenobiotics: isolation and characterization of a soybean O-glucosyltransferase of DDT metabolism.

    Science.gov (United States)

    Wetzel, A; Sandermann, H

    1994-11-01

    The insecticide DDT is metabolized in soybean and wheat cell cultures to the acylglucoside of 2,2-bis-(4-chlorophenyl)-acetic acid (DDA) (M. Arjmand and H. Sandermann, 1985, Pesticide Biochem. Physiol. 23, 389-397). An enzyme catalyzing the conjugation reaction has been highly purified from the soluble enzyme fraction of cultured soybean cells. After the initial ammonium sulfate fractionation, quercetin and pentachlorophenol were preferentially glucosylated. In the course of 367-fold purification, DDA became the preferred substrate. The purified enzyme was unstable. A molecular weight of approximately 50 kDa was estimated for the native enzyme (gel permeation chromatography) as well as the denatured protein (sodium dodecyl sulfate-gel electrophoresis). The isoelectric point for the enzyme was near pH 4.9. Apparent Km values of about 170 microM were determined for UDP-glucose as well as DDA. The maximal velocity was 257 microkat/kg protein, corresponding to a conjugation capacity of 855 micrograms DDA/h/g fresh weight of cells.

  12. Impact of hepatitis B virus infection on hepatic metabolic signaling pathway

    Science.gov (United States)

    Shi, Yi-Xian; Huang, Chen-Jie; Yang, Zheng-Gang

    2016-01-01

    A growing body of epidemiologic research has demonstrated that metabolic derangement exists in patients with hepatitis B virus (HBV) infection, indicating that there are clinical associations between HBV infection and host metabolism. In order to understand the complex interplay between HBV and hepatic metabolism in greater depth, we systematically reviewed these alterations in different metabolic signaling pathways due to HBV infection. HBV infection interfered with most aspects of hepatic metabolic responses, including glucose, lipid, nucleic acid, bile acid and vitamin metabolism. Glucose and lipid metabolism is a particular focus due to the significant promotion of gluconeogenesis, glucose aerobic oxidation, the pentose phosphate pathway, fatty acid synthesis or oxidation, phospholipid and cholesterol biosynthesis affected by HBV. These altered metabolic pathways are involved in the pathological process of not only hepatitis B, but also metabolic disorders, increasing the occurrence of complications, such as hepatocellular carcinoma and liver steatosis. Thus, a clearer understanding of the hepatic metabolic pathways affected by HBV and its pathogenesis is necessary to develop more novel therapeutic strategies targeting viral eradication. PMID:27688657

  13. Hepatic metabolism of toluene after gastrointestinal uptake in humans

    DEFF Research Database (Denmark)

    Bælum, Jesper; Mølhave, Lars; Honoré Hansen, S

    1993-01-01

    The metabolism of toluene and the influence of small doses of ethanol were measured in eight male volunteers after gastrointestinal uptake, the toluene concentration in alveolar air and the urinary excretion of hippuric acid and ortho-cresol being used as the measures of metabolism. During toluene...... exposure to 2 mg.min-1 for 3 h the alveolar toluene concentration was 0.07 (range 0-0.11) mg.m-3; exposure to 6 mg.min-1 for 30 min increased the alveolar concentration to 0.9 (range 0.03-2.6) mg.m-3. Ingestion of 0.08, 0.16, and 0.32 g of ethanol per kilogram of body weight during toluene exposure of 2 mg...... doses of ethanol inhibit toluene metabolism, and the procedure is sensitive enough to measure metabolic interactions between solvents and other xenobiotics in humans....

  14. Metabolic investigations in patients with hepatitis B and C

    Institute of Scientific and Technical Information of China (English)

    Abdul; Aziz; Mastoi; Bikha; Ram; Devrajani; Syed; Zulfiquar; Ali; Shah; Qasim; Rohopoto; Sikander; Ali; Memon; Marya; Baloch; Ghulam; Ali; Qureshi; Waqas; Sami

    2010-01-01

    AIM:To investigate the similarities and dissimilarities in patients with hepatitis B and hepatitis C,clinically and metabolically. METHODS:Fifty patients with hepatitis B virus and hepatitis C virus infection were included in this study, along with fifty healthy controls for comparison purposes.Intravenous blood(10 mL)samples from patients and healthy subjects were collected and made to clot before serum was separated and immediately levels of the enzymes,alkaline phosphatase(ALK),creatinine phosphokinase(C...

  15. Signalling mechanisms linking hepatic glucose and lipid metabolism.

    Science.gov (United States)

    Weickert, M O; Pfeiffer, A F H

    2006-08-01

    Fatty liver and hepatic triglyceride accumulation are strongly associated with obesity, insulin resistance and type 2 diabetes, and are subject to nutritional influences. Hepatic regulation of glucose and lipid homeostasis is influenced by a complex system of hormones, hormonally regulated signalling pathways and transcription factors. Recently, considerable progress has been made in elucidating molecular pathways and potential factors that are affected in insulin-resistant states. In this review we discuss some of the key factors that are involved in both the regulation of glucose and lipid metabolism in the liver. Understanding the molecular network that links hepatic lipid accumulation and impaired glucose metabolism may provide targets for dietary or pharmacological interventions.

  16. Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair.

    Science.gov (United States)

    Harth, Volker; Schafer, Martin; Abel, Josef; Maintz, Laura; Neuhaus, Thomas; Besuden, Mette; Primke, Robert; Wilkesmann, Anja; Thier, Ricarda; Vetter, Hans; Ko, Yon-Dschun; Bruning, Thomas; Bolt, Hermann M; Ickstadt, Katja

    2008-01-01

    Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.

  17. Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

    Science.gov (United States)

    Baron, Matthew G.; Mintram, Kate S.; Owen, Stewart F.; Hetheridge, Malcolm J.; Moody, A. John; Purcell, Wendy M.; Jackson, Simon K.; Jha, Awadhesh N.

    2017-01-01

    At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control. PMID:28045944

  18. Metabolism of bupropion by baboon hepatic and placental microsomes

    OpenAIRE

    2011-01-01

    The aim of this investigation was to determine the biotransformation of bupropion by baboon hepatic and placental microsomes, identify the enzyme(s) catalyzing the reaction(s) and determine its kinetics. Bupropion was metabolized by baboon hepatic and placental microsomes to hydroxybupropion (OH-BUP), threo- (TB) and erythrohydrobupropion (EB). OH-bupropion was the major metabolite formed by hepatic microsomes (Km 36 ± 6 µM, Vmax 258 ± 32 pmol mg protein−1 min−1), however the formation of OH-...

  19. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.

    Science.gov (United States)

    Ding, Xinxin; Kaminsky, Laurence S

    2003-01-01

    Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.

  20. Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice.

    Science.gov (United States)

    Jiang, Yanjun; Jin, Jingling; Iakova, Polina; Hernandez, Julio Cesar; Jawanmardi, Nicole; Sullivan, Emily; Guo, Grace L; Timchenko, Nikolai A; Darlington, Gretchen J

    2013-09-01

    Activation of xenobiotic metabolism pathways has been linked to lifespan extension in different models of aging. However, the mechanisms underlying activation of xenobiotic genes remain largely unknown. Here we showed that although farnesoid X receptor (FXR, Nr1h4) mRNA levels do not change significantly, FXR protein levels are elevated in the livers of the long-lived Little mice, leading to increased DNA binding activity of FXR. Hepatic FXR expression is sex-dependent in wild-type mice but not in Little mice, implying that up-regulation of FXR might be dependent on the reduction of growth hormone in Little mice. Growth hormone treatment decreased hepatic expression of FXR and xenobiotic genes Abcb1a, Fmo3 and Gsta2 in both wild-type and Little mice, suggesting an association between FXR and xenobiotic gene expression. We found that Abcb1a is transactivated by FXR via direct binding of FXR/retinoid X receptor α (RXRα) heterodimer to a response element at the proximal promoter. FXR also positively controls Fmo3 and Gsta2 expression through direct interaction with the response elements in these genes. Our study demonstrates that xenobiotic genes are direct transcriptional targets of FXR and suggests that FXR signaling may play a critical role in the lifespan extension observed in Little mice.

  1. Hepatitis C Virus Life Cycle and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Costin-Ioan Popescu

    2014-12-01

    Full Text Available Hepatitis C Virus (HCV infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus life cycle is intimately connected to lipid metabolism. In this review, we present an update on the lipids and apolipoproteins that are involved in the HCV infectious cycle steps: entry, replication and assembly. Moreover, the result of the assembly process is a lipoviroparticle, which represents a peculiarity of hepatitis C virion. This review illustrates an example of an intricate virus-host interaction governed by lipid metabolism.

  2. Metabolism of bupropion by baboon hepatic and placental microsomes.

    Science.gov (United States)

    Wang, Xiaoming; Abdelrahman, Doaa R; Fokina, Valentina M; Hankins, Gary D V; Ahmed, Mahmoud S; Nanovskaya, Tatiana N

    2011-08-01

    The aim of this investigation was to determine the biotransformation of bupropion by baboon hepatic and placental microsomes, identify the enzyme(s) catalyzing the reaction(s) and determine its kinetics. Bupropion was metabolized by baboon hepatic and placental microsomes to hydroxybupropion (OH-BUP), threo- (TB) and erythrohydrobupropion (EB). OH-bupropion was the major metabolite formed by hepatic microsomes (Km 36±6 μM, Vmax 258±32 pmol mg protein(-1) min(-1)), however the formation of OH-BUP by placental microsomes was below the limit of quantification. The apparent Km values of bupropion for the formation of TB and EB by hepatic and placental microsomes were similar. The selective inhibitors of CYP2B6 (ticlopidine and phencyclidine) and monoclonal antibodies raised against human CYP2B6 isozyme caused 80% inhibition of OH-BUP formation by baboon hepatic microsomes. The chemical inhibitors of aldo-keto reductases (flufenamic acid), carbonyl reductases (menadione), and 11β-hydroxysteroid dehydrogenases (18β-glycyrrhetinic acid) significantly decreased the formation of TB and EB by hepatic and placental microsomes. Data indicate that CYP2B of baboon hepatic microsomes is responsible for biotransformation of bupropion to OH-BUP, while hepatic and placental short chain dehydrogenases/reductases and to a lesser extent aldo-keto reductases are responsible for the reduction of bupropion to TB and EB.

  3. Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss)

    Energy Technology Data Exchange (ETDEWEB)

    Wassmur, Britt; Graens, Johanna; Kling, Peter [University of Gothenburg, Department of Zoology, Box 463, SE-405 30 Goeteborg (Sweden); Celander, Malin C., E-mail: malin.celander@zool.gu.se [University of Gothenburg, Department of Zoology, Box 463, SE-405 30 Goeteborg (Sweden)

    2010-10-01

    The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver > intestine > kidney > heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16{alpha}-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak concentration-dependent induction of CYP3A and P-gp mRNA levels, though, exposure to the higher concentration of LA (50 {mu}M) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg LA/kg fish resulted in a slight (albeit not significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10 mg omeprazole (OME)/kg fish had no effect on PXR and CYP3A mRNA levels, a 60% inhibition of CYP3A enzyme activities

  4. Exercise Intensity Modulation of Hepatic Lipid Metabolism

    OpenAIRE

    Lira, Fábio S.; Carnevali, Luiz C; Zanchi, Nelo E.; Ronaldo VT. Santos; Jean Marc Lavoie; Marília Seelaender

    2012-01-01

    Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL), ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations...

  5. Hepatic Steatosis as a Marker of Metabolic Dysfunction

    Directory of Open Access Journals (Sweden)

    Elisa Fabbrini

    2015-06-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG content is therefore a very good marker (and in some cases may be the cause of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.

  6. Sirtuin 1 deacetylase: a key regulator of hepatic lipid metabolism.

    Science.gov (United States)

    Kemper, Jongsook Kim; Choi, Sung-E; Kim, Dong Hyun

    2013-01-01

    Obesity is a serious medical problem worldwide and disruption of metabolic/energy homeostasis plays a pivotal role in this global epidemic. In obese people, fatty liver (steatosis) develops, which increases the risk for diabetes, cardiovascular disease, and even, liver cancer. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that functions as a key metabolic/energy sensor and mediates homeostatic responses to nutrient availability. Accumulating evidence indicates that SIRT1 is a master regulator of the transcriptional networks that control hepatic lipid metabolism. During energy-deprived conditions, SIRT1 deacetylates and alters the expression and activities of key transcriptional regulators involved in hepatic lipogenesis, fatty acid β-oxidation, and cholesterol/bile acid metabolism. This review will discuss the latest advances in this field, focusing on beneficial roles of SIRT1 in hepatic lipid metabolism including its potential as a therapeutic target for treatment of steatosis and other obesity-related metabolic diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Hepatic Steatosis as a Marker of Metabolic Dysfunction

    Science.gov (United States)

    Fabbrini, Elisa; Magkos, Faidon

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID:26102213

  8. Endoplasmic reticulum-mitochondria calcium signaling in hepatic metabolic diseases.

    Science.gov (United States)

    Rieusset, Jennifer

    2017-06-01

    The liver plays a central role in glucose homeostasis, and both metabolic inflexibility and insulin resistance predispose to the development of hepatic metabolic diseases. Mitochondria and endoplasmic reticulum (ER), which play a key role in the control of hepatic metabolism, also interact at contact points defined as mitochondria-associated membranes (MAM), in order to exchange metabolites and calcium (Ca(2+)) and regulate cellular homeostasis and signaling. Here, we overview the role of the liver in the control of glucose homeostasis, mainly focusing on the independent involvement of mitochondria, ER and Ca(2+) signaling in both healthy and pathological contexts. Then we focus on recent data highlighting MAM as important hubs for hormone and nutrient signaling in the liver, thus adapting mitochondria physiology and cellular metabolism to energy availability. Lastly, we discuss how chronic ER-mitochondria miscommunication could participate to hepatic metabolic diseases, pointing MAM interface as a potential therapeutic target for metabolic disorders. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Influences of 3-methylcholanthrene, phenobarbital and dexamethasone on xenobiotic metabolizing-related cytochrome P450 enzymes and steroidogenesis in human fetal adrenal cortical cells

    Institute of Scientific and Technical Information of China (English)

    Hui WANG; Min HUANG; Ren-xiu PENG; Jiang LE

    2006-01-01

    Aim: To explore the influence and possible mechanism of xenobiotics on adrenal steroidogenesis during fetal development. Methods: Primary human fetal adrenal cortical cells were prepared, cultured and treated with 3-methylcholanthrene, phenobarbital and dexamethasone. The activities of 7-ethoxyresorufin 0-dealkylase, benzphetamine, aminopyrine and erythromycin N-demethylases were measured by enzyme assays. At the same time, quantitative analysis of steroid hormones cortisol, aldosterone, testosterone and progesterone were carried out in cultural medium by radioimmunoassays. Results: The activities of benzphetamine and aminopyrine Ar-demethylase were increased in the cultural fetal adrenal cells treated with phenobarbital (0.25-1 mmol/L) for 24 h. Dexamethasone (25-100 μmol/L) also increased the activity of erythromycin W-demethylase. The activity of 7-ethoxyresorufin 0-dealkylase was undetected in the cells treated without and with 3-methylcholanthrene (0.5-2 μmol/L). Meanwhile, the contents of medium cortisol, aldosterone and progesterone were decreased after treatment with 3-methylcholanthrene. Cortisol, aldosterone and progesterone concentrations were also slightly decreased with phenobarbital. Dexamethasone enhanced the productions of cortisol and progesterone remarkably. The trend of testosterone concentration was uncertain after 3-methylcholanthrene, phenobarbital or dexamethasone treatment. Conclusion: 3-Methylcholanthrene, phenobarbital or dexamethasone could interfere with the synthesis of cortisol, aldosterone and progesterone in primary human fetal adrenal cortical cells, which likely act through xenobiotic metabolizing-related cytochrome P450 isoform activation.

  10. LIPID METABOLISM DISORDERS IN PATIENTS WITH CHRONIC HEPATITIS C

    Directory of Open Access Journals (Sweden)

    L. I. Tkachenko

    2015-01-01

    Full Text Available Purpose of the study. To study lipid metabolism in chronic hepatitis C and to assess its impact on the formation of insulin resistance, steatosis and progression of liver fibrosis.Materials and methods. The study included 205 patients with chronic hepatitis C (CHC. Conducts research, depending on the genotype C, viral load and body mass index (BMI of the patients.Results. CHC patients revealed a combined hyperlipoproteinemia on the background of op-pression synthesis of apolipoproteins A1 and B. Formation of hepatic steatosis was associated with HCV genotype 3 virus-induced viral load at ≥ 6 log10 IU/ml and metabolic in VL < 6 log10 IU/ml. In patients with chronic hepatitis C genotype 1, high viral load leads to inhibition of protein synthesis conveyor ApoA1 and increased synthesis of cholesterol, accompanied by abdominal obesity and the formation of insulin resistance. CHC patients with BMI < 25 kg/m2 viral load ≥ 6 log10 ME/ml was associated with dyslipidemia IV type on D. Fredriskson (1970, hyperglycemia, insulin resistance and diabetes. The advanced stage of liver fi brosis (F ≥ 3 on a scale METAVIR and non-response to treatment were associated with a decrease in HDL cholesterol below normal. With an increase in viral load > 5 log10 ME/ml signifi cantly increased the risk of lipid and carbohydrate metabolism.

  11. Passive rGE or Developmental Gene-Environment Cascade? An Investigation of the Role of Xenobiotic Metabolism Genes in the Association Between Smoke Exposure During Pregnancy and Child Birth Weight.

    Science.gov (United States)

    Marceau, Kristine; Palmer, Rohan H C; Neiderhiser, Jenae M; Smith, Taylor F; McGeary, John E; Knopik, Valerie S

    2016-05-01

    There is considerable evidence that smoke exposure during pregnancy (SDP) environmentally influences birth weight after controlling for genetic influences and maternal characteristics. However, maternal smoking during pregnancy-the behavior that leads to smoke exposure during pregnancy-is also genetically-influenced, indicating the potential role of passive gene-environment correlation. An alternative to passive gene-SDP correlation is a cascading effect whereby maternal and child genetic influences are causally linked to prenatal exposures, which then have an 'environmental' effect on the development of the child's biology and behavior. We describe and demonstrate a conceptual framework for disentangling passive rGE from this cascading GE effect using a systems-based polygenic scoring approach comprised of genes shown to be important in the xenobiotic (substances foreign to the body) metabolism pathway. Data were drawn from 5044 families from the Avon Longitudinal Study of Parents and Children with information on maternal SDP, birth weight, and genetic polymorphisms in the xenobiotic pathway. Within a k-fold cross-validation approach (k = 5), we created weighted maternal and child polygenic scores using 18 polymorphisms from 10 genes that have been implicated in the xenobiotic metabolism pathway. Mothers and children shared variation in xenobiotic metabolism genes. Amongst mothers who smoked during pregnancy, neither maternal nor child xenobiotic metabolism polygenic scores were associated with a higher likelihood of smoke exposure during pregnancy, or the severity of smoke exposure during pregnancy (and therefore, neither proposed mechanism was supported), or with child birth weight. SDP was consistently associated with lower child birth weight controlling for the polygenic scores, maternal educational attainment, social class, psychiatric problems, and age. Limitations of the study design and the potential of the framework using other designs are discussed.

  12. Metabolic Factors and Chronic Hepatitis C: A Complex Interplay

    Directory of Open Access Journals (Sweden)

    Fabio Salvatore Macaluso

    2013-01-01

    Full Text Available In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.

  13. Hepatitis

    Science.gov (United States)

    ... inflammation of the liver.” This inflammation can be caused by a wide variety of toxins, drugs, and metabolic diseases, as well as infection. There are at least 5 hepatitis viruses. Hepatitis A is contracted when a child eats food or drinks water that is contaminated with the virus or has ...

  14. Integrative Metabolic Signatures for Hepatic Radiation Injury.

    Directory of Open Access Journals (Sweden)

    Irwin Jack Kurland

    Full Text Available Radiation-induced liver disease (RILD is a dose-limiting factor in curative radiation therapy (RT for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice.Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI and were contrasted to mice, which received 10 Gy whole body irradiation (WBI. Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry.Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate, fatty acids (lineolate, n-hexadecanoic acid and DNA damage markers (uridine.We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.

  15. Hepatic insulin clearance is closely related to metabolic syndrome components.

    Science.gov (United States)

    Pivovarova, Olga; Bernigau, Wolfgang; Bobbert, Thomas; Isken, Frank; Möhlig, Matthias; Spranger, Joachim; Weickert, Martin O; Osterhoff, Martin; Pfeiffer, Andreas F H; Rudovich, Natalia

    2013-11-01

    Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome. Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated. Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97-1.31], P = 0.12, and HICISR 1.38 [0.88-2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92-1.36], P = 0.26, and HICISR 1.31 [0.74-2.33] P = 0.36), although point estimates reached no statistical significance. HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.

  16. Ethanol metabolism modifies hepatic protein acylation in mice.

    Directory of Open Access Journals (Sweden)

    Kristofer S Fritz

    Full Text Available Mitochondrial protein acetylation increases in response to chronic ethanol ingestion in mice, and is thought to reduce mitochondrial function and contribute to the pathogenesis of alcoholic liver disease. The mitochondrial deacetylase SIRT3 regulates the acetylation status of several mitochondrial proteins, including those involved in ethanol metabolism. The newly discovered desuccinylase activity of the mitochondrial sirtuin SIRT5 suggests that protein succinylation could be an important post-translational modification regulating mitochondrial metabolism. To assess the possible role of protein succinylation in ethanol metabolism, we surveyed hepatic sub-cellular protein fractions from mice fed a control or ethanol-supplemented diet for succinyl-lysine, as well as acetyl-, propionyl-, and butyryl-lysine post-translational modifications. We found mitochondrial protein propionylation increases, similar to mitochondrial protein acetylation. In contrast, mitochondrial protein succinylation is reduced. These mitochondrial protein modifications appear to be primarily driven by ethanol metabolism, and not by changes in mitochondrial sirtuin levels. Similar trends in acyl modifications were observed in the nucleus. However, comparatively fewer acyl modifications were observed in the cytoplasmic or the microsomal compartments, and were generally unchanged by ethanol metabolism. Using a mass spectrometry proteomics approach, we identified several candidate acetylated, propionylated, and succinylated proteins, which were enriched using antibodies against each modification. Additionally, we identified several acetyl and propionyl lysine residues on the same sites for a number of proteins and supports the idea of the overlapping nature of lysine-specific acylation. Thus, we show that novel post-translational modifications are present in hepatic mitochondrial, nuclear, cytoplasmic, and microsomal compartments and ethanol ingestion, and its associated

  17. Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.

    Science.gov (United States)

    Madiraju, Anila K; Alves, Tiago; Zhao, Xiaojian; Cline, Gary W; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T; Kibbey, Richard G; Shulman, Gerald I

    2016-06-14

    A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.

  18. Intestinal and hepatic metabolism of glutamine and citrulline in humans.

    Science.gov (United States)

    van de Poll, Marcel C G; Ligthart-Melis, Gerdien C; Boelens, Petra G; Deutz, Nicolaas E P; van Leeuwen, Paul A M; Dejong, Cornelis H C

    2007-06-01

    Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal-renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans.

  19. Chronic hepatitis C virus infection and lipoprotein metabolism.

    Science.gov (United States)

    Aizawa, Yoshio; Seki, Nobuyoshi; Nagano, Tomohisa; Abe, Hiroshi

    2015-09-28

    Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins.

  20. Cerebral hemodynamic and metabolic changes in fulminant hepatic failure

    Directory of Open Access Journals (Sweden)

    Fernando Mendes Paschoal Junior

    Full Text Available ABSTRACT Intracranial hypertension and brain swelling are a major cause of morbidity and mortality of patients suffering from fulminant hepatic failure (FHF. The pathogenesis of these complications has been investigated in man, in experimental models and in isolated cell systems. Currently, the mechanism underlying cerebral edema and intracranial hypertension in the presence of FHF is multi-factorial in etiology and only partially understood. The aim of this paper is to review the pathophysiology of cerebral hemodynamic and metabolism changes in FHF in order to improve understanding of intracranial dynamics complication in FHF.

  1. Mitigating role of baicalein on lysosomal enzymes and xenobiotic metabolizing enzyme status during lung carcinogenesis of Swiss albino mice induced by benzo(a)pyrene.

    Science.gov (United States)

    Naveenkumar, Chandrashekar; Raghunandakumar, Subramanian; Asokkumar, Selvamani; Binuclara, John; Rajan, Balan; Premkumar, Thandavamoorthy; Devaki, Thiruvengadam

    2014-06-01

    The lungs mainly serve as a primary site for xenobiotic metabolism and constitute an important defense mechanism against inhalation of carcinogens. Our current study aimed to evaluate the chemotherapeutic efficacy of baicalein (BE) in Swiss albino mice exposed to tobacco-specific carcinogen benzo(a)pyrene [B(a)P] for its ability to mitigate pulmonary carcinogenesis. Here, we report that altered activities/levels of lysosomal enzymes (cathepsin-D, cathepsin-B, acid phosphatase, β-D-galactosidase, β-D-glucuronidase, and β-D-N-acetyl glucosaminidase), phase I biotransformation enzymes (cytochrome P450, cytochrome b5, NADPH-cytochrome P450 reductase, and NADH-cytochrome b5 reductase), and phase II enzymes (glutathione S-transferase, UDP-glucuronyl transferase, and DT-diaphorase) were observed in the B(a)P-induced mice. Treatment with BE significantly restored back the activities/levels of lysosomal enzymes, phase I and phase II biotransformation enzymes. Moreover, assessment of lysosomal abnormalities by transmission electron microscopic examination revealed that BE treatment effectively counteract B(a)P-induced oxidative damages. Protein expression levels studied by immunohistochemistry, immunofluorescence, and immunoblot analysis of CYP1A1 revealed that BE treatment effectively negate B(a)P-induced upregulated expression of CYP1A1. Further analysis of scanning electron microscopic studies in lung was carried out to substantiate the anticarcinogenic effect of BE. The overall data suggest that BE treatment significantly inhibits lysosomal and microsomal dysfunction, thus revealing its potent anticarcinogenic effect.

  2. Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450.

    Science.gov (United States)

    Štěpánková, Martina; Krasulová, Kristýna; Dořičáková, Aneta; Kurka, Ondřej; Anzenbacher, Pavel; Dvořák, Zdeněk

    2016-11-16

    Dihydropyridine calcium channel blockers (CCBs) are used as anti-hypertensives and in the treatment of angina pectoris. Structurally, CCBs have at least one chiral center in the molecule, thereby existing in two or more different enantiomers. In the current paper we examined effects of benidipine, felodipine and isradipine enantiomers on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450. All CCBs dose-dependently activated aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), as revealed by gene reporter assays. Activation of AhR, but not PXR, was enantiospecific. Consistently, CCBs induced CYP1A1 and CYP1A2 mRNAs, but not protein, in human hepatocytes and HepG2 cells, with following pattern: benidipine (-)>(+), isradipine (-)>(+) and felodipine (+)>(-). All CCBs induced CYP2A6, CYP2B6 and CYP3A4 mRNA and protein in human hepatocytes, and there were not differences between the enantiomers. All CCBs transformed AhR in its DNA-binding form, as revealed by electromobility shift assay. Tested CCBs inhibited enzyme activities of CYP3A4 (benidipine (+)>(-); felodipine (-)>(+); isradipine (-)-(+)) and CYP2C9 (benidipine (-)>(+); felodipine (+)>(-); isradipine (-)>(+)). The data presented here might be of toxicological and clinical importance.

  3. Modulation of Kupffer cells on hepatic drug metabolism

    Institute of Scientific and Technical Information of China (English)

    Hong Ding; Jing Tong; Shi-Cheng Wu; Deng-Ke Yin; Xian-Fen Yuan; Jian-Yuan Wu; Jun Chen; Gang-Gang Shi

    2004-01-01

    AIM: To observe the effects of Kupffer cells on hepatic drug metabolic enzymes.METHODS: Kunming mice were ip injected with GdCl310,20, 40 mg/kg to decrease the number and block the function of kupffer cells selectively. The contents of drug metabolic enzymes, cytochrome P450, NADPH-cytochrom C redutase (NADPH-C), aniline hydroxylase (ANH), aminopyrine Ndemethylase (AMD), erythromycin N-demethylase (EMD),and glutathione s-transferase (mGST) in hepatic microsome and S9-GSTpi, S9-GST in supernatant of 9 000 g were accessed 1 d after the injection. The time course of alteration of drug metabolic enzymes was observed on d 1, 3, and 6 treated with a single dose GdCl3. Mice were treated with Angelica sinensis polysaccharides (ASP) of 30, 60, 120 mg/kg, ig, qd ×6 d, respectively and the same assays were performed.RESULTS: P450 content and NADPH-C, ANH, AMD, and END activities were obviously reduced 1 d after Kupffer cell blockade. However, mGST and S9-GST activities were significantly increased. But no relationship was observed between GdCl3 dosage and enzyme activities. With single dose GdCl3 treatment, P450 content, NADPH-C, and ANH activities were further decreased following Kupffer cell blockade lasted for 6 d, by 35.7%, 50.3%, 36.5% after 3 d, and 57.9%, 57.9%, 63.2% after 6 d, respectively. On the contrary, AMD, EMD, mGST, and Sg-GST activities were raised by 36.5%, 71.9%, 23.1%, 35.7% after 3 d,and 155%, 182%, 21.5%, 33.7% after 6 d, respectively.Furthermore, the activities of drug metabolic enzymes were markedly increased after 30 mg/kg ASP treatment,and decreased significantly after 120 mg/kg ASP treatment.No change in activity of Sg-GSTpi was observed in the present study.CONCLUSION: Kupffer cells play an important role in the modulation of drug metabolic enzymes. The changes of drug metabolic enzyme activities depend on the time of kupffer cell blockade and on the degree of Kupffer cells activated. A low concentration of ASP increases the activities of drug

  4. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

    NARCIS (Netherlands)

    Pols, T.W.H.; Ottenhoff, R.; Vos, M.; Levels, J.H.M.; Quax, P.H.A.; Meijers, J.C.M.; Pannekoek, H.; Groen, A.K.; Vries, C.J.M. de

    2008-01-01

    NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a m

  5. Roles of the Lipid Metabolism in Hepatic Stellate Cells Activation

    Institute of Scientific and Technical Information of China (English)

    Xin-yan Jing; Xue-feng Yang; Kai Qing; Yan Ou-Yang

    2013-01-01

    The lipids present in hepatic stellate cells (HSCs) lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to the development of fibrosis in liver disease. During activation, HSCs transform into myofibroblasts with concomitant loss of their lipid droplets and production of excessive extracellular matrix. Release of lipid droplets containing retinyl esters and triglyceride is a defining feature of activated HSCs. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit the activation of HSCs. In healthy liver, quiescent HSCs store 80%of total liver retinols and release them depending on the extracellular retinol status. However, in injured liver activated HSCs lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Further findings prove that lipid metabolism of HSCs is closely associated with its activation, yet relationship between activated HSCs and the lipid metabolism has remained mysterious.

  6. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.

    Science.gov (United States)

    Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-Hyun; King, Daniel; Huang, Jingyu; McClain, Donald A

    2015-04-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling.

  7. Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort.

    Science.gov (United States)

    Ghisari, Mandana; Long, Manhai; Røge, Durita Mohr; Olsen, Jørn; Bonefeld-Jørgensen, Eva C

    2017-04-01

    In the present case-cohort study based on prospective data from Danish women, we aimed to estimate the main effect of polymorphisms in genes known to be involved in the steroid hormone metabolic pathway and xenobiotic metabolism on the risk of developing breast cancer. We also studied a possible effect measure modification between genotypes and levels of serum perfluoroalkylated substances (PFASs) on the risk to breast cancer. We have previously reported a weak association between serum PFASs levels and the risk of breast cancer for this study population of Danish pregnant nulliparous women as well as in a smaller case-control study of Greenlandic women. The study population consisted of 178 breast cancer cases and 233 controls (tabnulliparous and frequency matched on age) nested within the Danish National Birth Cohort (DNBC), which was established in 1996-2002. Blood samples were drawn at the time of enrollment (6-14 week of gestation). Serum levels of 10 perfluorocarboxylated acids (PFCAs), 5 perfluorosulfonated acids (PFSAs) and 1 sulfonamide (perflurooctane-sulfonamide, PFOSA) were measured. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1→ A2; rs743572); CYP19A1 (C→T; rs10046) by the TaqMan allelic discrimination method. In overall, no significant associations were found between the investigated polymorphisms and the risk of breast cancer in this study among Danish women. The previously found association between PFOSA and risk of breast cancer did vary between different genotypes, with significantly increased risk confined to homozygous carriers of the following alleles: COMT (Met), CYP17 (A1) and CYP19 (C).

  8. Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

    Science.gov (United States)

    Sestak, Karol; Conroy, Lauren; Aye, Pyone P.; Mehra, Smriti; Doxiadis, Gaby G.; Kaushal, Deepak

    2011-01-01

    Background A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Methodology Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. Principal Findings When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. Conclusions/Significance A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID:21533263

  9. Improved xenobiotic metabolism and reduced susceptibility to cancer in gluten-sensitive macaques upon introduction of a gluten-free diet.

    Directory of Open Access Journals (Sweden)

    Karol Sestak

    Full Text Available BACKGROUND: A non-human primate (NHP model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta. METHODOLOGY: Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD and gluten-containing (GD diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies,targeting expression of over 20,000 genes. PRINCIPAL FINDINGS: When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function--this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function and actin-collagen-matrix metalloproteinases (MMP genes. CONCLUSIONS/SIGNIFICANCE: A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

  10. Abnormal erythrocyte metabolism in hepatic disease: effect of NADP repletion.

    Science.gov (United States)

    Smith, J R; Kay, N E; Gottlieb, A J; Oski, F A

    1979-01-01

    Erythrocytes from ten patients with severe liver disease displayed low methylene blue-stimulated hexose monophosphate (HMP) shunt activity and glucose recycling despite elevated total glucose consumption when compared to controls. Heinz body formation was increased and reduced glutathione concentration significantly decreased. After hemolysis, no differences in methylene-blue estimulated HMP shunt activity or glucose recycling could be demonstrated between patients and controls. The addition of 2- and 4-mM NADP to the hemolysates produced significantly greater HMP shunt activity and glucose recycling in the patients' hemolysates. The addition of NADPH to the incubation mixture produced no significant stimulation of either HMP shunt activity or glucose recycling, unless methylene blue was also added. Omission of NAD or phosphate from the incubation mixture produced no change in shunt metabolism. The absence of supplemental ATP resulted in extremely low shunt metabolism and refractoriness to NADP stimulation in both patients and controls. In the absence of additional magnesium, a reduction of shunt metabolism was noted. These data suggest that the defect in stimulated shunt metabolism in the intact erythrocytes of patients with hepatic disease does not result from an absolute enzyme deficiency, but rather from an unavailability of NADP or other cofactor.

  11. Effects of chlorinated drinking water on the xenobiotic metabolism in Cyprinus carpio treated with samples from two Italian municipal networks.

    Science.gov (United States)

    Cirillo, Silvia; Canistro, Donatella; Vivarelli, Fabio; Paolini, Moreno

    2016-09-01

    Drinking water (DW) disinfection represents a milestone of the past century, thanks to its efficacy in the reduction of risks of epidemic forms by water micro-organisms. Nevertheless, such process generates disinfection by-products (DBPs), some of which are genotoxic both in animals and in humans and carcinogenic in animals. At present, chlorination is one of the most employed strategies but the toxicological effects of several classes of DBPs are unknown. In this investigation, a multidisciplinary approach foreseeing the chemical analysis of chlorinated DW samples and the study of its effects on mixed function oxidases (MFOs) belonging to the superfamily of cytochrome P450-linked monooxygenases of Cyprinus carpio hepatopancreas, was employed. The experimental samples derived from aquifers of two Italian towns (plant 1, river water and plant 2, spring water) were obtained immediately after the disinfection (A) and along the network (R1). Animals treated with plant 1 DW-processed fractions showed a general CYP-associated MFO induction. By contrast, in plant 2, a complex modulation pattern was achieved, with a general up-regulation for the point A and a marked MFO inactivation in the R1 group, particularly for the testosterone metabolism. Together, the toxicity and co-carcinogenicity (i.e. unremitting over-generation of free radicals and increased bioactivation capability) of DW linked to the recorded metabolic manipulation, suggests that a prolonged exposure to chlorine-derived disinfectants may produce adverse health effects.

  12. Toxicokinetics of the food-toxin IQ in human placental perfusion is not affected by ABCG2 or xenobiotic metabolism

    DEFF Research Database (Denmark)

    Immonen, E; Kummu, M; Petsalo, A

    2010-01-01

    Metabolizing enzymes and transporters affect toxicokinetics of foreign compounds (e.g. drugs and carcinogens) in human placenta. The heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a food-borne carcinogen being metabolically activated by cytochrome P450 (CYP) enzymes, especially...... by CYP1A1/2. IQ is also a substrate for ABCG2 transporter. Placental transfer of (14)C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with (14)C-IQ alone (0.5 muM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 muM, n...... = 6) or Ko143 (specific inhibitor of ABCG2, 2 muM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with (14)C-IQ alone. Critical parameters (leak from fetal to maternal circulation, pH values, blood gases, glucose consumption, the production of h...

  13. Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 Polymorphisms in Breast Carcinoma

    Directory of Open Access Journals (Sweden)

    Gabbouj Sallouha

    2008-04-01

    Full Text Available Abstract Background Xenobiotic Metabolizing Enzymes (XMEs contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients. Methods The authors used polymerase chain reaction and restriction enzyme digestion to characterize the variation of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene in a total of 560 unrelated subjects (246 controls and 314 patients. Results The mEH (C/C mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk (p = 0.02; p = 0.01, respectively. For NAT2 the association was more pronounced among postmenopausal patients (p = 0.006. A significant association was found between CYP2D6 (G/G wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04. Association studies of genetic markers with the rates of breast carcinoma specific overall survival (OVS and the disease-free survival (DFS revealed among all breast carcinoma patients no association to DFS but significant differences in OVS only with the mEH gene polymorphisms (p = 0.02. In addition, the mEH wild genotype showed a significant association with decreased OVS in patients with axillary lymph node-negative patients (p = 0.03 and with decreasesd DFS in patients with axillary lymph node-positive patients (p = 0.001. However, the NAT2 intermediate acetylator genotype was associated with decreased DFS in axillary lymph node-negative patients. Conclusion The present study may prove that polymorphisms of some XME genes may predict the onset of breast carcinoma as well as survival after treatment.

  14. [Effects of rutin on the activity of antioxidant enzymes and xenobiotic-metabolizing enzymes in liver of rats fed diets with different level of fat].

    Science.gov (United States)

    Aksenov, I V; Trusov, N V; Avren'eva, L I; Guseva, G V; Lashneva, N V; Kravchenko, L V; Tutel'ian, V A

    2014-01-01

    The study has been carried out on 6 groups of male Wistar rats, which received semi-synthetic diets within 28 days. Rats of 1st and 4th group received fat-free diet, 2nid.and 5th - diet containing standard amount of fat (10% by weight, 26% by caloric content; lard/sunflower oil - 1/1); 3rd and 6th group - a high-fat diet (30% by weight, 56% by caloric content). During the last 14 days of the experiment rats received rutin in the dose of 40 mg/kg b.w. AOA, MDA level and the activity of paraoxonase I have been evaluated in blood serum. In rat liver along with the parameters of the antioxidant status (MDA level, activity of paraoxonase 1, quinone reductase, heme oxygenase-1) the activity of xenobiotic-metabolizing enzymes (XME) (CYP1A1, CYP1A2, CYP3A1, CYP2B1, UDP-glucuronosyl transferase and glutathione transferase) and the activity of lysosomal enzymes (arylsulfatase A and B, β-galactosidase and β-glucuronidase) have been investigated. Elevation of the activity of antioxidant enzymes and XME in liver with the increase of diet fat content has been-noted. Rutin admihistration had no effect onparamete6rs of antioxidant status and decreased unsedimentable activity of lysosomal enzymes that did not depend on fat content in the diet. Rutin receiving increased the activity of all studied XME in rats fed standard diet, but practically did not effect on their activity in rats fed by fat-free and high-fat diets. Thus, rutin in pharmacological dose has no effect on the activity of antioxidant enzymes that doesn't depend on the level of fat in the diet, while the decrease or increase of diet fat content modulates (weakens) the influence of rutin on the XME activity.

  15. Association of genetic variants of xenobiotic and estrogen metabolism pathway (CYP1A1 and CYP1B1) with gallbladder cancer susceptibility.

    Science.gov (United States)

    Sharma, Kiran Lata; Agarwal, Akash; Misra, Sanjeev; Kumar, Ashok; Kumar, Vijay; Mittal, Balraj

    2014-06-01

    Gallbladder carcinoma is a highly aggressive cancer with female predominance. Interindividual differences in the effectiveness of the activation/detoxification of environmental carcinogens and endogenous estrogens may play a crucial role in cancer susceptibility. The present study included 410 patients with carcinoma of the gallbladder (GBC) and 230 healthy subjects. This study examined association of CYP1A1-MspI, CYP1A1-Ile462Val, and CYP1B1-Val432Leu with GBC susceptibility. CYP1A1-MspI [CC] and CYP1A1-Ile462Val [iso/val] genotypes were found to be significantly associated with GBC (p=0.006 and p=0.03, respectively), as compared to healthy controls, while CYP1B1-Val432Leu was not associated with GBC. The CYP1A1 haplotype [C-val] showed a significant association with GBC (p=0.006). On stratification based on gender, the CYP1A1-MspI [CC] genotype showed an increased risk of GBC in females (p=0.018). In case-only analysis, tobacco users with CYP1A1-MspI [CT] genotypes were at a higher risk of GBC (p=0.008). Subdividing the GBC patients on the basis of gallstone status, the CYP1A1 haplotype [C-val] imparted a higher risk in patients without stones when compared to controls (p=0.001). The results remained significant even after applying Bonferroni correction. Multivariate analysis revealed an increased risk of CYP1A1 iso/val and val/val genotypes in GBC patients having BMI >25 (p=0.021). The CYP1A1 polymorphisms may confer increased risk of GBC, probably due to impaired xenobiotic or hormone metabolism through a gallstone-independent pathway.

  16. Effects of Cyclamen trochopteranthum on hepatic drug-metabolizing enzymes

    Directory of Open Access Journals (Sweden)

    Arslan Sevki

    2011-01-01

    Full Text Available The modulatory effects of the Cyclamen trochopterantum tuber extract on hepatic drug-metabolizing enzymes, including aniline 4-hydroxylase (A4H; CYP2E1, ethoxyresorufin O-deethylase (EROD; CYP1A, methoxyresorufin O-demethylase (MROD; CYP1A, caffeine N-demethylase (C3ND; CYP1A2 aminopyrene N-demethylase (APND; CYP2C6, and erythromycin N-demethylase (ERND; CYP3A1, were examined in vivo in rats. The activities of all of these enzymes were induced by the cyclamen extract. In addition, Western-blot and RT-PCR results clearly showed that CYP2E1, CYP1A1/CYP1A2 and CYP2C6 protein and mRNA levels were substantially increased by four different doses of cyclamen. Although, the CYP3A1 protein level was increased significantly, the mRNA level was not changed. These results indicate that cyclamen tuber extract might have a potential not only to inhibit and/or induce the metabolism of certain co-administered drugs but also influence the development of toxicity and carcinogenesis due to the induction of the cytochrome P450-dependent drug-metabolizing enzymes.

  17. Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes

    Institute of Scientific and Technical Information of China (English)

    Xin Li; Su Zeng

    2000-01-01

    AIM To study the influence of inducers BNF and PB on the stereoselective metabolism of propranolol in rat hepatic microsomes.METHODS Phase Ⅰ metabolism of propranolol was studied by using the microsomes induced by BNF and PB and the non-induced microsome as the control. The enzymatic kinetic parameters of propranolol enantiomers were calculated by regression analysis of Lineweaver-Burk plots.Propranolol concentrations were assayed by HPLC.RESULTS A RP-HPLC method was developed to determine propranolol concentration in rat hepatic microsomes. The linearity equations for R( + )-propranolol and S ( - )-propranolol were A=705.7C+ 311.2C (R =0.9987) and A=697.2C +311.4C (R = 0.9970) respectively. Recoveries of each enantiomer were 98.9%, 99.5%, 101.0% at 60 μmol/L, 120 μmol/L, 240 μmol/L respectively. At the concentration level of 120 μmol/L, propranolol enantiomers were metabolized at different rates in different microsomes. The concentration ratio R (+)/S (-) of control and PB induced microsomes increased with time, whereas that of microsome induced by BNF decreased. The assayed enzyme parameters were: 1. Km. Control group: R( + )30±8, S( - )18 ± 5; BNF group: R( + )34 ± 3, S (-)39±7; PB group: R(+)38±17, S(-)36± 10.2. Vmax. Control group: R(+ )1.5 ±0.2, S( - )2.9±0.3; BNF group: R(+)3.8±0.3, S(-)3.3±0.5; PB group: R( + )0.07±0.03, S( - )1.94±0.07.3.Clint. Control group: R( + )60±3, S(- )170±30; BNF group: R( + )111.0 ±1, S(- ) 84±5; PB group: R(+)2.0 ± 2, S(- )56.0 ± 1. The enzyme parameters compared with unpaired t tests showed that no stereoselectivity was observed in enzymatic affinity of three microsomes to enantiomers and their catalytic abilitieswere quite different and had stereoselectivities. Compared with the control,microsome induced by BNF enhanced enzyme activity to propranolol R ( + )-enantiomer, and microsome induced by PB showed less enzyme activity to propranolol S(- )-enantiomer which remains the same stereoselectivities as

  18. Changes in lipid metabolism in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Katalin Jármay; Gizella Karácsony; András Nagy; Zsuzsa Schaff

    2005-01-01

    AIM: To investigate the relationship between certain biochemical parameters of lipid metabolism in the serum and steatosis in the liver.METHODS: The grade of steatosis (0-3) and histological activity index (HAI, 0-18) in liver biopsy specimens were correlated with serum alanine aminotransferase (ALT), total cholesterol and triglyceride levels in 142 patients with chronic hepatitis C (CH-C), and 28 patients with non-alcoholic fatty liver disease (NAFLD) without hepatitis C virus (HCV) infection. The serum parameters were further correlated with 1 797 age and sex matched control patients without any liver diseases.RESULTS: Steatosis was detected in 90 out of 142 specimens (63%) with CH-C. The ALT levels correlated with the grade of steatosis, both in patients with CH-C and NAFLD (P<0.01). Inserting the score values of steatosis as part of the HAI, correlation with the ALT level (P<0.00001) was found. The triglyceride and cholesterol levels were significantly lower in patients with CH-C (with and without steatosis), compared to the NAFLD group and to the virus-free control groups.CONCLUSION: Our study confirms the importance of liver steatosis in CH-C which correlates with lower lipid levels in the sera. Inclusion of the score of steatosis into HAI, in case of CH-C might reflect the alterations in the liver tissue more precisely, while correlating with the ALT enzyme elevation.

  19. Effect of Semecarpus anacardium Linn. nut extract on mammary and hepatic expression of xenobiotic enzymes in DMBA-induced mammary carcinoma.

    Science.gov (United States)

    Mathivadhani, P; Shanthi, P; Sachdanandam, P

    2007-05-01

    Breast cancer is the major cause of cancer death in women worldwide. Environmental risk factors particularly genotoxic chemicals such as polycyclic aromatic hydrocarbons (PAH) are likely to account for a much higher mortality. Xenobiotic metabolising enzymes in breast tissue are potentially important determinants in both the susceptibility to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. The well known carcinogen 7,12-dimethylbenz(a)anthrazene of PAH family was given (25mg/ml) orally by gastric intubation to induce mammary carcinoma in Sprague-Dawley rats. Increased level of cytochromes (P(450), B(5)), EROD, PROD activities, Phase I biotransformation enzymes (NADPH-cytochrome (P(450)) reductase, NADPH-cytochrome (b(5)) reductase, epoxide hydrolase) and expression of CYP1A1, CYP1A2 and CYP1B1 in liver and breast tissue microsome were documented in DMBA treated group. Phase II enzyme activities (glutathione-S-transferase, gluthatione peroxidase, gluatathione reductase, UDP-glucuronyl transferease) were decreased markedly in cancerous rats. The nut extract of Semecarpus anacardium was administered orally (200mg/kg body wt/day) to the mammary carcinoma rats for 14 days. Drug treatment restored back the altered Phase I and II biotransformation enzymes thus achieving complete detoxification of the carcinogen. These findings suggest that S. anacardium can effectively modulate the catabolism of xenobiotics in rats. Copyright © 2007. Published by Elsevier B.V.

  20. Prediction of bacterial growth on xenobiotics

    DEFF Research Database (Denmark)

    Brock, Andreas Libonati; Kästner, Matthias; Trapp, Stefan

    2016-01-01

    method, we evaluated it with both simple substrates (e.g. acetate, methanol, and glyoxylate) and xenobiotics (e.g 2,4-D, linuron, carbofuran, carbon tetrachloride, and toluene). Experimental data for the simple substrates were taken from [4], for xenobiotics from [6] and own experimental data. For simple...... thermodynamic considerations of stoichiometrically balanced reactions is typically done in biotechnology and wastewater treatment [5], an approach recently adopted by Helbling et al. [6]. More recent methods specifically incorporate detailed knowledge of the degradation pathway and bacterial metabolism...

  1. Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes.

    Science.gov (United States)

    Götz, Christine; Pfeiffer, Roland; Tigges, Julia; Ruwiedel, Karsten; Hübenthal, Ulrike; Merk, Hans F; Krutmann, Jean; Edwards, Robert J; Abel, Josef; Pease, Camilla; Goebel, Carsten; Hewitt, Nicola; Fritsche, Ellen

    2012-05-01

    The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first-pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals. Thus, there is an urgent need to understand the xenobiotic-metabolizing capacities of human skin and to compare these activities to models developed to replace animal testing. We have measured the activity of the phase II enzymes glutathione S-transferase, UDP-glucuronosyltransferase and N-acetyltransferase in ex vivo human skin, the 3D epidermal model EpiDerm 200 (EPI-200), immortalized keratinocyte-based cell lines (HaCaT and NCTC 2544) and primary normal human epidermal keratinocytes. We show that all three phase II enzymes are present and highly active in skin as compared to phase I. Human skin, therefore, represents a more detoxifying than activating organ. This work systematically compares the activities of three important phase II enzymes in four different in vitro models directly to human skin. We conclude from our studies that 3D epidermal models, like the EPI-200 employed here, are superior over monolayer cultures in mimicking human skin xenobiotic metabolism and thus better suited for dermatotoxicity testing. © 2012 John Wiley & Sons A/S.

  2. In Ovo injection of betaine affects hepatic cholesterol metabolism through epigenetic gene regulation in newly hatched chicks.

    Science.gov (United States)

    Hu, Yun; Sun, Qinwei; Li, Xiaoliang; Wang, Min; Cai, Demin; Li, Xi; Zhao, Ruqian

    2015-01-01

    Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations.

  3. Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression.

    Science.gov (United States)

    Donepudi, Ajay C; Cheng, Qiuqiong; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L

    2016-04-01

    Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor- and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport.

  4. Effects of saturated and unsaturated fats given with and without dietary cholesterol on hepatic cholesterol synthesis and hepatic lipid metabolism.

    Science.gov (United States)

    Bochenek, W; Rodgers, J B

    1978-01-27

    Hepatic cholesterol synthesis was studied in rats after consuming diets of varying neutral lipid and cholesterol content. Cholesterol synthesis was evaluated by measuring 3-hydroxy-3-methylglutaryl-CoA reductase and by determining the rate of 3H-labeled sterol production from [3H]mevalonate. Results were correlated with sterol balance data and hepatic lipid content. Hepatic cholesterol synthesis was relatively great when cholesterol was excluded from the diet. The source of neutral dietary lipids, saturated vs. unsaturated, produced no change in hepatic sterol synthesis. Values for fecal sterol outputs and hepatic cholesterol levels were also similar in rats consuming either saturated or unsaturated fats. When 1% cholesterol was added to the diet, hepatic cholesterol synthesis was suppressed but the degree of suppression was greater in rats consuming unsaturated vs. saturated fats. This was associated with greater accumulation of cholesterol in livers from rats consuming unsaturates and a reduction in fecal neutral sterol output in this group as opposed to results from rats on saturated fats. Cholesterol consumption also altered the fatty acid composition of hepatic phospholipids producing decreases in the percentages of essential polyunsaturated fatty acids. It is concluded that dietary cholesterol alters cholesterol and fatty acid metabolism in the liver and that this effect is enhanced by dietary unsaturated fats.

  5. Avocado oils and hepatic lipid metabolism in growing rats.

    Science.gov (United States)

    Werman, M J; Neeman, I; Mokady, S

    1991-02-01

    The effect of various avocado oils on liver metabolism was studied in growing female rats. The rats were fed diets containing 10% (w/w) avocado oil for 4 wk. In comparison with rats fed refined avocado oil obtained from cored fruit by centrifugal separation, rats fed unrefined avocado oil obtained by organic solvent extraction from intact fruit, or its unsaponifiable components, showed a significant increase in total liver lipogenesis as well as in phospholipid and triglceride synthesis. Rats fed avocado-seed oil exhibited enhanced [1-14C]acetate incorporation into total liver lipids but showed the same distribution of label in the three main lipid classes as that of rats fed refined avocado oil. In addition, a significant reduction of triglycerides and protein content of plasma very-low-density lipoprotein and high-density lipoprotein fractions was observed in rats fed avocado-seed oil as compared with rats fed refined oil. Electron micrographs suggested that the alterations in hepatic lipogenesis are related to the marked proliferation of the smooth endoplasmic reticulum, which is known to be associated with induction of enzymes involved with lipid biosynthesis. The differences between the animals fed seed oil and those fed the unrefined oils, in the distribution of label within the main lipid classes, indicate that more than one factor is involved in the alterations caused by these oils.

  6. Drug metabolism and genetic polymorphism in subjects with previous halothane hepatitis

    DEFF Research Database (Denmark)

    Ranek, L; Dalhoff, K; Poulsen, H E

    1993-01-01

    To test the hypothesis that halothane hepatitis is caused by a combination of altered drug metabolism and an immunoallergic disposition, the metabolism of antipyrine, metronidazole, sparteine, phenytoin, and racemic R- and S-mephenytoin was investigated in seven subjects with previous halothane...... hepatitis do not appear to be different from controls with regard to drug metabolism and HLA tissue type. The possibility of a higher frequency of complement C3 phenotype F and FS needs further investigation....... hepatitis. The HLA tissue types and the complement C3 phenotypes were also determined. The metabolism of antipyrine and metronidazole was within normal range in all subjects, and they were all fast or extensive metabolizers of sparteine, mephenytoin, and phenytoin. HLA tissue types were unremarkable. Five...

  7. Enantioselective metabolism of hydroxychloroquine employing rats and mice hepatic microsomes

    Directory of Open Access Journals (Sweden)

    Carmem Dickow Cardoso

    2009-12-01

    Full Text Available Hydroxychloroquine (HCQ is an important chiral drug used, mainly, in the treatment of rheumatoid arthritis, systemic lupus erythematosus and malaria, and whose pharmacokinetic and pharmacodynamic properties look to be stereoselective. Respecting the pharmacokinetic properties, some previous studies indicate that the stereoselectivity could express itself in the processes of metabolism, distribution and excretion and that the stereoselective metabolism looks to be a function of the studied species. So, the in vitro metabolism of HCQ was investigated using hepatic microsomes of rats and mice. The microsomal fraction of livers of Wistar rats and Balb-C mice was separated by ultracentrifugation and 500 μL were incubated for 180 minutes with 10 μL of racemic HCQ 1000 μg mL-1. Two stereospecific analytical methods, high performance liquid chromatography (HPLC and capillary electrophoresis (CE, were used to separate and quantify the formed metabolites. It was verified that the main formed metabolite is the (--(R-desethyl hydroxychloroquine for both animal species.A hidroxicloroquina (HCQ é um importante fármaco quiral usado, principalmente, no tratamento de artrite reumatóide, lupus eritematoso sistêmico e malária e cujas propriedades farmacocinéticas e farmacodinâmicas parecem ser estereosseletivas. Em relação às propriedades farmacocinéticas, alguns estudos prévios indicam que a estereosseletividade pode se expressar nos processos de metabolismo, distribuição e excreção e que o metabolismo estereosseletivo parece ser função da espécie estudada. Sendo assim, o metabolismo in vitro da HCQ foi investigado usando microssomas de fígado de ratos e de camundongos. A fração microssômica de fígados de ratos Wistar e de camundongos Balb-C foi isolada por ultracentrifugação e 500 μL foram incubados por 180 minutos com 10 μL de HCQ racêmica 1000 μg mL-1. Dois métodos analíticos estereoespecíficos, por cromatografia líquida de

  8. Comprehensive Analysis of PPARa-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

    NARCIS (Netherlands)

    Rakhshandehroo, M.; Sanderson-Kjellberg, L.M.; Matilainen, M.; Stienstra, R.

    2007-01-01

    PPARa is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARa in hepatic lipid metabolism, many PPARa-dependent pathways and genes have yet to be discovered. In order to obtain an overvi

  9. Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis

    Institute of Scientific and Technical Information of China (English)

    Umbreen Ahmed; Patricia S Latham; Phillip S Oates

    2012-01-01

    The liver is an important site for iron and lipid metabolism and the main site for the interactions between these two metabolic pathways.Although conflicting results have been obtained,most studies support the hypothesis that iron plays a role in hepatic lipogenesis.Iron is an integral part of some enzymes and transporters involved in lipid metabolism and,as such,may exert a direct effect on hepatic lipid load,intrahepatic metabolic pathways and hepatic lipid secretion.On the other hand,iron in its ferrous form may indirectly affect lipid metabolism through its ability to induce oxidative stress and inflammation,a hypothesis which is currently the focus of much research in the field of nonalcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH).The present review will first discuss how iron might directly interact with the metabolism of hepatic lipids and then consider a new perspective on the way in which iron may have a role in the two hit hypothesis for the progression of NAFLD via ferroportin and the iron regulatory molecule hepcidin.The review concludes that iron has important interactions with lipid metabolism in the liver that can impact on the development of NAFLD/NASH.More defined studies are required to improve our understanding of these effects.

  10. Comprehensive Analysis of PPARa-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

    OpenAIRE

    Rakhshandehroo, M.; Sanderson-Kjellberg, L.M.; Matilainen, M.; Stienstra, R.

    2007-01-01

    PPARa is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARa in hepatic lipid metabolism, many PPARa-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARa-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPAR¿ target genes, livers from several animal studies in which PPARa was activated and/or disabled were a...

  11. Comprehensive Analysis of PPARα-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

    OpenAIRE

    Rakhshandehroo, Maryam; Sanderson, Linda M.; Matilainen, Merja; Stienstra, Rinke; Carlberg, Carsten; Philip J de Groot; Müller, Michael; Kersten, Sander

    2007-01-01

    PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were a...

  12. Comprehensive insights into microcystin-LR effects on hepatic lipid metabolism using cross-omics technologies.

    Science.gov (United States)

    Zhang, Zongyao; Zhang, Xu-Xiang; Wu, Bing; Yin, Jinbao; Yu, Yunjiang; Yang, Liuyan

    2016-09-05

    Microcystin-LR (MC-LR) can induce hepatic tissue damages and molecular toxicities, but its effects on lipid metabolism remain unknown. This study investigated the effects of MC-LR exposure on mice lipid metabolism and uncovered the underlying mechanism through metabonomic, transcriptomic and metagenomic analyses after administration of mice with MC-LR by gavage for 28 d. Increased liver weight and abdominal fat weight, and evident hepatic lipid vacuoles accumulation were observed in the mice fed with 0.2mg/kg/d MC-LR. Serum nuclear magnetic resonance analysis showed that MC-LR treatment altered the levels of serum metabolites including triglyceride, unsaturated fatty acid (UFA) and very low density lipoprotein. Digital Gene Expression technology was used to reveal differential expression of hepatic transcriptomes, demonstrating that MC-LR treatment disturbed hepatic UFA biosynthesis and activated peroxisome proliferator-activated receptor (PPAR) signaling pathways via Pparγ, Fabp1 and Fabp2 over-expression. Metagenomic analyses of gut microbiota revealed that MC-LR exposure also increased abundant ratio of Firmicutes vs. Bacteroidetes in gut and altered biosynthetic pathways of various microbial metabolic and pro-inflammatory molecules. In conclusion, oral MC-LR exposure can induce hepatic lipid metabolism disorder mediated by UFA biosynthesis and PPAR activation, and gut microbial community shift may play an important role in the metabolic disturbance.

  13. Comprehensive insights into microcystin-LR effects on hepatic lipid metabolism using cross-omics technologies

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zongyao [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023 (China); Center for Environmental Health Research, South China Institute of Environmental Sciences, The Ministry of Environmental Protection of PRC, Guangzhou 510655 (China); Zhang, Xu-Xiang, E-mail: zhangxx@nju.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023 (China); Wu, Bing; Yin, Jinbao [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023 (China); Yu, Yunjiang [Center for Environmental Health Research, South China Institute of Environmental Sciences, The Ministry of Environmental Protection of PRC, Guangzhou 510655 (China); Yang, Liuyan, E-mail: yangly@nju.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023 (China)

    2016-09-05

    Highlights: • Use of cross-omics technologies to evaluate toxic effects of microcystin-LR. • Disturbance of hepatic lipid metabolism by oral exposure to microcystin-LR. • Crucial roles of gut microbial community shift in the metabolic disturbance induced by microcystin-LR. - Abstract: Microcystin-LR (MC-LR) can induce hepatic tissue damages and molecular toxicities, but its effects on lipid metabolism remain unknown. This study investigated the effects of MC-LR exposure on mice lipid metabolism and uncovered the underlying mechanism through metabonomic, transcriptomic and metagenomic analyses after administration of mice with MC-LR by gavage for 28 d. Increased liver weight and abdominal fat weight, and evident hepatic lipid vacuoles accumulation were observed in the mice fed with 0.2 mg/kg/d MC-LR. Serum nuclear magnetic resonance analysis showed that MC-LR treatment altered the levels of serum metabolites including triglyceride, unsaturated fatty acid (UFA) and very low density lipoprotein. Digital Gene Expression technology was used to reveal differential expression of hepatic transcriptomes, demonstrating that MC-LR treatment disturbed hepatic UFA biosynthesis and activated peroxisome proliferator-activated receptor (PPAR) signaling pathways via Pparγ, Fabp1 and Fabp2 over-expression. Metagenomic analyses of gut microbiota revealed that MC-LR exposure also increased abundant ratio of Firmicutes vs. Bacteroidetes in gut and altered biosynthetic pathways of various microbial metabolic and pro-inflammatory molecules. In conclusion, oral MC-LR exposure can induce hepatic lipid metabolism disorder mediated by UFA biosynthesis and PPAR activation, and gut microbial community shift may play an important role in the metabolic disturbance.

  14. Gender and Species-Mediated Differences in the In Vitro Metabolism of Triadimefon by Rodent Hepatic Microsomes

    Science.gov (United States)

    Understanding how metabolism kinetics differ between genders and species is important in developing informative pharmacokinetic models and accurately assessing risk. Metabolism of the conazole fungicide Triadimefon (TDN) was studied in hepatic microsomes of SD rats and CD-1 mice...

  15. EFFECT OF COLD EXPOSURE AND FASTING ON HEPATIC ACETATE METABOLISM

    Science.gov (United States)

    present investigation the carbohydrate content of the liver was drastically reduced by fasting rats both at 25 C. and 0 C. Acetate oxidation is greatly depressed by the lowering of the hepatic carbohydrate level. (Author)

  16. Dynamical modeling of liver Aquaporin-9 expression and glycerol permeability in hepatic glucose metabolism.

    Science.gov (United States)

    Gena, Patrizia; Buono, Nicoletta Del; D'Abbicco, Marcello; Mastrodonato, Maria; Berardi, Marco; Svelto, Maria; Lopez, Luciano; Calamita, Giuseppe

    2017-01-01

    Liver is crucial in the homeostasis of glycerol, an important metabolic intermediate. Plasma glycerol is imported by hepatocytes mainly through Aquaporin-9 (AQP9), an aquaglyceroporin channel negatively regulated by insulin in rodents. AQP9 is of critical importance in glycerol metabolism since hepatic glycerol utilization is rate-limited at the hepatocyte membrane permeation step. Glycerol kinase catalyzes the initial step for the conversion of the imported glycerol into glycerol-3-phosphate, a major substrate for de novo synthesis of glucose (gluconeogenesis) and/or triacyglycerols (lipogenesis). A model addressing the glucose-insulin system to describe the hepatic glycerol import and metabolism and the correlation with the glucose homeostasis is lacking so far. Here we consider a system of first-order ordinary differential equations delineating the relevance of hepatocyte AQP9 in liver glycerol permeability. Assuming the hepatic glycerol permeability as depending on the protein levels of AQP9, a mathematical function is designed describing the time course of the involvement of AQP9 in mouse hepatic glycerol metabolism in different nutritional states. The resulting theoretical relationship is derived fitting experimental data obtained with murine models at the fed, fasted or re-fed condition. While providing useful insights into the dynamics of liver AQP9 involvement in male rodent glycerol homeostasis our model may be adapted to the human liver serving as an important module of a whole body-model of the glucose metabolism both in health and metabolic diseases. Copyright © 2016 Elsevier GmbH. All rights reserved.

  17. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism

    Science.gov (United States)

    Peterson, Jonathan M.; Seldin, Marcus M.; Wei, Zhikui; Aja, Susan

    2013-01-01

    CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis. PMID:23744740

  18. Contrasting Influence of NADPH and a NADPH-Regenerating System on the Metabolism of Carbonyl-Containing Compounds in Hepatic Microsomes

    Science.gov (United States)

    Carbonyl containing xenobiotics may be susceptible to NADPH-dependent cytochrome P450 (P450) and carbonyl-reduction reactions. In vitro hepatic microsome assays are routinely supplied NADPH either by direct addition of NADPH or via an NADPH-regenerating system (NRS). In contrast ...

  19. Tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) by biocomputation.

    Science.gov (United States)

    Wang, Lin; Huang, Juxiang; Jiang, Minghu; Lin, Hong

    2012-06-01

    We constructed the low-expression tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) compared with high-expression (fold change ≥ 2) human hepatocellular carcinoma in GEO data set, by using integration of gene regulatory network inference method with gene ontology analysis of TSTA3-activated up- and downstream networks. Our results showed TSTA3 upstream-activated CCNB2, CKS1B, ELAVL3, GAS7, NQO1, NTN1, OCRL, PLA2G1B, REG3A, SSTR5, etc. and TSTA3 downstream-activated BAP1, BRCA1, CCL20, MCM2, MS4A2, NTN1, REG1A, TP53I11, VCAN, SLC16A3, etc. in no-tumor hepatitis/cirrhotic tissues. TSTA3-activated network enhanced the regulation of apoptosis, cyclin-dependent protein kinase activity, cell migration, insulin secretion, transcription, cell division, cell proliferation, DNA replication, postreplication repair, cell differentiation, T-cell homeostasis, neutrophil-mediated immunity, neutrophil chemotaxis, interleukin-8 production, inflammatory response, immune response, B-cell activation, humoral immune response, actin filament organization, xenobiotic metabolism, lipid metabolism, phospholipid metabolism, leukotriene biosynthesis, organismal lipid catabolism, phosphatidylcholine metabolism, arachidonic acid secretion, activation of phospholipase A2, deoxyribonucleotide biosynthesis, heterophilic cell adhesion, activation of MAPK activity, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, G-protein-coupled receptor protein signaling pathway, response to toxin, acute-phase response, DNA damage response, intercellular junction assembly, cell communication, and cell recognition, as a result of inducing immune response-mediated metabolism coupling cell cycle to postreplication repair in no-tumor hepatitis/cirrhotic tissues.

  20. Reliance of Host Cholesterol Metabolic Pathways for the Life Cycle of Hepatitis C Virus

    OpenAIRE

    Jin Ye

    2007-01-01

    Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, infects more than 170 million people worldwide and is the leading cause of liver failure in the United States. A unique feature of HCV is that the viral life cycle depends on cholesterol metabolism in host cells. This review summarizes the cholesterol metabolic pathways that are required for the replication, secretion, and entry of HCV. The potential application of drugs that alter host cholesterol...

  1. A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Adeeba Ahmed

    Full Text Available CONTEXT: Non alcoholic fatty liver disease (NAFLD is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH and cirrhosis. The potential role of glucocorticoids (GC in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F from inactive cortisone (E (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR. OBJECTIVE AND METHODS: In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. RESULTS: In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. CONCLUSION: Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11

  2. Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress

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    Yang Chaofeng

    2012-10-01

    Full Text Available Abstract Background Endocrine FGF19 and FGF21 exert their effects on metabolic homeostasis through fibroblast growth factor receptor (FGFR and co-factor betaKlotho (KLB. Ileal FGF19 regulates bile acid metabolism through specifically FGFR4-KLB in hepatocytes where FGFR1 is not significant. Both FGF19 and FGF21 activate FGFR1-KLB whose function predominates in adipocytes. Recent studies using administration of FGF19 and FGF21 and genetic ablation of KLB or adipocyte FGFR1 indicate that FGFR1-KLB mediates the response of adipocytes to both FGF21 and FGF19. Here we show that adipose FGFR1 regulates lipid metabolism through direct effect on adipose tissue and indirect effects on liver under starvation conditions that cause hepatic stress. Methods We employed adipocyte-specific ablations of FGFR1 and FGFR2 genes in mice, and analyzed metabolic consequences in adipose tissue, liver and systemic parameters under normal, fasting and starvation conditions. Results Under normal conditions, the ablation of adipose FGFR1 had little effect on adipocytes, but caused shifts in expression of hepatic genes involved in lipid metabolism. Starvation conditions precipitated a concurrent elevation of serum triglycerides and non-esterified fatty acids, and increased hepatic steatosis and adipose lipolysis in the FGFR1-deficient mice. Little effect on glucose or ketone bodies due to the FGFR1 deficiency was observed. Conclusions Our results suggest an adipocyte-hepatocyte communication network mediated by adipocyte FGFR1 that concurrently dampens hepatic lipogenesis and adipocyte lipolysis. We propose that this serves overall to mete out and extend lipid reserves for neural fuels (glucose and ketone bodies, while at the same time governing extent of hepatosteatosis during metabolic extremes and other conditions causing hepatic stress.

  3. Altered metal metabolism in patients with HCV-related cirrhosis and hepatic encephalopathy.

    Science.gov (United States)

    Marano, Massimo; Vespasiani Gentilucci, Umberto; Altamura, Claudia; Siotto, Mariacristina; Squitti, Rosanna; Bucossi, Serena; Quintiliani, Livia; Migliore, Simone; Greco, Federico; Scarciolla, Laura; Quattrocchi, Carlo Cosimo; Picardi, Antonio; Vernieri, Fabrizio

    2015-12-01

    Dysfunctional metal homeostasis contributes to oxidative stress and neuronal damage. These have been implicated in hepatic encephalopathy pathogenesis. To investigate whether altered metal metabolism is associated with hepatic encephalopathy. Twenty-one controls and 34 HCV-cirrhotic patients (ENC/NEC patients according to presence/absence of previous overt episodes of hepatic encephalopathy) and a control group were studied. Serum iron, copper, ceruloplasmin, ceruloplasmin activity, transferrin, and ceruloplasmin/transferrin ratio were determined. Neuropsychological tests were performed by the repeatable battery of neuropsychological status. Magnetic resonance assessed basal ganglia volumes and metal deposition (pallidal index and T2*). Cirrhotic patients performed worse than controls at cognitive tests, especially ENC patients,. At biochemical analysis copper concentrations, ceruloplasmin activity and transferrin levels were lower in ENC than in NEC patients and controls (p hepatic encephalopathy.

  4. An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle

    Directory of Open Access Journals (Sweden)

    Sara Della Torre

    2016-04-01

    Full Text Available Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα mediates the broad effects of ERα on the hepatic lipid metabolism.

  5. Xenobiotics: Interaction with the Intestinal Microflora.

    Science.gov (United States)

    Lu, Kun; Mahbub, Ridwan; Fox, James G

    2015-01-01

    The human body is host to 100 trillion gut microbes, approximately 10-times more than all human cells. It is estimated that the approximately 500-1000 species residing in the human gut encode 150-fold more unique genes than the human genome. The gut microbiota has important functions in metabolic processing, such as energy production, immune cell development, food digestion, and epithelial homeostasis. It has been increasingly recognized that a dysregulated gut microbiome contributes in a significant way to a variety of diseases, including diabetes, obesity, cardiovascular diseases, allergies, and inflammatory bowel disease. In particular, accumulating evidence indicates that functional interactions between the gut microbiome and xenobiotics play a role in mediating chemical toxicity and causing or exacerbating human disease. This review summarizes emerging evidence that illustrates how xenobiotics can affect the gut microbiome structure, create functional changes to the gut microbiome, and become biotransformed by the gut microbiome.

  6. Quantification of hepatic carbohydrate metabolism in conscious mice using serial blood and urine spots

    NARCIS (Netherlands)

    van Dijk, TH; Boer, TS; Havinga, R; Stellaard, F; Kuipers, F; Reijngoud, DJ

    2003-01-01

    In vivo studies of hepatic carbohydrate metabolism in (genetically modified) conscious mice are hampered by limitations of blood and urine sample sizes. We developed and validated methods to quantify stable isotope dilution and incorporation in small blood and urine samples spotted onto filter paper

  7. Quantification of hepatic carbohydrate metabolism in conscious mice using serial blood and urine spots

    NARCIS (Netherlands)

    van Dijk, TH; Boer, TS; Havinga, R; Stellaard, F; Kuipers, F; Reijngoud, DJ

    2003-01-01

    In vivo studies of hepatic carbohydrate metabolism in (genetically modified) conscious mice are hampered by limitations of blood and urine sample sizes. We developed and validated methods to quantify stable isotope dilution and incorporation in small blood and urine samples spotted onto filter

  8. Xenobiotic transporters: ascribing function from gene knockout and mutation studies.

    Science.gov (United States)

    Klaassen, Curtis D; Lu, Hong

    2008-02-01

    Transporter-mediated absorption, secretion, and reabsorption of chemicals are increasingly recognized as important determinants in the biological activities of many xenobiotics. In recent years, the rapid progress in generating and characterizing mice with targeted deletion of transporters has greatly increased our knowledge of the functions of transporters in the pharmacokinetics/toxicokinetics of xenobiotics. In this introduction, we focus on functions of transporters learned from experiments on knockout mice as well as humans and rodents with natural mutations of these transporters. We limit our discussion to transporters that either directly transport xenobiotics or are important in biliary excretion or cellular defenses, namely multidrug resistance, multidrug resistance-associated proteins, breast cancer resistance protein, organic anion transporting polypeptides, organic anion transporters, organic cation transporters, nucleoside transporters, peptide transporters, bile acid transporters, cholesterol transporters, and phospholipid transporters, as well as metal transporters. Efflux transporters in intestine, liver, kidney, brain, testes, and placenta can efflux xenobiotics out of cells and serve as barriers against the entrance of xenobiotics into cells, whereas many xenobiotics enter the biological system via uptake transporters. The functional importance of a given transporter in each tissue depends on its substrate specificity, expression level, and the presence/absence of other transporters with overlapping substrate preferences. Nevertheless, a transporter may affect a tissue independent of its local expression by altering systemic metabolism. Further studies on the gene regulation and function of transporters, as well as the interrelationship between transporters and phase I/II xenobiotic-metabolizing enzymes, will provide a complete framework for developing novel strategies to protect us from xenobiotic insults.

  9. Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia.

    Science.gov (United States)

    Houin, Satya S; Rozance, Paul J; Brown, Laura D; Hay, William W; Wilkening, Randall B; Thorn, Stephanie R

    2015-02-15

    Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-¹³C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

  10. Metformin and metabolic diseases: a focus on hepatic aspects.

    Science.gov (United States)

    Zheng, Juan; Woo, Shih-Lung; Hu, Xiang; Botchlett, Rachel; Chen, Lulu; Huo, Yuqing; Wu, Chaodong

    2015-06-01

    Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

  11. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    Science.gov (United States)

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1.

  12. Natural sex steroids and their xenobiotic analogs in animal production: growth, carcass quality, pharmacokinetics, metabolism, mode of action, residues, methods, and epidemiology.

    Science.gov (United States)

    Lone, K P

    1997-03-01

    Natural and xenobiotic compounds having sex-related actions have long been used for growth promotion and various changes in carcass quality in meat animals. The first compounds used were synthetic estrogens; however, later on a whole battery of compounds having androgenic, and progestogenic actions have also been involved. In surveying the effects of these compounds in meat-producing animals, it became clear that these drugs increase the growth rate of the treated animals and bring about changes in the carcass that are generally characterized by lower fat content and more lean mass. Extensive studies undertaken in various countries, including the European Economic Community (EEC), have shown that if used according to good husbandry practices, the meat from treated animals does not have excessive amounts of residues compared with the endogenous amount of steroid production in the animals in question and also in human beings. The banning of these compounds in the European community brought a new phenomenon of illegal or black market cocktails. These mixtures of anabolic steroids are injected into the body of the animals rather than implanted in the ears, which is the normal practice in countries where they have not yet been banned. Several screening and confirmatory methods are now available for monitoring programs. However, these programs need excessive resources in terms of manpower, funds, and proper legislation, which in underdeveloped countries is questionable, particularly in the absence of strong scientific evidence for the exercise.

  13. In vitro rat hepatic and intestinal metabolism of the organophosphate pesticides chlorpyrifos and diazinon.

    Science.gov (United States)

    Poet, T S; Wu, H; Kousba, A A; Timchalk, C

    2003-04-01

    Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate (OP) insecticides; their toxicity is mediated through CYP metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYPs also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase (PON1) metabolism of CPF- and DZN-oxon also forms TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in both the activation and detoxification of CPF and DZN in Sprague-Dawley rats. Similar CYP- and PON1-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. The metabolic efficiency was estimated by calculating the psuedo-1st order rate constant from the metabolic constants by dividing Vmax/Km. In enterocyte microsomes, the CYP metabolic efficiency for metabolism to the oxon metabolites was approximately 28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was approximately 2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The Michaelis-Menten rate constant (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes; however, the enterocyte Km for TCP production was higher (indicating a lower affinity). The smaller volume of intestine, lower amount of CYP, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. PON1-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although PON1 affinity for the substrates was comparable in hepatic and enterocytic microsomes, the Vmax were 48- to 275-fold higher, in the liver. These results suggest that intestinal metabolism may impact the metabolism of CPF and DZN, especially following low-dose oral exposures.

  14. Metabolism of Oxycodone in Human Hepatocytes from Different Age Groups and Prediction of Hepatic Plasma Clearance

    Science.gov (United States)

    Korjamo, Timo; Tolonen, Ari; Ranta, Veli-Pekka; Turpeinen, Miia; Kokki, Hannu

    2012-01-01

    Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1, and 10 μM) was incubated with hepatocytes for 4 h, and 1 μM oxycodone also with CYP3A inhibitor ketoconazole (1 μM). Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography–mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. The data suggests that there are no children-specific metabolites of oxycodone. Moreover, CYP3A activity seems to be the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches. PMID:22291644

  15. Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

    Directory of Open Access Journals (Sweden)

    Blanka Kucejova

    2016-07-01

    Full Text Available Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Given that obesity impairs insulin action but paradoxically activates mTORC1, we tested whether insulin action and mammalian target of rapamycin complex 1 (mTORC1 contribute to altered in vivo hepatic mitochondrial metabolism. Loss of hepatic insulin action for 2 weeks caused increased gluconeogenesis, mitochondrial anaplerosis, tricarboxylic acid (TCA cycle oxidation, and ketogenesis. However, activation of mTORC1, induced by the loss of hepatic Tsc1, suppressed these fluxes. Only glycogen synthesis was impaired by both loss of insulin receptor and mTORC1 activation. Mice with a double knockout of the insulin receptor and Tsc1 had larger livers, hyperglycemia, severely impaired glycogen storage, and suppressed ketogenesis, as compared to those with loss of the liver insulin receptor alone. Thus, activation of hepatic mTORC1 opposes the catabolic effects of impaired insulin action under some nutritional states.

  16. Sirtuin 1 Deacetylase: A Key Regulator of Hepatic Lipid Metabolism

    OpenAIRE

    Kemper, Jongsook Kim; Choi, Sunge; Kim, Dong Hyun

    2013-01-01

    Obesity is a serious medical problem worldwide and disruption of metabolic/energy homeostasis plays a pivotal role in this global epidemic. In obese people, fatty liver (steatosis) develops, which increases the risk for diabetes, cardiovascular disease, and even, liver cancer. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that functions as a key metabolic/energy sensor and mediates homeostatic responses to nutrient availability. Accumulating evidence indicates that SIRT1 is a master regul...

  17. Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes.

    Science.gov (United States)

    Gancheva, Sofiya; Bierwagen, Alessandra; Kaul, Kirti; Herder, Christian; Nowotny, Peter; Kahl, Sabine; Giani, Guido; Klueppelholz, Birgit; Knebel, Birgit; Begovatz, Paul; Strassburger, Klaus; Al-Hasani, Hadi; Lundbom, Jesper; Szendroedi, Julia; Roden, Michael

    2016-07-01

    Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.

  18. Combined effect of sesamin and soybean phospholipid on hepatic fatty acid metabolism in rats.

    Science.gov (United States)

    Ide, Takashi

    2014-05-01

    We studied the combined effect of sesamin (1:1 mixture of sesamin and episesamine) and soybean phospholipid on lipid metabolism in rats. Male rats were fed diets supplemented with 0 or 2 g/kg sesamin, and containing 0 or 50 g/kg soybean phospholipid, for 19 days. Sesamin and soybean phospholipid decreased serum triacylglycerol concentrations and the combination of these compounds further decreased the parameter in an additive fashion. Soybean phospholipid but not sesamin reduced the hepatic concentration of triacylglycerol. The combination failed to cause a strong decrease in hepatic triacylglycerol concentration, presumably due to the up-regulation of Cd36 by sesamin. Combination of sesamin and soybean phospholipid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Sesamin strongly increased the parameters of hepatic fatty acid oxidation enzymes. Soybean phospholipid increased hepatic activity of 3-hydroxyacyl-CoA dehydrogenase although it failed to affect the activity of other enzymes involved in fatty acid oxidation. Sesamin strongly increased hepatic concentration of carnitine. Sesamin and soybean phospholipid combination further increased this parameter, accompanying a parallel increase in mRNA expression of carnitine transporter. These changes can account for the strong decrease in serum triacylglycerol in rats fed a diet containing both sesamin and soybean phospholipid.

  19. Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    Science.gov (United States)

    Mailloux, Ryan J; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co

  20. Exposure to a northern contaminant mixture (NCM alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    Directory of Open Access Journals (Sweden)

    Ryan J Mailloux

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with

  1. In Vitro Rat Hepatic and Intestinal Metabolism of the Organophosphate Pesticides Chlorpyrifos and Diazinon

    Energy Technology Data Exchange (ETDEWEB)

    Poet, Torka S.(BATTELLE (PACIFIC NW LAB)); Wu, Hong (BATTELLE (PACIFIC NW LAB)); Kousba, Ahmed A.(BATTELLE (PACIFIC NW LAB)); Timchalk, Charles (Pacific Northwest National Laboratory)

    2003-04-01

    Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate, insecticides; their toxicity is mediated through CYP450 metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYP450s also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase metabolism of CPF- and DZN-oxon also form TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in the first-pass elimination of CPF and DZN. Similar CYP450- and A-esterase-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. In enterocyte microsomes, the CYP450 metabolic efficiency (Vmax/Km) for metabolism to the oxon metabolites was~5-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was~2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The affinity (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes, however the enterocyte Km for TCP production was higher (lower affinity). The smaller volume of intestine, lower amount of CYP450, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. A-esterase-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although A-esterase affinity for the substrates were comparable in hepatic and enterocyte microsomes, the Vmax were 48 - to 275-fold, in the liver. These results suggest that intestinal metabolism may impact first-pass metabolism of CPF and DZN, especially following low-dose oral exposures.

  2. Hepatic methionine homeostasis is conserved in C57BL/6N mice on high-fat diet despite major changes in hepatic one-carbon metabolism.

    Directory of Open Access Journals (Sweden)

    Christoph Dahlhoff

    Full Text Available Obesity is an underlying risk factor in the development of cardiovascular disease, dyslipidemia and non-alcoholic fatty liver disease (NAFLD. Increased hepatic lipid accumulation is a hallmark in the progression of NAFLD and impairments in liver phosphatidylcholine (PC metabolism may be central to the pathogenesis. Hepatic PC biosynthesis, which is linked to the one-carbon (C1 metabolism by phosphatidylethanolamine N-methyltransferase, is known to be important for hepatic lipid export by VLDL particles. Here, we assessed the influence of a high-fat (HF diet and NAFLD status in mice on hepatic methyl-group expenditure and C1-metabolism by analyzing changes in gene expression, protein levels, metabolite concentrations, and nuclear epigenetic processes. In livers from HF diet induced obese mice a significant downregulation of cystathionine β-synthase (CBS and an increased betaine-homocysteine methyltransferase (BHMT expression were observed. Experiments in vitro, using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARα agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-α-amino-n-butyrate concentrations as part of the transsulfuration pathway and reduced hepatic betaine concentrations, but no metabolite changes in the methionine cycle in HF diet fed mice compared to controls. Furthermore, we detected diminished hepatic gene expression of de novo DNA methyltransferase 3b but no effects on hepatic global genomic DNA methylation or hepatic DNA methylation in the Cbs promoter region upon HF diet. Our data suggest that HF diet induces a PPARα-mediated downregulation of key enzymes in the hepatic transsulfuration pathway and upregulates BHMT expression in mice to accommodate to enhanced dietary fat processing while preserving the essential amino acid methionine.

  3. Dietary extra-virgin olive oil and corn oil differentially modulate the mRNA expression of xenobiotic-metabolizing enzymes in the liver and in the mammary gland in a rat chemically induced breast cancer model.

    Science.gov (United States)

    Manzanares, Miguel Á; Solanas, Montserrat; Moral, Raquel; Escrich, Raquel; Vela, Elena; Costa, Irmgard; Escrich, Eduard

    2015-05-01

    High extra-virgin olive oil (EVOO) and corn oil diets differentially modulate experimental mammary carcinogenesis. We have investigated their influence on the initiation stage through the modulation of the expression of xenobiotic-metabolizing enzymes (XMEs) in the liver and the mammary gland. Female Sprague-Dawley rats were fed a low-fat (LF), high corn oil (HCO), or high EVOO (HOO) diet from weaning and gavaged with 7,12-dimethylbenz(a)anthracene (DMBA). The HCO diet increased the mRNA levels of the phase I enzymes CYP1A1, CYP1A2 and, to a lesser extent, CYP1B1, in the liver. The Aryl hydrocarbon receptor (AhR) seemed to be involved in this upregulated CYP1 expression. However, a slight trend toward an increase in the mRNA levels of the phase II enzymes GSTP1 and NQO1 was observed with the HOO diet. At least in the case of GSTP1, this effect was linked to an increased Nrf2 transactivation activity. This different regulation of the XMEs expression led, in the case of the HCO diet, to a balance between the production of active carcinogenic compounds and their inactivation tilted toward phase I, which would stimulate DMBA-induced cancer initiation, whereas the HOO diet was associated with a slower phase I metabolism accompanied by a faster phase II detoxification, thus reducing the output of the active compounds to the target tissues. In the mammary gland, the differential effects of diets may be conditioned by the state of cell differentiation, sexual maturity, and hormone metabolism.

  4. Colostrum yield and piglet growth during lactation are related to gilt metabolic and hepatic status prepartum.

    Science.gov (United States)

    Loisel, F; Farmer, C; Ramaekers, P; Quesnel, H

    2014-07-01

    It was hypothesized that colostrum production could be influenced by sow peripartum endocrine, metabolic, and hepatic status. The plant extract silymarin was shown to influence endocrine and hepatic status in several species. The aims of the present study were to investigate the effects of silymarin intake during late pregnancy on sow hormonal and hepatic status and to determine whether relations exist between sow hepatic and metabolic status during the peripartum period and colostrum yield and piglet performances during lactation. From d 107 of pregnancy until farrowing, nulliparous sows were either fed 12 g/d of silymarin (SIL; n = 15) or no treatment (Control; n = 12). Piglet BW was recorded directly after birth, 24 h after birth of the first piglet, and at 7, 14, and 21 d of lactation. Blood samples were collected from sows on d 107 and 109 of pregnancy, daily from d 111 of pregnancy until d 2 of lactation, and on d 7 and 21 of lactation. They were assayed for endocrine, metabolic, and hepatic variables. Colostrum yield was estimated during 24 h starting at the onset of farrowing. Silymarin did not influence colostrum yield (3.7 ± 0.3 kg) or gross composition (P > 0.10), nor did it affect serum prolactin concentrations or plasma concentrations of progesterone, estradiol-17β, or cortisol (P > 0.10). Mean litter BW gain was lower (P 0.10). Colostrum yield was positively correlated with urea (r = 0.50; P = 0.01) and creatinine (r = 0.43; P = 0.03) concentrations in sows on the day before farrowing. Mean litter BW gain over 2 wk was negatively correlated with concentrations of β-hydroxybutyric acid (r = -0.50; P = 0.01) and γ-GT (r = -0.42; P = 0.03) on the day before farrowing and was positively correlated with urea concentrations on the day before farrowing (r = 0.54; P = 0.01). In conclusion, at the dose of 12 g/d, silymarin did not influence prolactin concentrations or the hepatic status of sows, had no impact on colostrum production, and decreased litter

  5. In vitro metabolic clearance of pyrethroid pesticides by rat and human hepatic microsomes and cytochrome P450 isoforms

    Science.gov (United States)

    Species differences in the intrinsic clearance (CLint) and the enzymes involved in the metabolism of pyrethroid pesticides were examined in rat and human hepatic microsomes. The pyrethroids bifenthrin, S-bioallethrin, bioresmethrin, β-cyfluthrin, cypermethrin, cis-per...

  6. Strain differences in the induction of hepatic microsomal cytochrome P450 and drug-metabolizing enzymes by climbazole in rats

    National Research Council Canada - National Science Library

    Michiya Suzuki; Yasuna Kobayashi; Takashi Sunagawa; Takiko Oguro; Shogo Tokuyama; Toshinori Yamamoto; Takemi Yoshida

    2000-01-01

    .... Climbazole is one of imidazole-ring containing antifungal agents. However, there is not enough data concerned with their effect on hepatic drug metabolizing enzymes with respect to the strain differences...

  7. Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection.

    Science.gov (United States)

    Wong, Robert J; Gish, Robert G

    2016-05-01

    Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality.

  8. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism

    DEFF Research Database (Denmark)

    Feng, Dan; Liu, Tao; Sun, Zheng;

    2011-01-01

    Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when...... HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes...... hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis....

  9. Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing.

    Science.gov (United States)

    Renaud, Helen J; Cui, Yue Julia; Lu, Hong; Zhong, Xiao-bo; Klaassen, Curtis D

    2014-01-01

    The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age). The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5-Day 5 (perinatal-enriched), Day 10-Day 20 (pre-weaning-enriched), and Day 25-Day 60 (adolescence/adulthood-enriched). Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty acids-like 3. These

  10. Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing.

    Directory of Open Access Journals (Sweden)

    Helen J Renaud

    Full Text Available The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age. The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5-Day 5 (perinatal-enriched, Day 10-Day 20 (pre-weaning-enriched, and Day 25-Day 60 (adolescence/adulthood-enriched. Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty

  11. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development.

    Science.gov (United States)

    Mueller, Kristina M; Themanns, Madeleine; Friedbichler, Katrin; Kornfeld, Jan-Wilhelm; Esterbauer, Harald; Tuckermann, Jan P; Moriggl, Richard

    2012-09-25

    Growth hormone (GH) and glucocorticoids (GCs) are involved in the control of processes that are essential for the maintenance of vital body functions including energy supply and growth control. GH and GCs have been well characterized to regulate systemic energy homeostasis, particular during certain conditions of physical stress. However, dysfunctional signaling in both pathways is linked to various metabolic disorders associated with aberrant carbohydrate and lipid metabolism. In liver, GH-dependent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 controls a variety of physiologic functions within hepatocytes. Similarly, GCs, through activation of the glucocorticoid receptor (GR), influence many important liver functions such as gluconeogenesis. Studies in hepatic Stat5 or GR knockout mice have revealed that they similarly control liver function on their target gene level and indeed, the GR functions often as a cofactor of STAT5 for GH-induced genes. Gene sets, which require physical STAT5-GR interaction, include those controlling body growth and maturation. More recently, it has become evident that impairment of GH-STAT5 signaling in different experimental models correlates with metabolic liver disease, ranging from hepatic steatosis to hepatocellular carcinoma (HCC). While GH-activated STAT5 has a protective role in chronic liver disease, experimental disruption of GC-GR signaling rather seems to ameliorate metabolic disorders under metabolic challenge. In this review, we focus on the current knowledge about hepatic GH-STAT5 and GC-GR signaling in body growth, metabolism, and protection from fatty liver disease and HCC development.

  12. Individual effects of different selenocompounds on the hepatic proteome and energy metabolism of mice.

    Science.gov (United States)

    Lennicke, Claudia; Rahn, Jette; Kipp, Anna P; Dojčinović, Biljana P; Müller, Andreas S; Wessjohann, Ludger A; Lichtenfels, Rudolf; Seliger, Barbara

    2017-01-01

    Selenium (Se) exerts its biological activity largely via selenoproteins, which are key enzymes for maintaining the cellular redox homeostasis. However, besides these beneficial effects there is also evidence that an oversupply of Se might increase the risk towards developing metabolic disorders. To address this in more detail, we directly compared effects of feeding distinct Se compounds and concentrations on hepatic metabolism and expression profiles of mice. Male C57BL6/J mice received either a selenium-deficient diet or diets enriched with adequate or high doses of selenite, selenate or selenomethionine for 20weeks. Subsequently, metabolic parameters, enzymatic activities and expression levels of hepatic selenoproteins, Nrf2 targets, and additional redox-sensitive proteins were analyzed. Furthermore, 2D-DIGE-based proteomic profiling revealed Se compound-specific differentially expressed proteins. Whereas heterogeneous effects between high concentrations of the Se compounds were observed with regard to body weight and metabolic activities, selenoproteins were only marginally increased by high Se concentrations in comparison to the respective adequate feeding. In particular the high-SeMet group showed a unique response compromising higher hepatic Se levels in comparison to all other groups. Accordingly, hepatic glutathione (GSH) levels, glutathione S-transferase (GST) activity, and GSTpi1 expression were comparably high in the high-SeMet and Se-deficient group, indicating that compound-specific effects of high doses appear to be independent of selenoproteins. Not only the nature, but also the concentration of Se compounds differentially affect biological processes. Thus, it is important to consider Se compound-specific effects when supplementing with selenium. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Combined effect of sesamin and soybean phospholipid on hepatic fatty acid metabolism in rats

    OpenAIRE

    Ide, Takashi

    2014-01-01

    We studied the combined effect of sesamin (1:1 mixture of sesamin and episesamine) and soybean phospholipid on lipid metabolism in rats. Male rats were fed diets supplemented with 0 or 2 g/kg sesamin, and containing 0 or 50 g/kg soybean phospholipid, for 19 days. Sesamin and soybean phospholipid decreased serum triacylglycerol concentrations and the combination of these compounds further decreased the parameter in an additive fashion. Soybean phospholipid but not sesamin reduced the hepatic c...

  14. Kinetics of glyburide metabolism by hepatic and placental microsomes of human and baboon.

    Science.gov (United States)

    Zharikova, Olga L; Ravindran, Selvan; Nanovskaya, Tatiana N; Hill, Ronald A; Hankins, Gary D V; Ahmed, Mahmoud S

    2007-06-15

    Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent K(m) values between 4 and 12 microM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36% of total), formed by human hepatic microsomes with V(max) of 80+/-13 pmol mg protein(-1)min(-1), and together with M2, accounted for only 51% of the total. M5 was the major metabolite (87%) formed by human placental microsomes with V(max) of 11 pmol mg protein(-1)min(-1). In baboon liver, M5 had the highest rate of formation (V(max) 135+/-32 pmol mg protein(-1)min(-1), 39% of total), and in its placenta, was M4 (V(max) 0.7+/-0.1 pmol mg protein(-1)min(-1), 65%). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7% and 0.3% of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.

  15. Hepatitis C eradication with sofosbuvir leads to significant metabolic changes

    Science.gov (United States)

    Morales, Amilcar L; Junga, Zachary; Singla, Manish B; Sjogren, Maria; Torres, Dawn

    2016-01-01

    AIM To assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control. METHODS This is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis. RESULTS Two hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684). CONCLUSION Eradication of HCV with a

  16. Metabolic profile of mephedrone: Identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites.

    Science.gov (United States)

    Linhart, Igor; Himl, Michal; Židková, Monika; Balíková, Marie; Lhotková, Eva; Páleníček, Tomáš

    2016-01-01

    Metabolic profile of mephedrone (4-methylmethcathinone, 4-MMC), a frequently abused recreational drug, was determined in rats in vivo. The urine of rats dosed with a subcutaneous bolus dose of 20mg 4-MMC/kg was analysed by LC/MS. Ten phase I and five phase II metabolites were identified by comparison of their retention times and MS(2) spectra with those of authentic reference standards and/or with the MS(2) spectra of previously identified metabolites. The main metabolic pathway was N-demethylation leading to normephedrone (4-methylcathinone, 4-MC) which was further conjugated with succinic, glutaric and adipic acid. Other phase I metabolic pathways included oxidation of the 4-methyl group, carbonyl reduction leading to dihydro-metabolites and ω-oxidation at the position 3'. Five of the metabolites detected, namely, 4-carboxynormephedrone (4-carboxycathinone, 4-CC), 4-carboxydihydronormephedrone (4-carboxynorephedrine, 4-CNE), hydroxytolyldihydro-normephedrone (4-hydroxymethylnorephedrine, 4-OH-MNE) and conjugates of 4-MC with glutaric and adipic acid, have not been reported as yet. The last two conjugates represent a novel, hitherto unexploited, type of phase II metabolites in mammals together with an analogous succinic acid conjugate of 4-MC identified by Pozo et al. (2015). These conjugates might be potentially of great importance in the metabolism of other psychoactive amines.

  17. Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake

    DEFF Research Database (Denmark)

    Dam, Gitte; Keiding, Susanne; Munk, Ole L

    2013-01-01

    Studies have shown decreased cerebral oxygen metabolism (CMRO(2)) and blood flow (CBF) in patients with cirrhosis with hepatic encephalopathy (HE). It remains unclear, however, whether these disturbances are associated with HE or with cirrhosis itself and how they may relate to arterial blood...... ammonia concentration and cerebral metabolic rate of blood ammonia (CMRA). We addressed these questions in a paired study design by investigating patients with cirrhosis during and after recovery from an acute episode of HE type C. CMRO(2), CBF, and CMRA were measured by dynamic positron emission...

  18. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

    Science.gov (United States)

    Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M.; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N.

    2014-01-01

    The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level. PMID:25082895

  19. Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism.

    Science.gov (United States)

    Liu, Qingqing; Yuan, Bingbing; Lo, Kinyui Alice; Patterson, Heide Christine; Sun, Yutong; Lodish, Harvey F

    2012-09-04

    The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO mice fed a chow diet exhibited decreased mRNA expression of rate-limiting enzymes in several important glucose and lipid metabolic pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid activation and synthesis, triglyceride synthesis, and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weight compared with WT mice. When fed a high-fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the liver. These lipogenic defects are consistent with the down-regulation of lipogenic genes in the KO mice.

  20. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    Science.gov (United States)

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens.

  1. Xenobiotic biotransformation in livestock: comparison to other species commonly used in toxicity testing.

    Science.gov (United States)

    Watkins, J B; Klaassen, C D

    1986-09-01

    Wildlife, domesticated animals and humans are exposed daily to myriad chemicals present in our environment. The risk posed by these chemicals to one species is often determined by extrapolation from data gathered from another species. Several extensive studies have examined the capability of the liver to biotransform xenobiotics in animals commonly used in toxicity testing and in livestock. The present paper is a compilation of these data into a single source to permit comprehensive examination of inter-species variation in rates of hepatic biotransformation. Several substrates were studied for each enzyme system, including cytochrome P-450-dependent monooxygenases, epoxide hydrolases, UDP-glucuronosyltransferases, N-acetyltransferases, glutathione S-transferases and sulfotransferases. The numerous differences in substrate specificity for an individual enzymatic pathway reflect the apparent multiplicity of these enzymes in all 11 species studied. Several hundred- to several thousand-fold differences between species in enzymatic activities for certain substrates under well-defined conditions emphasize the need for caution and the risk of error in extrapolation of xenobiotic metabolism from one species to another. In spite of these uncertainties, knowledge of the rate of biotransformation may help us predict the fate of new chemicals in various species.

  2. Evaluation of hepatic glucose metabolism via gluconeogenesis and glycogenolysis after oral administration of insulin nanoparticles.

    Science.gov (United States)

    Woitiski, Camile B; Neufeld, Ronald J; Soares, Ana F; Figueiredo, Isabel V; Veiga, Francisco J; Carvalho, Rui A

    2012-12-01

    Nanoparticles were designed to promote insulin intestinal absorption via the oral route, to increase portal insulin levels to better mimic the physiological pathway, providing enhanced glucose control through glycogenolysis and gluconeogenesis. Nanoparticles were formulated with insulin encapsulated in the core material consisting of alginate and dextran sulfate, associated with poloxamer and subsequently coated with chitosan then albumin. A spherical and slightly rough core was observed in electron micrographs with the appearance of a concentration gradient of the polysaccharide structure toward the periphery of the nanoparticle. Atomic force microscopy showed that the fully formed nanoparticles are about 200 nm in diameter with smooth and spherical morphology. Histopathological analysis of organs and tissues of diabetic rats dosed daily for 15 days with insulin nanoparticles was used to evaluate toxicological issues. No morphological or pathological alterations were observed in rat liver, spleen, pancreas, kidney or intestinal sections. Following, the effect of nanoencapsulated insulin on inhibiting hepatic gluconeogenesis was evaluated after a single insulin administration and oral glucose tolerance test, which represents a significant metabolic challenge to the liver. Alterations in the hepatic glucose metabolism of fasted streptozotocin-diabetic rats were determined by the percent contribution of glycogenolysis and gluconeogenesis, measured by using metabolic tracers, however similar gluconeogenesis contribution to the hepatic metabolism was observed between diabetic rats receiving nanoencapsulated insulin or insulin solution. The metabolic results may be explained by the inability of a single dose in shifting the gluconeogenesis/glycogenolysis contributions, sampling time, fasting period or by influence of the kidney enzymes and impairment in insulin signaling observed in stz-diabetic rats.

  3. Flavin-containing monooxygenase-mediated metabolism of N-deacetyl ketoconazole by rat hepatic microsomes.

    Science.gov (United States)

    Rodriguez, R J; Proteau, P J; Marquez, B L; Hetherington, C L; Buckholz, C J; O'Connell, K L

    1999-08-01

    Although ketoconazole is extensively metabolized by hepatic microsomal enzymes, the route of formation and toxicity of suspected metabolites are largely unknown. Reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite in mice. DAK may be susceptible to successive oxidative attacks on the N-1 position by flavin-containing monooxygenases (FMO) producing potentially toxic metabolites. Previous laboratory findings have demonstrated that postnatal rat hepatic microsomes metabolize DAK by NADPH-dependent monooxygenases to two metabolites as determined by HPLC. Our current investigation evaluated DAK's metabolism in adult male and female rats and identified metabolites that may be responsible for ketoconazole's hepatotoxicity. DAK was extensively metabolized by rat liver microsomal monooxygenases at pH 8.8 in pyrophosphate buffer containing the glucose 6-phosphate NADPH-generating system to three metabolites as determined by HPLC. The initial metabolite of DAK was a secondary hydroxylamine, N-deacetyl-N-hydroxyketoconazole, which was confirmed by liquid chromatography/mass spectrometry and NMR spectroscopy. Extensive metabolism of DAK occurred at pH 8.8 in pyrophosphate buffer (female 29% and male 53% at 0.25 h; female 55% and male 57% at 0.5 h; and female 62% and male 66% at 1.0 h). Significantly less metabolism of DAK occurred at pH 7.4 in phosphate buffer (female 11%, male 17% at 0.25 h; female 20%, male 31% at 0.5 h; and female 27%, male 37% at 1 h). Heat inactivation of microsomal-FMO abolished the formation of these metabolites from DAK. SKF-525A did not inhibit this reaction. These results suggest that DAK appears to be extensively metabolized by adult FMO-mediated monooxygenation.

  4. Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

    Directory of Open Access Journals (Sweden)

    Hong Lu

    2016-09-01

    Full Text Available The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs, lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4α. However, the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α, and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.

  5. Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents.

    Science.gov (United States)

    Cooper, Arthur J L; Krasnikov, Boris F; Niatsetskaya, Zoya V; Pinto, John T; Callery, Patrick S; Villar, Maria T; Artigues, Antonio; Bruschi, Sam A

    2011-06-01

    Cysteine S-conjugate β-lyases are pyridoxal 5'-phosphate-containing enzymes that catalyze β-elimination reactions with cysteine S-conjugates that possess a good leaving group in the β-position. The end products are aminoacrylate and a sulfur-containing fragment. The aminoacrylate tautomerizes and hydrolyzes to pyruvate and ammonia. The mammalian cysteine S-conjugate β-lyases thus far identified are enzymes involved in amino acid metabolism that catalyze β-lyase reactions as non-physiological side reactions. Most are aminotransferases. In some cases the lyase is inactivated by reaction products. The cysteine S-conjugate β-lyases are of much interest to toxicologists because they play an important key role in the bioactivation (toxication) of halogenated alkenes, some of which are produced on an industrial scale and are environmental contaminants. The cysteine S-conjugate β-lyases have been reviewed in this journal previously (Cooper and Pinto in Amino Acids 30:1-15, 2006). Here, we focus on more recent findings regarding: (1) the identification of enzymes associated with high-M(r) cysteine S-conjugate β-lyases in the cytosolic and mitochondrial fractions of rat liver and kidney; (2) the mechanism of syncatalytic inactivation of rat liver mitochondrial aspartate aminotransferase by the nephrotoxic β-lyase substrate S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (the cysteine S-conjugate of tetrafluoroethylene); (3) toxicant channeling of reactive fragments from the active site of mitochondrial aspartate aminotransferase to susceptible proteins in the mitochondria; (4) the involvement of cysteine S-conjugate β-lyases in the metabolism/bioactivation of drugs and natural products; and (5) the role of cysteine S-conjugate β-lyases in the metabolism of selenocysteine Se-conjugates. This review emphasizes the fact that the cysteine S-conjugate β-lyases are biologically more important than hitherto appreciated.

  6. Tryptophan-Kynurenine Metabolism and Insulin Resistance in Hepatitis C Patients

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    G. F. Oxenkrug

    2013-01-01

    Full Text Available Chronic hepatitis C virus (HCV infection is associated with 50% incidence of insulin resistance (IR that is fourfold higher than that in non-HCV population. IR impairs the outcome of antiviral treatment. The molecular mechanisms of IR in HCV are not entirely clear. Experimental and clinical data suggested that hepatitis C virus per se is diabetogenic. However, presence of HCV alone does not affect IR. It was proposed that IR is mediated by proinflammatory cytokines, mainly by TNF-alpha. TNF-alpha potentiates interferon-gamma-induced transcriptional activation of indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan- (TRP- kynurenine (KYN metabolism. Upregulation of TRP-KYN metabolism was reported in HCV patients. KYN and some of its derivatives affect insulin signaling pathways. We hypothesized that upregulation of TRP-KYN metabolism might contribute to the development of IR in HCV. To check this suggestion, we evaluated serum concentrations of TRP and KYN and HOMA-IR and HOMA-beta in 60 chronic HCV patients considered for the treatment with IFN-alpha. KYN and TRP concentrations correlated with HOMA-IR and HOMA-beta scores. Our data suggest the involvement of KYN and its metabolites in the development of IR in HCV patients. TRP-KYN metabolism might be a new target for prevention and treatment of IR in HCV patients.

  7. Dietary Conjugated Linoleic Acid and Hepatic Steatosis: Species-Specific Effects on Liver and Adipose Lipid Metabolism and Gene Expression

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    Diwakar Vyas

    2012-01-01

    Full Text Available Objective. To summarize the recent studies on effect of conjugated linoleic acid (CLA on hepatic steatosis and hepatic and adipose lipid metabolism highlighting the potential regulatory mechanisms. Methods. Sixty-four published experiments were summarized in which trans-10, cis-12 CLA was fed either alone or in combination with other CLA isomers to mice, rats, hamsters, and humans were compared. Summary and Conclusions. Dietary trans-10, cis-12 CLA induces a severe hepatic steatosis in mice with a more muted response in other species. Regardless of species, when hepatic steatosis was present, a concurrent decrease in body adiposity was observed, suggesting that hepatic lipid accumulation is a result of uptake of mobilized fatty acids (FA from adipose tissue and the liver's inability to sufficiently increase FA oxidation and export of synthesized triglycerides. The potential role of liver FA composition, insulin secretion and sensitivity, adipokine, and inflammatory responses are discussed as potential mechanisms behind CLA-induced hepatic steatosis.

  8. Hyperoxia exposure alters hepatic eicosanoid metabolism in newborn mice.

    Science.gov (United States)

    Rogers, Lynette K; Tipple, Trent E; Britt, Rodney D; Welty, Stephen E

    2010-02-01

    Prematurely born infants are often treated with supraphysiologic amounts of oxygen, which is associated with lung injury and the development of diseases such as bronchopulmonary dysplasia. Complimentary responses between the lung and liver during the course of hyperoxic lung injury have been studied in adult animals, but little is known about this relationship in neonates. These studies tested the hypothesis that oxidant stress occurs in the livers of newborn mice in response to continuous hyperoxia exposure. Greater levels of glutathione disulfide and nitrotyrosine were detected in lung tissues but not liver tissues from newborn mice exposed to hyperoxia than in room air-exposed controls. However, early increases in 5-lipoxygenase and cyclooxygenases-2 protein levels and increases in total hydroxyeicosatetraenoic acid and prostaglandin levels were observed in the liver tissues of hyperoxia-exposed pups. These studies indicate that free radical oxidation occurs in the lungs of newborn pups exposed to hyperoxia, and alterations in lipid metabolism could be a primary response in the liver tissues. The findings of this study identify possible new mechanisms associated with hyperoxic lung injury in a newborn model of bronchopulmonary dysplasia and thus open opportunities for research.

  9. Hyperoxia Exposure Alters Hepatic Eicosanoid Metabolism in Newborn Mice

    Science.gov (United States)

    ROGERS, LYNETTE K.; TIPPLE, TRENT E.; BRITT, RODNEY D.; WELTY, STEPHEN E.

    2013-01-01

    Prematurely born infants are often treated with supraphysiologic amounts of oxygen, which is associated with lung injury and the development of diseases such as bronchopulmonary dysplasia. Complimentary responses between the lung and liver during the course of hyperoxic lung injury have been studied in adult animals, but little is known about this relationship in neonates. These studies tested the hypothesis that oxidant stress occurs in the livers of newborn mice in response to continuous hyperoxia exposure. Greater levels of glutathione disulfide and nitrotyrosine were detected in lung tissues but not liver tissues from newborn mice exposed to hyperoxia than in room air-exposed controls. However, early increases in 5-lipoxygenase and cyclooxygenases-2 protein levels and increases in total hydroxyeicosatetraenoic acid and prostaglandin levels were observed in the liver tissues of hyperoxia-exposed pups. These studies indicate that free radical oxidation occurs in the lungs of newborn pups exposed to hyperoxia, and alterations in lipid metabolism could be a primary response in the liver tissues. The findings of this study identify possible new mechanisms associated with hyperoxic lung injury in a newborn model of bronchopulmonary dysplasia and thus open opportunities for research. PMID:19809377

  10. Effects of phenoxyherbicides and glyphosate on the hepatic and intestinal biotransformation activities in the rat.

    Science.gov (United States)

    Hietanen, E; Linnainmaa, K; Vainio, H

    1983-08-01

    The effects of phenoxyacid herbicides 2,4-D (2,4-dichlorophenoxyacetic acid) and MCPA (4-chloro-2-methylphenoxyacetic acid), clofibrate, and glyphosate on hepatic and intestinal drug metabolizing enzyme activities were studied in rats intragastrically exposed for 2 weeks. The hepatic ethoxycoumarin O-deethylase activity increased about 2-fold with MCPA. Both 2,4-D and MCPA increased the hepatic epoxide hydrolase activity and decreased the hepatic glutathione S-transferase activity. MCPA also increased the intestinal activities of ethoxycoumarin O-deethylase and epoxide hydrolase. Glyphosate decreased the hepatic level of cytochrome P-450 and monooxygenase activities and the intestinal activity of aryl hydrocarbon hydroxylase. Clofibrate decreased the hepatic activities of UDPglucuronosyltransferase with p-nitrophenol or methylumbelliferone as the substrate. Also 2,4-D decreased the hepatic activity of UDPglucuronosyltransferase with p-nitrophenol as the substrate. MCPA decreased the intestinal activities of UDPglucuronosyltransferase with either p-nitrophenol or methylumbelliferone as the substrate. The results indicate that phenoxyacetic acids, especially MCPA, may have potent effects on the metabolism of xenobiotics. Glyphosate, not chemically related to phenoxyacids, seems to inhibit monooxygenases. Whether these changes are related to the toxicity of these xenobiotics remains to be clarified in further experiments.

  11. Antioxidant and Antimutagenic Metabolites in Animals with Opposite Sensitivity to Tuberculosis Mycobacteria and Mutagenic Xenobiotics.

    Science.gov (United States)

    Pavlov, V A; Kotomtsev, V V; Doronin, A I; Sabadash, E V

    2016-11-01

    Different sensitivity of guinea pigs and rats to Mycobacterium tuberculosis and membranotropic mutagenic xenobiotics is associated with differences in the metabolism of amino acid precursors of phospholipids. In turn, specific features of phospholipid metabolism are determined by differences in the level of sulfur-containing regulatory metabolites (methionine, taurine, and glutathione) in tissues. Taurine and methionine increase organism's resistance to Mycobacterium tuberculosis (typical of rats), glutathione and its constituent amino acids improve resistance to the mutagenic effects of xenobiotics (typical of guinea pigs). These metabolites can be used for strengthening of natural resistance to tuberculosis and mutagenic and carcinogenic xenobiotics.

  12. FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action.

    Science.gov (United States)

    Shin, Dong-Ju; Osborne, Timothy F

    2009-04-24

    The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7alpha hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.

  13. Glucose absorption, hormonal release and hepatic metabolism after guar gum ingestion

    Science.gov (United States)

    Simoes Nunes, C.; Malmlof, K.

    1992-01-01

    Six non-anaesthetized Large White pigs (mean body weight 59 +/- 1.7 kg) were fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein and with electromagnetic flow probes around the portal vein and the hepatic artery. The animals were provided a basal none-fibre diet (diet A) alone or together with 6% guar gum (diet B) or 15% purified cellulose (diet C). The diets were given for 1 week and according to a replicated 3 x 3 latin-square design. On the last day of each adaptation period test meals of 800 g were given prior to blood sampling. The sampling was continued for 8 h. Guar gum strongly reduced the glucose absorption as well as the insulin, gastric inhibitory polypeptide (GIP) and insulin-like growth factor-1 (IGF-1) production. However, the reduction in peripheral blood insulin levels caused by guar gum was not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly produced by the gut. The liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut produced IGF-1. Guar gum ingestion also appeared to decrease pancreatic glucagon secretion. Cellulose at the level consumed had very little effect on the parameters considered. It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the latter internal metabolic effects.

  14. Metabolism of 17alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons.

    Science.gov (United States)

    Yan, Ru; Nanovskaya, Tatiana N; Zharikova, Olga L; Mattison, Donald R; Hankins, Gary D V; Ahmed, Mahmoud S

    2008-05-01

    Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone caproate (17-HPC), used for treatment of preterm deliveries, during its perfusion across the dually perfused human placental lobule. Previously, we demonstrated that the drug is not hydrolyzed, neither in vivo nor in vitro, to progesterone and caproate. Therefore, the hypothesis for this investigation is that 17-HPC is actively metabolized by human and baboon (Papio cynocephalus) hepatic and placental microsomes. Baboon hepatic and placental microsomes were investigated to validate the nonhuman primate as an animal model for drug use during pregnancy. Data presented here indicate that human and baboon hepatic microsomes formed several mono-, di-, and tri-hydroxylated derivatives of 17-HPC. However, microsomes of human and baboon placentas metabolized 17-HPC to its mono-hydroxylated derivatives only in quantities that were a fraction of those formed by their respective livers, except for two metabolites (M16' and M17') that are unique for placenta and contributed to 25% and 75% of the total metabolites formed by human and baboon, respectively. The amounts of metabolites formed, relative to each other, by human and baboon microsomes were different suggesting that the affinity of 17-HPC to CYP enzymes and their activity could be species-dependent.

  15. Molecular mechanism of hepatitis C virus-induced glucose metabolic disorders

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    Ikuo eShoji

    2012-01-01

    Full Text Available Hepatitis C virus (HCV infection causes not only intrahepatic diseases but also extrahepatic manifestations, including metabolic disorders. Chronic HCV infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Glucose is transported into hepatocytes via glucose transporter 2 (GLUT2. Hepatocytes play a crucial role in maintaining plasma glucose homeostasis via the gluconeogenic and glycolytic pathways. We have been investigating the molecular mechanism of HCV-related type 2 diabetes using HCV RNA replicon cells and HCV J6/JFH1 system. We found that HCV replication down-regulates cell surface expression of GLUT2 at the transcriptional level. We also found that HCV infection promotes hepatic gluconeogenesis in HCV J6/JFH1-infected Huh-7.5 cells. HCV infection transcriptionally up-regulated the genes for PEPCK and G6Pase, the rate-limiting enzymes for hepatic gluconeogenesis. Gene expression of PEPCK and G6Pase was regulated by the transcription factor forkhead box O1 (FoxO1 in HCV-infected cells. Phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells, resulting in increased nuclear accumulation of FoxO1. HCV NS5A protein was directly linked with the FoxO1-dependent increased gluconeogenesis. This paper will discuss the current model of HCV-induced glucose metabolic disorders.

  16. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice

    Science.gov (United States)

    Sala-Vila, Aleix; Navarro-Lérida, Inmaculada; Sánchez-Alvarez, Miguel; Bosch, Marta; Calvo, Carlos; López, Juan Antonio; Calvo, Enrique; Ferguson, Charles; Giacomello, Marta; Serafini, Annalisa; Scorrano, Luca; Enriquez, José Antonio; Balsinde, Jesús; Parton, Robert G.; Vázquez, Jesús; Pol, Albert; Del Pozo, Miguel A.

    2016-01-01

    The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed. PMID:27272971

  17. Comprehensive Analysis of PPARα-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

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    Maryam Rakhshandehroo

    2007-01-01

    Full Text Available PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip, electron-transferring-flavoprotein β polypeptide (Etfb, electron-transferring-flavoprotein dehydrogenase (Etfdh, phosphatidylcholine transfer protein (Pctp, endothelial lipase (EL, Lipg, adipose triglyceride lipase (Pnpla2, hormone-sensitive lipase (HSL, Lipe, and monoglyceride lipase (Mgll. Using an in silico screening approach, one or more PPAR response elements (PPREs were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver.

  18. Comprehensive Analysis of PPARα-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

    Science.gov (United States)

    Rakhshandehroo, Maryam; Sanderson, Linda M.; Matilainen, Merja; Stienstra, Rinke; Carlberg, Carsten; de Groot, Philip J.; Müller, Michael; Kersten, Sander

    2007-01-01

    PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver. PMID:18288265

  19. Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling.

    Science.gov (United States)

    Rakhshandehroo, Maryam; Sanderson, Linda M; Matilainen, Merja; Stienstra, Rinke; Carlberg, Carsten; de Groot, Philip J; Müller, Michael; Kersten, Sander

    2007-01-01

    PPARalpha is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARalpha in hepatic lipid metabolism, many PPARalpha-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARalpha-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARalpha target genes, livers from several animal studies in which PPARalpha was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARalpha-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARalpha-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein beta polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARalpha agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARalpha. Our study illustrates the power of transcriptional profiling to uncover novel PPARalpha-regulated genes and pathways in liver.

  20. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    Science.gov (United States)

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.

  1. Increasing Physical Activity Decreases Hepatic Fat and Metabolic Risk Factors.

    Science.gov (United States)

    Alderete, Tanya L; Gyllenhammer, Lauren E; Byrd-Williams, Courtney E; Spruijt-Metz, Donna; Goran, Michael I; Davis, Jaimie N

    2012-04-01

    This study assessed the changes in time spent in moderate to vigorous physical activity (MVPA) on fat depots, insulin action, and inflammation. Longitudinal data were generated from 66 Hispanic adolescents (15.6±1.1 yr; BMI percentile 97.1±3.0) who participated in a 16-wk nutrition or nutrition+exercise intervention. There were no effects of the intervention on PA, but there were inter-individual changes in PA. For purposes of this analysis, all intervention groups were combined to assess how changes in PA during 16 wk affected changes in adiposity, insulin action, and markers of inflammation. MVPA was assessed by 7-day accelerometry, total body fat via DXA, liver fat by MRI, and insulin, glucose and HOMA-IR via a fasting blood draw. A repeated measures ANCOVA was used to assess the effect of MVPA on fat depots, insulin action, and inflammatory markers. Sixty-two percent of participants increased MVPA (mean increase, 19.7±16.5 min/day) and 38% decreased MVPA (mean decrease, 10.7±10.1 min/day). Those who increased MVPA by as little as 20 min per day over 16 wk, compared to those who decreased MVPA, had significant reductions in liver fat (-13% vs. +3%; P=0.01), leptin levels (-18% vs. +4%; P=0.02), and fasting insulin (-23% vs. +5%; P=0.05). These findings indicate that a modest increase in MVPA can improve metabolic health in sedentary overweight Hispanic adolescents.

  2. Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors

    Energy Technology Data Exchange (ETDEWEB)

    Glahn, Felix; Wiese, Jan; Foth, Heidi [Martin-Luther-University, Halle-Wittenberg, Institute of Environmental Toxicology, Halle/Saale (Germany); Schmidt-Heck, Wolfgang; Guthke, Reinhard [Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena (Germany); Zellmer, Sebastian; Gebhardt, Rolf [University of Leipzig, Institute of Biochemistry, Medical Faculty, Leipzig (Germany); Golka, Klaus; Degen, Gisela H.; Hermes, Matthias; Schormann, Wiebke; Brulport, Marc; Bauer, Alexander; Bedawy, Essam [IfADo, Leibniz Research Centre for Working Environment and Human Factors, Dortmund (Germany); Hergenroeder, Roland [ISAS, Institute for Analytical Sciences, Dortmund (Germany); Lehmann, Thomas [Translational Centre for Regenerative Medicine, Leipzig (Germany); Hengstler, Jan G. [IfADo, Leibniz Research Centre for Working Environment and Human Factors, Dortmund (Germany)

    2008-08-15

    Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15{mu}g/l Cd(II), 25{mu}g/l Co(II) and 550{mu}g/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes. (orig.)

  3. A preliminary investigation demonstrating the effect of quercetin on the expression of genes related to cell-cycle arrest, apoptosis and xenobiotic metabolism in human CO115 colon-adenocarcinoma cells using DNA microarray.

    Science.gov (United States)

    Murtaza, Imtiyaz; Marra, Giancarlo; Schlapbach, Ralph; Patrignani, Andrea; Künzli, Marzana; Wagner, Ulrich; Sabates, Jacob; Dutt, Amit

    2006-07-01

    The role of the natural dietary flavonoid chemical quercetin (an antioxidant) in the prevention and treatment of colon cancer is receiving a great deal of attention. However, little is known about the molecular mechanisms of action of this flavonoid. In the present study, whole genome DNA microarrays were used to evaluate the effect of quercetin on gene expression in the CO115 colon-adenocarcinoma cell line with the completely deleted chromosome 18 harbouring the SMAD4 tumour-suppressor gene related to colon carcinogenesis. The study demonstrated that quercetin, widely present in fruit and vegetables, inhibited the growth of CO115 cells at 100 microM concentration in both the G(1)/S and the G(2)/M phases by modulating cell-cycle and apoptosis-related genes. Differential changes in accumulation of transcripts analysed for cells treated with 100 microM quercetin for 24 and 48 h in three independent repeated experiments revealed 5060-7000 differentially expressed genes. This means that quercetin probably does have a broad modulatory effect on gene expression in colon cancer. Out of these differentially expressed genes, the expression of 35 and 23 unique set of genes involved in cell-cycle control, apoptosis and xenobiotic metabolism were significantly altered after 24 and 48 h quercetin treatment respectively. Our results represent a novel aspect of the biological profile of quercetin that induces cell-cycle arrest through modulation of cell-cycle-related and apoptosis genes. The present study demonstrates a new step in elucidating the underlying molecular mechanisms of the antitumour action of quercetin, which could become a chemopreventive or chemotherapeutic agent for colon cancer.

  4. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism.

    Directory of Open Access Journals (Sweden)

    Yinfang Wang

    Full Text Available Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2 is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2 potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL/Very-Low-density (VLDL lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl amino-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.

  5. Cocoa butter and safflower oil elicit different effects on hepatic gene expression and lipid metabolism in rats.

    Science.gov (United States)

    Gustavsson, Carolina; Parini, Paolo; Ostojic, Jovanca; Cheung, Louisa; Hu, Jin; Zadjali, Fahad; Tahir, Faheem; Brismar, Kerstin; Norstedt, Gunnar; Tollet-Egnell, Petra

    2009-11-01

    The aim of this study was to compare the effects of cocoa butter and safflower oil on hepatic transcript profiles, lipid metabolism and insulin sensitivity in healthy rats. Cocoa butter-based high-fat feeding for 3 days did not affect plasma total triglyceride (TG) levels or TG-rich VLDL particles or hepatic insulin sensitivity, but changes in hepatic gene expression were induced that might lead to increased lipid synthesis, lipotoxicity, inflammation and insulin resistance if maintained. Safflower oil increased hepatic beta-oxidation, was beneficial in terms of circulating TG-rich VLDL particles, but led to reduced hepatic insulin sensitivity. The effects of safflower oil on hepatic gene expression were partly overlapping with those exerted by cocoa butter, but fewer transcripts from anabolic pathways were altered. Increased hepatic cholesterol levels and increased expression of hepatic CYP7A1 and ABCG5 mRNA, important gene products in bile acid production and cholesterol excretion, were specific effects elicited by safflower oil only. Common effects on gene expression included increased levels of p8, DIG-1 IGFBP-1 and FGF21, and reduced levels of SCD-1 and SCD-2. This indicates that a lipid-induced program for hepatic lipid disposal and cell survival was induced by 3 days of high-fat feeding, independent on the lipid source. Based on the results, we speculate that hepatic TG infiltration leads to reduced expression of SCD-1, which might mediate either neutral, beneficial or unfavorable effects on hepatic metabolism upon high-fat feeding, depending on which fatty acids were provided by the diet.

  6. Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression.

    Science.gov (United States)

    Jia, Hong-Mei; Li, Qi; Zhou, Chao; Yu, Meng; Yang, Yong; Zhang, Hong-Wu; Ding, Gang; Shang, Hai; Zou, Zhong-Mei

    2016-03-23

    Depression is a complex disease characterized by a series of pathological changes. Research on depression is mainly focused on the changes in brain, but not on liver. Therefore, we initially explored the metabolic profiles of hepatic extracts from rats treated with chronic unpredictive mild stress (CUMS) by UPLC-Q-TOF/MS. Using multivariate statistical analysis, a total of 26 altered metabolites distinguishing CUMS-induced depression from normal control were identified. Using two-stage receiver operating characteristic (ROC) analysis, 18 metabolites were recognized as potential biomarkers related to CUMS-induced depression via 12 metabolic pathways. Subsequently, we detected the mRNA expressions levels of apoptosis-associated genes such as Bax and Bcl-2 and four key enzymes including Pla2g15, Pnpla6, Baat and Gad1 involved in phospholipid and primary bile acid biosynthesis in liver tissues of CUMS rats by real-time qRT-PCR assay. The expression levels of Bax, Bcl-2, Pla2g15, Pnpla6 and Gad1 mRNA were 1.43,1.68, 1.74, 1.67 and 1.42-fold higher, and those of Baat, Bax/Bcl-2 ratio mRNA were 0.83, 0.85-fold lower in CUMS rats compared with normal control. Results of liver-targeted metabonomics and mRNA expression demonstrated that CUMS-induced depression leads to variations in hepatic metabolic profile and gene expression, and ultimately results in liver injury.

  7. Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes.

    Science.gov (United States)

    Olsson, Bob; Bohlooly-Y, Mohammad; Brusehed, Ola; Isaksson, Olle G P; Ahrén, Bo; Olofsson, Sven-Olof; Oscarsson, Jan; Törnell, Jan

    2003-09-01

    Transgenic mice overexpressing growth hormone (GH) have been extensively used to study the chronic effects of elevated serum levels of GH. GH is known to have many acute effects in the liver, but little is known about the chronic effects of GH overexpression on hepatic gene expression. Therefore, we used DNA microarray to compare gene expression in livers from bovine GH (bGH)-transgenic mice and littermates. Hepatic expression of peroxisome proliferator-activated receptor-alpha (PPARalpha) and genes involved in fatty acid activation, peroxisomal and mitochondrial beta-oxidation, and production of ketone bodies was decreased. In line with this expression profile, bGH-transgenic mice had a reduced ability to form ketone bodies in both the fed and fasted states. Although the bGH mice were hyperinsulinemic, the expression of sterol regulatory element-binding protein (SREBP)-1 and most lipogenic enzymes regulated by SREBP-1 was reduced, indicating that these mice are different from other insulin-resistant models with respect to expression of SREBP-1 and its downstream genes. This study also provides several candidate genes for the well-known association between elevated GH levels and cardiovascular disease, e.g., decreased expression of scavenger receptor class B type I, hepatic lipase, and serum paraoxonase and increased expression of serum amyloid A-3 protein. We conclude that bGH-transgenic mice display marked changes in hepatic genes coding for metabolic enzymes and suggest that GH directly or indirectly regulates many of these hepatic genes via decreased expression of PPARalpha and SREBP-1.

  8. Leptin and Adiponectin Levels in Patients with Chronic Hepatitis C with Carbohydrate and Lipid Metabolism Disorders

    Directory of Open Access Journals (Sweden)

    T. V. Antonova

    2014-01-01

    Full Text Available Aim: to analyze leptin and adiponectin serum levels in patients with chronic hepatitis C in comparison with metabolic syndrome components, biochemical features and stage of hepatitis.Materials and methods: In 93 patients with chronic HCV in age 20-55 with a few symptomatic HCV-infection and minimal liver fibrosis stage serum leptin and adiponectin was measured. Associations between leptin, adiponectin and metabolic abnormalities, biochemical features, and hepatic fibrosis were determined.Results: Abdominal obesity was revealed at 40% patients, overweight – at 41%, insulin resistance – at 36,6% cases. The leptin and adiponectin levels were within normal limits range at most patients. Patients with minimal liver fibrosis had higher index of leptin by comparison to patients with moderate and severe fibrosis (r= – 0,402, р= 0,018. In patients with HCV genotype 3a the adiponectin level was below, than in HCV genotype 1b. Patients with abdominal obesity and overweight had higher leptin and lower adiponectin indexes by comparison to patients without these metabolic abnormalities. Direct cross-correlation between the leptin level and body mass index (r=0,358, p=0,001, waist circumference (r=0,292, p=0,01; negative cross-correlation between the adiponectin level and body mass index (r=- 0,435, р <0,021, waist circumference (r=- 0,386, р =0,001 were displayed.Conclusion: Leptin and adiponectin blood levels in HCVpatientis associated with abdominal obesity and overweight. The connection of leptin level and liver fibrosis stage was revealed. Difference of adiponectin level in HCV-patients with 3a and 1b genotypes of virus was found.

  9. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930140 Hepatocyte stimulator peptide and itsclinical significance in viral hepatitis.ZHOUWeiping(周卫平),et al.Instit Viral Hepatitis,Chongqing Med Univ,630010.Chin J InternMed 1992;31(10):626-628.Hepatocyte stimulator peptide(HSP)is anewly developed hepatic stimulator substance.Its monoclonal antibodies have been obtained inour laboratory.In this study,HSP was deter-mined in the sera of 315 subjects including pa-

  10. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010349 Relationships between serum hepatitis B virus load in mothers,free maternal DNA in peripheral blood of newborns and hepatitis B virus infection of newborns. WEI Junni(魏俊妮),et al. Dept Epidemiol,Shanxi Med Univ,Taiyuan 030001. Chin J Infect Dis 2010;28(5):297-300. Objective To study the relationships between serum hepatitis B virus (HBV) DNA level

  11. Kupffer cells facilitate the acute effects of leptin on hepatic lipid metabolism.

    Science.gov (United States)

    Metlakunta, Anantha; Huang, Wan; Stefanovic-Racic, Maja; Dedousis, Nikolaos; Sipula, Ian; O'Doherty, Robert M

    2017-01-01

    Leptin has potent effects on lipid metabolism in a number of peripheral tissues. In liver, an acute leptin infusion (~120 min) stimulates hepatic fatty acid oxidation (~30%) and reduces triglycerides (TG, ~40%), effects that are dependent on phosphoinositol-3-kinase (PI3K) activity. In the current study we addressed the hypothesis that leptin actions on liver-resident immune cells are required for these metabolic effects. Myeloid cell-specific deletion of the leptin receptor (ObR) in mice or depletion of liver Kupffer cells (KC) in rats in vivo prevented the acute effects of leptin on liver lipid metabolism, while the metabolic effects of leptin were maintained in mice lacking ObR in hepatocytes. Notably, liver TG were elevated in both lean and obese myeloid cell ObR, but the degree of obesity and insulin resistance induced by a high-fat diet was similar to control mice. In isolated primary hepatocytes (HEP), leptin had no effects on HEP lipid metabolism and only weakly stimulated PI3K. However, the coculture of KC with HEP restored leptin action on HEP fatty acid metabolism and stimulation of HEP PI3K. Notably, leptin stimulated the release from KC of a number of cytokines. However, the exposure of HEP to these cytokines individually [granulocyte macrophage colony-stimulating factor, IL-1α, IL-1β, IL-6, IL-10, and IL-18] or in combination had no effects on HEP lipid metabolism. Together, these data demonstrate a role for liver mononuclear cells in the regulation of liver lipid metabolism by leptin. Copyright © 2017 the American Physiological Society.

  12. The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism

    Directory of Open Access Journals (Sweden)

    Katsumi Iizuka

    2017-02-01

    Full Text Available Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP is a glucose-activated transcription factor that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase, fructolysis (Glut5, ketohexokinase, and lipogenesis (acetyl CoA carboxylase, fatty acid synthase. ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp−/− mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as fibroblast growth factor-21 and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome.

  13. The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism.

    Science.gov (United States)

    Iizuka, Katsumi

    2017-02-22

    Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP) is a glucose-activated transcription factor that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase), fructolysis (Glut5, ketohexokinase), and lipogenesis (acetyl CoA carboxylase, fatty acid synthase). ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp(-/-) mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as fibroblast growth factor-21 and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome.

  14. Strategies towards Improved Feed Efficiency in Pigs Comprise Molecular Shifts in Hepatic Lipid and Carbohydrate Metabolism

    Directory of Open Access Journals (Sweden)

    Henry Reyer

    2017-08-01

    Full Text Available Due to the central role of liver tissue in partitioning and metabolizing of nutrients, molecular liver-specific alterations are of considerable interest to characterize an efficient conversion and usage of feed in livestock. To deduce tissue-specific and systemic effects on nutrient metabolism and feed efficiency (FE twenty-four animals with extreme phenotypes regarding residual feed intake (RFI were analyzed. Transcriptome and fatty acid profiles of liver tissue were complemented with measurements on blood parameters and thyroid hormone levels. Based on 803 differentially-abundant probe sets between low- and high-FE animals, canonical pathways like integrin signaling and lipid and carbohydrate metabolism, were shown to be affected. Molecular alterations of lipid metabolism show a pattern of a reduced hepatic usage of fatty acids in high-FE animals. Complementary analyses at the systemic level exclusively pointed to increased circulating triglycerides which were, however, accompanied by considerably lower concentrations of saturated and polyunsaturated fatty acids in the liver of high-FE pigs. These results are in accordance with altered muscle-to-fat ratios usually ascribed to FE animals. It is concluded that strategies to improve FE might favor a metabolic shift from energy storage towards energy utilization and mobilization.

  15. Hepatic metabolism of anaesthetized growing pigs during acute portal infusion of volatile fatty acids and hydroxy-methyl butyrate

    DEFF Research Database (Denmark)

    Theil, Peter Kappel; Larsen, Uffe Krogh; Bjerre-Harpøth, Vibeke

    2016-01-01

    ABSTRACT: The objective of the experiment was to study hepatic metabolism during infusion of volatile fatty acids (VFA) differing in amounts and composition or infusion of HMB. Three fasted (20 h) pigs (mean BW ± SE; 58 kg ± 1) were fitted with indwelling catheters in the portal vein, hepatic vein......, mesenteric artery and two in mesenteric veins. One of the mesenteric vein catheters was used to infuse VFA in the anesthetized pigs to mimic effects of increased consumption of dietary fibers. Sixteen sets of blood samples were simultaneously drawn from the artery and portal and hepatic veins at 15 min...... accounting for repeated measurements. A net hepatic uptake of propionate, butyrate, and lactate was observed, whereas the liver released acetate, glucose, and urea. The portal lactate absorption could not account for the net hepatic uptake of lactate, suggesting lactate originated from partial oxidation...

  16. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    Science.gov (United States)

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  17. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    Directory of Open Access Journals (Sweden)

    Yi-Chieh Li

    Full Text Available Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  18. Co-ordination of hepatic and adipose tissue lipid metabolism after oral glucose

    DEFF Research Database (Denmark)

    Bülow, J; Simonsen, L; Wiggins, D

    1999-01-01

    lipoprotein (VLDL)-triacylglycerol (TAG) output when plasma insulin levels increased after glucose. Adipose tissue extraction of VLDL-TAG tended to vary in time in a manner similar to splanchnic VLDL-TAG output and the two were significantly related. The area-under-curves (AUC) for splanchnic extraction...... to be regulated by a number of factors and in turn controls TAG extraction in adipose tissue. Insulin does not seem to play a key role in the acute regulation of hepatic VLDL metabolism under these particular conditions in vivo.......The integration of lipid metabolism in the splanchnic bed and in subcutaneous adipose tissue before and after ingestion of a 75 g glucose load was studied by Fick's principle in seven healthy subjects. Six additional subjects were studied during a hyperinsulinemic euglycemic clamp. Release of non...

  19. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure

    DEFF Research Database (Denmark)

    Strauss, Gitte Irene; Knudsen, Karen Birgitte Moos; Kondrup, Jens;

    2001-01-01

    BACKGROUND & AIMS: High circulating levels of ammonia have been suggested to be involved in the development of cerebral edema and herniation in fulminant hepatic failure (FHF). The aim of this study was to measure cerebral metabolism of ammonia and amino acids, with special emphasis on glutamine...... metabolism. METHODS: The study consisted of patients with FHF (n = 16) or cirrhosis (n = 5), and healthy subjects (n = 8). Cerebral blood flow was measured by the 133Xe washout technique. Blood samples for determination of ammonia and amino acids were drawn simultaneously from the radial artery...... and the internal jugular bulb. RESULTS: A net cerebral ammonia uptake was only found in patients with FHF (1.62 +/- 0.79 micromol x 100 g(-1) x min(-1)). The cerebral glutamine efflux was higher in patients with FHF than in the healthy subjects and cirrhotics, -6.11 +/- 5.19 vs. -1.93 +/- 1.17 and -1.50 +/- 0...

  20. Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism

    DEFF Research Database (Denmark)

    Perry, Rachel J; Borders, Candace B; Cline, Gary W;

    2016-01-01

    In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography....../tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-(13)C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously...... glucagon suppressed VPyr-Cyc/VMito These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable...

  1. Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling.

    Science.gov (United States)

    Fernández-Rojo, Manuel A; Gongora, Milena; Fitzsimmons, Rebecca L; Martel, Nick; Martin, Sheree D; Nixon, Susan J; Brooks, Andrew J; Ikonomopoulou, Maria P; Martin, Sally; Lo, Harriet P; Myers, Stephen A; Restall, Christina; Ferguson, Charles; Pilch, Paul F; McGee, Sean L; Anderson, Robin L; Waters, Michael J; Hancock, John F; Grimmond, Sean M; Muscat, George E O; Parton, Robert G

    2013-07-25

    Caveolae and caveolin-1 (CAV1) have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1-/- mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1-/- mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1) hepatic lipid homeostasis and (2) nuclear hormone receptor (PPARα, FXRα, and SHP) and bile acid signaling.

  2. Caveolin-1 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling

    Directory of Open Access Journals (Sweden)

    Manuel A. Fernández-Rojo

    2013-07-01

    Full Text Available Caveolae and caveolin-1 (CAV1 have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1−/− mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1−/− mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1 hepatic lipid homeostasis and (2 nuclear hormone receptor (PPARα, FXRα, and SHP and bile acid signaling.

  3. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970349 Primary structure and variability of partialsequences in nonstructural gene 5 region of hepatitis Gvirus, CHANG Jinhong(常锦红), et al. Hepatol Instis,People’s Hosp, Beijing Med Univ, Beijing, 100044. NatlMed J China 1997; 77(3): 178-182. Objective: To sequence partial genome of hepatitis G

  4. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009209 Effects of chronic hepatitis B virus infection on human hepatic cytochrome P450 2C9.ZHO Fuping(周福平),et al.Dept Infect Dis,Shanghai Changzheng Hosp,Shanghai 200003.Chin J Infect Dis,2009;27(2):94-98.

  5. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    1992-01-01

    920691 The determination of serum hepa-titis B virus DNA by polymerase chain rea-ction in hepatitis B patients treated withalpha-interferon. XU. Jianye(徐建业), et al.Centr Lab, Chongqing Cancer Instit, 630030.Chin J Intern Med, 1992; 31(5): 278-280. To clarify the status of HBV in serum of

  6. Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling.

    Science.gov (United States)

    Wanders, Desiree; Stone, Kirsten P; Dille, Kelly; Simon, Jacob; Pierse, Alicia; Gettys, Thomas W

    2015-01-01

    Dietary leucine was incrementally restricted to test whether limiting this essential amino acid (EAA) would fully reproduce the beneficial responses produced by dietary methionine restriction. Restricting leucine by 85% increased energy intake and expenditure within 5 to 7 days of its introduction and reduced overall accumulation of adipose tissue. Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of fibroblast growth factor 21 into the blood stream, and enhanced insulin-dependent activation of Akt in liver. However, LR had no effect on hepatic lipid levels and failed to lower lipogenic gene expression in the liver. LR did affect remodeling of white and brown adipose tissues, increasing expression of both thermogenic and lipogenic genes. These findings illustrate that dietary LR reproduces many but not all of the physiological responses of methionine restriction. The primary differences occur in the liver, where methionine and LR cause opposite effects on tissue lipid levels and expression of lipogenic genes. Altogether, these findings suggest that the sensing systems which detect and respond to dietary restriction of EAAs act through mechanisms that both leucine and methionine are able to engage, and in the case of hepatic lipid metabolism, may be unique to specific EAAs such as methionine. © 2015 International Union of Biochemistry and Molecular Biology.

  7. Beneifcial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Rui Guo; Emily C Liong; Kwok Fai So; Man-Lung Fung; George L Tipoe

    2015-01-01

    BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneifcial effects of aerobic exercise on NAFLD. DATA SOURCE:We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. RESULTS:The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing in-trahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptorγ expression levels; (ii) decreas-ing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inlfammation via the inhibition of pro-inlfammatory media-tors such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy. CONCLUSION:Aerobic exercise, via different mechanisms, signiifcantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

  8. Hepatic Glucocorticoid Receptor Plays a Greater Role Than Adipose GR in Metabolic Syndrome Despite Renal Compensation.

    Science.gov (United States)

    Bose, Sandip K; Hutson, Irina; Harris, Charles A

    2016-12-01

    Exogenous glucocorticoid administration results in hyperglycemia, insulin resistance, hepatic dyslipidemia, and hypertension, a constellation of findings known as Cushing's syndrome. These effects are mediated by the glucocorticoid receptor (GR). Because GR activation in liver and adipose has been implicated in metabolic syndrome (MS), we wanted to determine the role of GR in these tissues in the development of MS. Because GR knockout (KO) mice (whole-body KO) exhibit perinatal lethality due to respiratory failure, we generated tissue-specific (liver or adipose) GRKO mice using cre-lox technology. Real-time PCR analysis of liver mRNA from dexamethasone-treated wildtype (WT) and liver GRKO mice indicated that hepatic GR regulates the expression of key genes involved in gluconeogenesis and glycogen metabolism. Interestingly, we have observed that liver-specific deletion of GR resulted in a significant increase in mRNA expression of key genes involved in gluconeogenesis and glycogen metabolism in kidney tissue, indicating a compensatory mechanism to maintain glucose homeostasis. We have also observed that GR plays an important role in regulating the mRNA expression of key genes involved in lipid metabolism. Liver GRKO mice demonstrated decreased fat mass and liver glycogen content compared with WT mice administered dexamethasone for 2 weeks. Adipose-specific deletion of GR did not alter glucose tolerance or insulin sensitivity of adipose GRKO mice compared with WT mice administrated dexamethasone. This indicates that liver GR might be more important in development of MS in dexamethasone-treated mice, whereas adipose GR plays a little role in these paradigms.

  9. Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data.

    Science.gov (United States)

    Cubitt, Helen E; Houston, J Brian; Galetin, Aleksandra

    2011-05-01

    The current study assesses hepatic and intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CL(int, SULT)) was determined in human intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CL(int, UGT)) and P450 clearance (CL(int, CYP)) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CL(int, SULT) ranged between 0.7 and 11.4 ml · min(-1) · g(-1) liver and 0.1 and 3.3 ml · min(-1) · g(-1) intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CL(int) for liver and intestine, respectively) and also significant renal clearance (26-57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44-86% of observed clearance) compared with predictions based only on the primary pathway (22-36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3-22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation

  10. 大鼠体外肝星状细胞活化过程中代谢活化相关 CYP450亚型的变化%MuItipIe xenobiotic metaboIism-associated cytochrome P450 isoforms might be invoIved in earIy activation of rat hepatic steIIate ceIIs in vitro

    Institute of Scientific and Technical Information of China (English)

    廖长秀; 吴勇; 平洁; 敖英; 印宪; 汪晖

    2014-01-01

    OBJECTIVE To investigate the role of several xenobiotic metabolism-associated CYP450 isoforms in the auto-activation of hepatic stellate cells(HSCs) invitro. METHODS HSCs were isolated from adult Wistar rats and cultured on plastic as an in vitroauto-activation model. Positive expression of α-smooth muscle actin(α-SMA)was used as an activated marker of HSCs and detected by immunocytochemical staining in HSCs cultured for 1,2,5 or 11 d. The expressions of CYP450 isoforms were analyzed by real-time RT-PCR in the HSCs. RESULTS The immunocytochemical stai-ning showed no α-SMA expression in HSCs cultured for 1 d,while its expression gradually increased during culture since day 2. ln terms of α-SMA expression,HSCs cultured for 1,2,5,and 11 d were classified as the quiescent,early,middle and later stages of activation,respectively. The RT-PCR results revealed that CYP1B1,CYP2B1/ 2,and CYP2E1 mRNA were expressed at high levels in the early stage of HSCs activation(at day 2),which were 2.1-,1.6-,and 23.9-fold those in the quiescent HSCs(day 1),respectively. Further study revealed that mRNA expressions of these up-regulated CYPs in the early stage of activation were diminished at the subsequent two stages. The levels of CYP1A1 and CYP1A2 mRNA decreased constantly throughtout the activation process. CONCLUSION Multiple xenobi-otic metabolism-associated CYP450 isoforms might be involved in the auto-activation of rat HSCs invitro.%目的:观察大鼠肝星状细胞(HSC)活化不同时期外源活化相关 CYP450亚型CYP1A1, CYP1B1,CYP1A2,CYP2B1/2和 CYP2E1 mRNA 表达水平的变化规律。方法分离大鼠 HSC,接种在无包被塑料培养瓶中作为 HSC 自氧化活化模型,免疫细胞化学法检测不同培养时间 HSC 活化标志物α-平滑肌肌动蛋白(α-SMA)表达。实时定量 RT-PCR 法测定 HSC 自氧化激活的不同时期多种外源物活化相关 CYP450亚型 mRNA 的表达变化。结果免疫细胞化学结果表明

  11. The effect of thyroxin on hepatic redox equilibrium and lipid metabolism in rats treated with doxorubicin

    Directory of Open Access Journals (Sweden)

    Czuba Bartosz

    2014-12-01

    Full Text Available The main side effects of the administration of doxorubicin, a widely used anticancer drug, is the generation of a reactive oxygen species (ROS in normal cells. As a result, redox disorders and secondary oxidative stress are developed. Doxorubicin ROS generation is attributed to enzymes that are produced abundantly in hepatocytes. Oxidative stress has been a well-known risk factor of doxorubicin-related toxicity. However, in addition, according to the data collected in the last decade, changes in thyroxin status can propagate ROS generation, and, thus, initiate the doxorubicin hepatic effect. Moreover, both compounds have an impact on the cell metabolism. The aim of the study was to verify the thesis that thyroxin can modulate the effect of doxorubicin with regard to redox status and lipid metabolism disorders. In our work, we determined the ratio of NADP+/ NADPH and NAD+/NADH in liver homogenates, blood ketone bodies and triglycerides in the liver and blood in rats treated with doxorubicin and thyroxin. Our results indicate that thyroxin has an insignificant effect on NAD+/NADH, NADP+/NADPH ratios and on hepatic and blood triglycerides. Moreover, thyroxin administration normalized the level of blood ketone bodies that was disturbed by doxorubicin.

  12. Effects of the Crotalus durissus terrificus snake venom on hepatic metabolism and oxidative stress.

    Science.gov (United States)

    da Silva, Jonas Golart; da Silva Soley, Bruna; Gris, Vanessa; do Rocio Andrade Pires, Amanda; Caderia, Silvia Maria Suter Correia; Eler, Gabrielle Jackin; Hermoso, Aparecida Pinto Munhos; Bracht, Adelar; Dalsenter, Paulo Roberto; Acco, Alexandra

    2011-01-01

    Snake venoms present different action mechanisms because of their complex composition, represented mainly by toxins and enzymes. This work aimed to investigate the effects of the Crotalus durissus terrificus(Cdt) venom in the liver. Wistar rats were inoculated intraperitoneally with saline (control) or Cdt venom. After 3, 4, or 6 h, the following parameters were analyzed: (a) hepatic function, (b) oxidative stress parameters, and (c) the metabolism of alanine in the isolated perfused liver. Plasma activities of alanine aminotransferase and aspartate aminotransferase and hepatic glutathione S-transferase and catalase presented significant elevation in rats inoculated with 300 μg ⋅ kg(-1) Cdt venom. Liver lipoperoxidation was enormously increased by venom doses of 100, 200, and 300 μg ⋅kg(-1) , whereas glutathione S-transferase was not changed. Perfused livers from rats inoculated with 1500 μg ⋅kg(-1) venom showed increased production of lactate, pyruvate, and ammonia when alanine was the metabolic substrate. These results demonstrate that the Cdt venom can produce several changes in hepatocytes. The causes of the changes are possibly related to the disequilibrium in the redox homeostasis but also to specific needs of the poisoned organism, for example, an increased supply of lactate and pyruvate in response to an increased activity of the Cori cycle. Copyright © 2010 Wiley Periodicals, Inc.

  13. Modulation of hepatic lipid metabolism by olive oil and its phenols in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Priore, Paola; Cavallo, Alessandro; Gnoni, Antonio; Damiano, Fabrizio; Gnoni, Gabriele V; Siculella, Luisa

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in western countries, being considered the hepatic manifestation of metabolic syndrome. Cumulative lines of evidence suggest that olive oil, used as primary source of fat by Mediterranean populations, may play a key role in the observed health benefits on NAFLD. In this review, we summarize the state of the art of the knowledge on the protective role of both major and minor components of olive oil on lipid metabolism during NAFLD. In particular, the biochemical mechanisms responsible for the increase or decrease in hepatic lipid content are critically analyzed, taking into account that several studies have often provided different and/or conflicting results in animal models fed on olive oil-enriched diet. In addition, new findings that highlight the hypolipidemic and the antisteatotic actions of olive oil phenols are presented. As mitochondrial dysfunction plays a key role in the pathogenesis of NAFLD, the targeting of these organelles with olive oil phenols as a powerful therapeutic approach is also discussed.

  14. Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.

    Science.gov (United States)

    Caesar, Robert; Nygren, Heli; Orešič, Matej; Bäckhed, Fredrik

    2016-03-01

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

  15. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice.

    Science.gov (United States)

    Cheng, Licai; Yu, Yinghua; Szabo, Alexander; Wu, Yizhen; Wang, Hongqin; Camer, Danielle; Huang, Xu-Feng

    2015-05-01

    The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity.

  16. Subchronic Exposure of Mice to Cadmium Perturbs Their Hepatic Energy Metabolism and Gut Microbiome.

    Science.gov (United States)

    Zhang, Songbin; Jin, Yuanxiang; Zeng, Zhaoyang; Liu, Zhenzhen; Fu, Zhengwei

    2015-10-19

    Cadmium (Cd) is an environmental pollutant known to cause liver damage; however, the mechanisms of its hepatotoxicity remain poorly understood. In this study, the effects of subchronic exposure in mice to low doses of Cd on energy metabolism and the gut microbiome were evaluated. The exposure of mice to 10 mg/L Cd supplied in drinking water for 10 weeks increased hepatic triacylglycerol (TG), serum free fatty acid (FFA), and TG levels. The mRNA levels of several key genes involved in both de novo FFA synthesis and transport pathways and in TG synthesis in the liver also increased significantly in the Cd-treated mice, indicating that alterations of these genes may be a possible mechanism to explain subchronic Cd exposure induced hepatic toxicity at a molecular level. As for the gut microbiome, at the phylum level, the amounts of Firmicutes and γ-proteobacteria decreased significantly in the feces after 4 weeks of Cd exposure, and the quantity of Firmicutes decreased significantly in the cecum contents after 10 weeks of Cd exposure. In addition, 16S rRNA gene sequencing further revealed that Cd exposure significantly perturbed the gut microflora structure and richness at family and genus levels. The alteration of gut microbiome composition might result in an increase in serum lipopolysaccharide (LPS) and induce hepatic inflammation, which may indirectly cause perturbations of energy homeostasis after Cd exposure. Taken together, the present study indicated that subchronic Cd exposure caused the dysregulation of energy metabolism and changed the gut microbiome composition in mice.

  17. Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats.

    Science.gov (United States)

    Zhang, Min; Xie, Zongkai; Gao, Weina; Pu, Lingling; Wei, Jingyu; Guo, Changjiang

    2016-03-01

    Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography-based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and

  18. In Ovo injection of betaine affects hepatic cholesterol metabolism through epigenetic gene regulation in newly hatched chicks.

    Directory of Open Access Journals (Sweden)

    Yun Hu

    Full Text Available Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P < 0.05 and the hepatic content (P < 0.01 of cholesterol. Accordingly, the cholesterol biosynthetic enzyme HMGCR was up-regulated (P < 0.05 for both mRNA and protein, while CYP7A1 which converts cholesterol to bile acids was down-regulated (P < 0.05 for mRNA and P = 0.07 for protein. Moreover, hepatic protein content of the sterol-regulatory element binding protein 1 which regulates cholesterol and lipid biosynthesis, and the mRNA abundance of ATP binding cassette sub-family A member 1 (ABCA1 which mediates cholesterol counter transport were significantly (P < 0.05 increased in betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P < 0.05, which was associated with global genomic DNA hypermethylation (P < 0.05 and diminished gene repression mark histone H3 lysine 27 trimethylation (P < 0.05. Furthermore, CpG methylation level on gene promoters was found to be increased (P < 0.05 for CYP7A1 yet decreased (P < 0.05 for ABCA1. These results indicate that in ovo betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations.

  19. Alterations in cytochrome P-450 levels in adult rats following neonatal exposure to xenobiotics

    Energy Technology Data Exchange (ETDEWEB)

    Zangar, R.C. (Oregon State Univ., Corvallis (United States) Pacific Northwest Laboratories, Richland, WA (United States)); Springer, D.L. (Pacific Northwest Laboratories, Richland, WA (United States)); Buhler, D.R. (Oregon State Univ., Corvallis (United States))

    1993-01-01

    Neonatal exposure to certain xenobiotics has been shown to alter hepatic metabolism in adult rats in a manner that indicates long-term changes in enzyme regulation. Previously, the authors have observed changes in adult testosterone metabolism and in cytochrome P-450 (P-450) mRNA levels in animals neonatally exposed to phenobarbital (PB) or diethylstilbestrol (DES). In order to test for other enzyme alterations, they used Western blot procedures for specific P-450s to analyze hepatic microsomes from adult rats (24 wk old) that had been exposed neonatally to DES, PB, 7,12-dimethylbenz[a]anthracene (DMBA), or pregnenolone 16[alpha]-carbonitrile (PCN). The most striking effects were observed in the DES-treated males: P-4502C6 and an immunologically similar protein were increased 60 and 90%, respectively, relative to control values, but P-4503A2 was decreased by 44%. No changes were observed in the DES-treated males in levels of P-4502E1, P-4502B, or the male-specific P-4502C13. Adult males neonatally treated with PB had 150% increase in levels of anti-P4502B-reactive protein without significant changes in the other enzymes. The DES- and DMBA-treated females had increased levels of the female-specific P-4502C12 of 38 and 48%, respectively, but no other observed alterations. The results confirm that neonatal exposure to DES or PB can cause alterations in adult hepatic cytochrome P-450 levels but show that these chemicals act on different enzymes. Neonatal DMBA resulted in changes in adult females similar to those produced by the synthetic estrogen DES, but did so at about two-thirds lower dose. 37 refs., 5 figs.

  20. Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet.

    Science.gov (United States)

    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-01

    Herein, we investigated the hypoglycemic effect of plant gallic acid (GA) on glucose uptake in an insulin-resistant cell culture model and on hepatic carbohydrate metabolism in rats with a high-fructose diet (HFD)-induced diabetes. Our hypothesis is that GA ameliorates hyperglycemia via alleviating hepatic insulin resistance by suppressing hepatic inflammation and improves abnormal hepatic carbohydrate metabolism by suppressing hepatic gluconeogenesis and enhancing the hepatic glycogenesis and glycolysis pathways in HFD-induced diabetic rats. Gallic acid increased glucose uptake activity by 19.2% at a concentration of 6.25 μg/mL in insulin-resistant FL83B mouse hepatocytes. In HFD-induced diabetic rats, GA significantly alleviated hyperglycemia, reduced the values of the area under the curve for glucose in an oral glucose tolerance test, and reduced the scores of the homeostasis model assessment of insulin resistance index. The levels of serum C-peptide and fructosamine and cardiovascular risk index scores were also significantly decreased in HFD rats treated with GA. Moreover, GA up-regulated the expression of hepatic insulin signal transduction-related proteins, including insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3 kinase, Akt/protein kinase B, and glucose transporter 2, in HFD rats. Gallic acid also down-regulated the expression of hepatic gluconeogenesis-related proteins, such as fructose-1,6-bisphosphatase, and up-regulated expression of hepatic glycogen synthase and glycolysis-related proteins, including hexokinase, phosphofructokinase, and aldolase, in HFD rats. Our findings indicate that GA has potential as a health food ingredient to prevent diabetes mellitus.

  1. Is hepatic lipid metabolism of beef cattle influenced by breed and dietary silage level?

    Science.gov (United States)

    2014-01-01

    Background In ruminants, unsaturated dietary fatty acids are biohydrogenated in the rumen and are further metabolised in various tissues, including liver, which has an important role in lipid and lipoprotein metabolism. Therefore, manipulation of muscle fatty acid composition should take into account liver metabolism. In the present study, the influence of breed and diet on liver lipid composition and gene expression was investigated in order to clarify the role of this organ in the lipid metabolism of ruminants. Forty purebred young bulls from two phylogenetically distant autochthonous cattle breeds, Alentejana and Barrosã, were assigned to two different diets (low vs. high silage) and slaughtered at 18 months of age. Liver fatty acid composition, mRNA levels of enzymes and transcription factors involved in lipid metabolism, as well as the plasma lipid profile, were assessed. Results In spite of similar plasma non-esterified fatty acids levels, liver triacylglycerols content was higher in Barrosã than in Alentejana bulls. Moreover, the fatty acid composition of liver was clearly distinct from the remaining tissues involved in fatty acid metabolism of ruminants, as shown by Principal Components Analysis. The hepatic tissue is particularly rich in α-linolenic acid and their products of desaturation and elongation. Results indicate that DGAT1, ELOVL2, FADS1 and FADS2 genes influence the fatty acid composition of the liver the most. Moreover, genes such as DGAT1 and ELOVL2 appear to be more sensitive to genetic background than to dietary manipulation, whereas genes encoding for desaturases, such as FADS1, appear to be modulated by dietary silage level. Conclusions Our results indicate that liver plays an important role in the biosynthesis of n-3 LC-PUFA. It is also suggested that dietary silage level influences the hepatic fatty acid metabolism in a breed-dependent manner, through changes in the expression of genes encoding for enzymes associated with the

  2. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    Energy Technology Data Exchange (ETDEWEB)

    Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. [West Los Angeles VA Medical Center, CA (United States). Lipid Research Lab.]|[Univ. of California, Los Angeles, CA (United States). Dept. of Medicine; Giometti, C.S.; Mishler, K. [Argonne National Lab., IL (United States); Slavin, B.G. [Univ. of Southern California, Los Angeles, CA (United States)

    1997-07-01

    Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and these droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.

  3. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases.

    Science.gov (United States)

    Rodriguez, R J; Acosta, D

    1997-06-01

    Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism. Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity of suspected metabolites are largely unknown. Recent reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite in mice, which, like lipophilic 4-alkylpiperazines, is susceptible to successive oxidative attacks on the N-1 position producing ring-opened dialdehydes. The rate of formation of DAK from hepatic rat microsomal incubations of KT was determined by HPLC. The rate of disappearance for KT was almost equal to the rate of DAK formation: 5.96 and 5.88 microM/hr, respectively. Also, the potential bioactivation of DAK was evaluated by measuring substrate activity of DAK with purified pig liver flavin-containing monooxygenase (FMO) and rat liver microsomes. Activity was measured by following DAK-dependent oxygen uptake polarographically at 37 degrees C in pyrophosphate buffer (pH 8.8) containing the glucose-6-phosphate NADPH-generating system. The K(M)'s of DAK were 34.6 and 77.4 microM for the purified FMO and rat microsomal FMO, respectively. Lastly, DAK was found to be metabolized by an NADPH-dependent rat liver microsomal monooxygenases at pH 8.8 to two metabolites as determined by HPLC. Heat inactivation of rat liver microsomal FMO abolished the formation of these metabolites from DAK. SKF-525A and anti-rat NADPH cytochrome P450 reductase did not inhibit this reaction. These results suggest that deacetylation of KT yields a major product, DAK, for further metabolism by microsomal monooxygenases that seem to be FMO-related.

  4. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005226 Characteristics of peripheral blood T lymphocyte subsets in hepatitis B patients. FAN Zhen-ping(范振平),et al. Center Bio Ther, Instit Infect Dis, 302 Hosp Chin PLA, Beijing 100039. World Chin J Digestol, 2005;13(2): 194-197. Objective: To characterize the T-lymphocyte subsets in peripheral blood of patients with acute and chronic hepatitis B, and to explore their relations with the disease state. Methods: Peripheral blood

  5. Transgenic plants for enhanced biodegradation and phytoremediation of organic xenobiotics.

    Science.gov (United States)

    Abhilash, P C; Jamil, Sarah; Singh, Nandita

    2009-01-01

    Phytoremediation--the use of plants to clean up polluted soil and water resources--has received much attention in the last few years. Although plants have the inherent ability to detoxify xenobiotics, they generally lack the catabolic pathway for the complete degradation of these compounds compared to microorganisms. There are also concerns over the potential for the introduction of contaminants into the food chain. The question of how to dispose of plants that accumulate xenobiotics is also a serious concern. Hence the feasibility of phytoremediation as an approach to remediate environmental contamination is still somewhat in question. For these reasons, researchers have endeavored to engineer plants with genes that can bestow superior degradation abilities. A direct method for enhancing the efficacy of phytoremediation is to overexpress in plants the genes involved in metabolism, uptake, or transport of specific pollutants. Furthermore, the expression of suitable genes in root system enhances the rhizodegradation of highly recalcitrant compounds like PAHs, PCBs etc. Hence, the idea to amplify plant biodegradation of xenobiotics by genetic manipulation was developed, following a strategy similar to that used to develop transgenic crops. Genes from human, microbes, plants, and animals are being used successfully for this venture. The introduction of these genes can be readily achieved for many plant species using Agrobacterium tumefaciens-mediated plant transformation or direct DNA methods of gene transfer. One of the promising developments in transgenic technology is the insertion of multiple genes (for phase 1 metabolism (cytochrome P450s) and phase 2 metabolism (GSH, GT etc.) for the complete degradation of the xenobiotics within the plant system. In addition to the use of transgenic plants overexpressed with P450 and GST genes, various transgenic plants expressing bacterial genes can be used for the enhanced degradation and remediation of herbicides, explosives

  6. A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice.

    Science.gov (United States)

    Grimsley, Aidan; Foster, Alison; Gallagher, Richard; Hutchison, Michael; Lundqvist, Anders; Pickup, Kathryn; Wilson, Ian D; Samuelsson, Kristin

    2014-12-15

    The hepatic cytochrome P450 reductase null (HRN) mouse, which has no functional hepatic Cyp P450s, may represent a useful model for examining extra-hepatic P450-related oxidative metabolism. Here the pharmacokinetics and metabolic fate of midazolam, a drug known to undergo such extra-hepatic metabolism, have been investigated in the HRN mouse and compared with a phenotypically normal strain (C57BL/6J). In addition, the effects of co-administration of the pan-P450 inhibitor 1'-aminobenzotriazole (ABT) on the metabolic profile have been compared in both strains. Significant pharmacokinetic differences for midazolam were observed between the two strains of mice with the HRN mice showing lower circulating concentrations of 1'-hydroxymidazolam but higher concentrations of 1'-hydroxymidazolam-O-glucuronide. A significant increase in midazolam exposure was seen upon ABT exposure for both strains of mice, but no differences in the area under the concentration time curves (AUC) for the monitored metabolites were observed. Although oxidative metabolism of midazolam was not abolished, significant decreases in 1'-hydroxymidazolam formation ratios were observed for both strains of mice exposed to ABT. Metabolite profiling of blood and bile showed a number of qualitative and quantitative differences between HRN and normal mice. These differences in midazolam metabolism between the two strains of mice clearly demonstrate the role that liver P450 enzymes play in the murine metabolism of midazolam. The fate of the compound in the HRN mice shows the importance of extrahepatic metabolism and also showed that these mice appear to be more capable of forming circulating phase II glucuronides than the normal strain.

  7. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.

    Science.gov (United States)

    Panchal, Sunil K; Poudyal, Hemant; Brown, Lindsay

    2012-06-01

    Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

  8. 13C Mrs Studies of the Control of Hepatic Glycogen Metabolism at High Magnetic Fields

    Science.gov (United States)

    Miller, Corin O.; Cao, Jin; Zhu, He; Chen, Li M.; Wilson, George; Kennan, Richard; Gore, John C.

    2017-06-01

    Introduction: Glycogen is the primary intracellular storage form of carbohydrates. In contrast to most tissues where stored glycogen can only supply the local tissue with energy, hepatic glycogen is mobilized and released into the blood to maintain appropriate circulating glucose levels, and is delivered to other tissues as glucose in response to energetic demands. Insulin and glucagon, two current targets of high interest in the pharmaceutical industry, are well known glucose-regulating hormones whose primary effect in liver is to modulate glycogen synthesis and breakdown. The purpose of these studies was to develop methods to measure glycogen metabolism in real time non-invasively both in isolated mouse livers, and in non-human primates (NHPs) using 13C MRS. Methods: Livers were harvested from C57/Bl6 mice and perfused with [1-13C] Glucose. To demonstrate the ability to measure acute changes in glycogen metabolism ex-vivo, fructose, glucagon, and insulin were administered to the liver ex-vivo. The C1 resonance of glycogen was measured in real time with 13C MRS using an 11.7T (500 MHz) NMR spectrometer. To demonstrate the translatability of this approach, NHPs (male rhesus monkeys) were studied in a 7 T Philips MRI using a partial volume 1H/13C imaging coil. NPHs were subjected to a variable IV infusion of [1-13C] glucose (to maintain blood glucose at 3-4x basal), along with a constant 1 mg/kg/min infusion of fructose. The C1 resonance of glycogen was again measured in real time with 13C MRS. To demonstrate the ability to measure changes in glycogen metabolism in vivo, animals received a glucagon infusion (1 μg/kg bolus followed by 40 ng/kg/min constant infusion) half way through the study on the second study session. Results: In both perfused mouse livers and in NHPs, hepatic 13C-glycogen synthesis (i.e. monotonic increases in the 13C-glycogen NMR signal) was readily detected. In both paradigms, addition of glucagon resulted in cessation of glycogen synthesis

  9. In ovo leptin administration affects hepatic lipid metabolism and microRNA expression in newly hatched broiler chickens

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    Hu Yan

    2012-06-01

    Full Text Available Abstract Background A leptin-like immunoreactive substance has been found in chicken eggs and has been implicated in serving as a maternal signal to program offspring growth and metabolism. In the present study, we investigated the effects of in ovo leptin administration on hatch weight, serum and hepatic concentrations of metabolites and hormones, as well as on the expression of genes involved in hepatic lipid metabolism and the predicted microRNAs (miRNAs targeting the affected genes. To this end we injected fertile eggs with either 0.5 μg of recombinant murine leptin or vehicle (PBS before incubation. Results Prenatally leptin-exposed chicks showed lower hatch weight, but higher liver weight relative to the body weight, compared to the control group. In ovo leptin treatment increased the hepatic content and serum concentration of leptin in newly hatched chickens. The hepatic contents of triglycerides (TG and total cholesterol (Tch were decreased, whereas the serum levels of TG, Tch and apolipoprotein B (ApoB were increased. The hepatic mRNA expression of sterol regulator element binding protein 1 (SREBP-1c, SREBP-2, hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR and cholesterol 7α-hydroxylase 1 (CYP7A1 was significantly up-regulated, as was the protein content of both SREBP-1c and SREBP-2 in hepatic nuclear extracts of leptin-treated chickens. Moreover, out of 12 miRNAs targeting SREBP-1c and/or HMGCR, five were significantly up-regulated in liver of leptin-treated chicks, including gga-miR-200b and gga-miR-429, which target both SREBP-1c and HMGCR. Conclusions These results suggest that leptin in ovo decreases hatch weight, and modifies hepatic leptin secretion and lipid metabolism in newly hatched broiler chickens, possibly via microRNA-mediated gene regulation.

  10. Quantification of hepatic and visceral fat by CT and MR imaging: relevance to the obesity epidemic, metabolic syndrome and NAFLD.

    Science.gov (United States)

    Graffy, Peter M; Pickhardt, Perry J

    2016-06-01

    Trends in obesity have continued to increase in the developed world over the past few decades, along with related conditions such as metabolic syndrome, which is strongly associated with this epidemic. Novel and innovative methods to assess relevant obesity-related biomarkers are needed to determine the clinical significance, allow for surveillance and intervene if appropriate. Aggregations of specific types of fat, specifically hepatic and visceral adiposity, are now known to be correlated with these conditions, and there are a variety of imaging techniques to identify and quantify their distributions and provide diagnostic information. These methods are particularly salient for metabolic syndrome, which is related to both hepatic and visceral adiposity but currently not defined by it. Simpler non-specific fat measurements, such as body weight, abdominal circumference and body mass index are more frequently used but lack the ability to characterize fat location. In addition, non-alcoholic fatty liver disease (NAFLD) is a related condition that carries relevance not only for obesity-related diseases but also for the progression of the liver-specific disease, including non-alcoholic steatohepatitis and cirrhosis, albeit at a much lower frequency. Recent CT and MRI techniques have emerged to potentially optimize diagnosing metabolic syndrome and NAFLD through non-invasive quantification of visceral fat and hepatic steatosis with high accuracy. These imaging modalities should aid us in further understanding the relationship of hepatic and visceral fat to the obesity-related conditions such as metabolic syndrome, NAFLD and cardiovascular disease.

  11. Effects of an oral insulin nanoparticle administration on hepatic glucose metabolism assessed by 13C and 2H isotopomer analysis

    NARCIS (Netherlands)

    Reis, C.P.; Neufeld, R.; Veiga, F.; Figueiredo, I.V.; Jones, J.; Soares, A.F.; Nunes, P.M.; Damg\\'e, C.; Carvalho, R.A.

    2012-01-01

    The purpose of this study was to evaluate hepatic glucose metabolism of diabetic induced rats after a daily oral load of insulin nanoparticles over 2 weeks. After the 2-week treatment, an oral glucose tolerance test was performed with [U-‘‘C] glucose and ‘H2O. Plasma glucose ‘H and ‘‘C enrichments w

  12. A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction

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    Maria Mavilio

    2016-07-01

    Full Text Available The effect of gut microbiota on obesity and insulin resistance is now recognized, but the underlying host-dependent mechanisms remain poorly undefined. We find that tissue inhibitor of metalloproteinase 3 knockout (Timp3−/− mice fed a high-fat diet exhibit gut microbiota dysbiosis, an increase in branched chain and aromatic (BCAA metabolites, liver steatosis, and an increase in circulating soluble IL-6 receptors (sIL6Rs. sIL6Rs can then activate inflammatory cells, such as CD11c+ cells, which drive metabolic inflammation. Depleting the microbiota through antibiotic treatment significantly improves glucose tolerance, hepatic steatosis, and systemic inflammation, and neutralizing sIL6R signaling reduces inflammation, but only mildly impacts glucose tolerance. Collectively, our results suggest that gut microbiota is the primary driver of the observed metabolic dysfunction, which is mediated, in part, through IL-6 signaling. Our findings also identify an important role for Timp3 in mediating the effect of the microbiota in metabolic diseases.

  13. Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.

    Science.gov (United States)

    Padilla, Nadège; Maraninchi, Marie; Béliard, Sophie; Berthet, Bruno; Nogueira, Juan-Patricio; Wolff, Estelle; Nicolay, Alain; Bégu, Audrey; Dubois, Noémie; Grangeot, Rachel; Mattei, Catherine; Vialettes, Bernard; Xiao, Changting; Lewis, Gary F; Valéro, René

    2014-10-01

    The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (Psurgery (Pbariatric surgery. This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. http://www.ClinicalTrials.gov. Unique identifier: NCT01277068. © 2014 American Heart Association, Inc.

  14. Correlation between liver function tests and metabolic syndrome in hepatitis-free elderly

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    Hung-Sheng Shang

    2015-01-01

    Full Text Available Background: We aimed to investigate the relationship between liver function tests (LFTs and metabolic syndrome (MetS as several studies have shown positive correlations between some of the LFTs, including alanine aminotransferase (ALT and γ-glutamyl transpeptidase (γ-GT, and MetS but have not fully explored the same in the elderly. Owing to the progress in public health, the aging of the general population becomes a major issue. Design: We enrolled subjects aged over 60 years who underwent routine health checkups in a Health Screening Center after excluding subjects with a history of hepatitis B or C infection, excessive alcohol consumption, liver fibrosis, cirrhosis, acute hepatitis, diabetes, hypertension, dyslipidemia, cardiovascular disease, or receiving medications for these diseases. Finally, 9,282 participants were eligible for analysis. Statistical Analysis: All data were tested for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variances with the Levene′s test. A t-test was used to evaluate the differences between the two groups. Univariate and multivariate regressions were used to observe correlations between different parameters. Receiver operating characteristic curves of each LFT were used to predict MetS. Areas under curves and 95% confidence interval were also estimated and compared. Results: With the exception of aspartate aminotransferase and α-fetal protein, the results of LFTs, including total and direct bilirubin, alkaline phosphatase (ALP, ALT, and γ-GT, were altered in the group with MetS. Furthermore, the levels of γ-GT in men and ALP in women were independently associated with all MetS components and had the highest areas under receiver operating characteristic curves. Conclusion: Abnormal LFTs are highly correlated with MetS in the hepatitis-free elderly, with levels of γ-GT in men and ALP in women being the most important factors. LFTs may represent an auxiliary tool for the

  15. Impact of chronic fructose infusion on hepatic metabolism during TPN administration.

    Science.gov (United States)

    Donmoyer, Christine M; Lacy, D Brooks; Zhang, Yiqun; Chen, Sheng-Song; McGuinness, Owen P

    2002-12-01

    During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) is markedly elevated. However, NHGU is reduced by the presence of an infection. We recently demonstrated that a small, acute (3-h) intraportal fructose infusion can correct the infection-induced impairment in NHGU. The aim of this study was to determine whether the addition of fructose to the TPN persistently enhances NHGU in the presence of an infection. TPN was infused continuously into the inferior vena cava of chronically catheterized dogs for 5 days. On day 3, a bacterial clot was implanted in the peritoneal cavity, and either saline (CON, n = 5) or fructose (+FRUC, 1.0 mg. kg(-1). min(-1), n = 6) infusion was included with the TPN. Forty-two hours after the infection was induced, hepatic glucose metabolism was assessed in conscious dogs with arteriovenous and tracer methods. Arterial plasma glucose concentration was lower with chronic fructose infusion (120 +/- 4 vs. 131 +/- 3 mg/dl, +FRUC vs. CON, P vs. 2.8 +/- 0.4 mg. kg(-1). min(-1)). Acute removal of the fructose infusion dramatically decreased NHGU (2.2 +/- 0.5 to -0.2 +/- 0.5 mg. kg(-1). min(-1)), and net hepatic lactate release also fell (1.6 +/- 0.3 to 0.5 +/- 0.3 mg. kg(-1). min(-1)). This led to an increase in the arterial plasma glucose (Delta13 +/- 3 mg/dl, P fructose infusion to TPN during infection does not lead to a persistent augmentation of NHGU.

  16. Metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin by human hepatic cytochrome P450 isoforms.

    Science.gov (United States)

    Renwick, A B; Surry, D; Price, R J; Lake, B G; Evans, D C

    2000-10-01

    M sulphaphenazole, 50-500 microm S-mephenytoin and 2-50 microM quinidine had little effect. 6. The metabolism of 20 microM BFC to HFC in human liver microsomes was also inhibited by an antibody to CYP3A4, whereas antibodies to CYP2C8/9 and CYP2D6 had no effect. 7. In summary, by correlation analysis, use of cDNA-expressed CYP isoforms, chemical inhibition and inhibitory antibodies, BFC appears metabolized by a number of CYP isoforms in human liver. BFC metabolism appears to be primarily catalysed by CYP1A2 and CYP3A4, with possibly some contribution by CYP2C9, CYP2C19 and perhaps other CYP isoforms. 8. The results also demonstrate the importance of the selection of an appropriate substrate concentration when conducting reaction phenotyping studies with human hepatic CYP isoforms.

  17. Effect of dietary fats on hepatic lipid metabolism in the growing turkey.

    Science.gov (United States)

    Mossab, Amal; Lessire, Michel; Guillaumin, Solange; Kouba, Maryline; Mourot, Jacques; Peiniau, Philippe; Hermier, Dominique

    2002-06-01

    The influence of dietary fatty acids on hepatic capacity of lipid synthesis and secretion was investigated in 7-week-old male turkeys. They were fed 10% of either lard (rich in saturated and monounsaturated fatty acids) or linseed oil (rich in polyunsaturated fatty acids, especially 18:3n-3). Fattening was identical with both diets (0.15-0.20% of abdominal adipose tissue), but the proportion of muscle Pectoralis major was lower with linseed oil (6.6 vs. 7.4%). Specific activities of lipogenic enzymes (ME, G6PDH, ACX, and Delta9-desaturase) were not influenced by the diet, however, FAS activity was lower with linseed oil (14.3 vs. 25.4 nM NADPH fixed/min). Fasting concentrations of lipoproteins synthesized and secreted by the liver, VLDL and HDL, were also lower with linseed oil, as well as plasma concentrations of phospholipids and cholesteryl esters. However, when VLDL catabolism was inhibited by injection of an antiserum against LPL, VLDL concentration was identical in both groups (100-120 mg/l), whereas that of phospholipids and cholesteryl esters, that are transported by HDL mainly, remained lower with linseed oil. Thus, in the growing turkeys, and contrary to mammals and the chicken, feeding n-3 polyunsaturated fatty acids did not decrease hepatic triglyceride synthesis and secretion, nor fattening. By contrast, in this species, n-3 polyunsaturated fatty acids appear to influence mostly HDL metabolism, with a negative impact on muscular growth.

  18. Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism

    DEFF Research Database (Denmark)

    Caesar, Robert; Nygren, Heli; Orešič, Matej;

    2016-01-01

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene...... of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl...... esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota...

  19. The Comparative effects of synthetic choline and herbal choline on hepatic lipid metabolism in broilers

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    G.R.Gangane1

    Full Text Available An experiment of 0-42 days in day old 150 Vencobb broiler chickens was conducted to determine comparative effects of synthetic choline and herbal sources of choline on hepatic lipid metabolism in broilers. Birds were randomly distributed into three groups (T0- T2, one untreated control and two treatments. Chicks in Group T0 were given feed without any additional source choline chloride. Chicks of Group T1 were fed with feed mixed with herbal product (Repchol supplied by Ayurvet Ltd., Baddi, India @ 500gm/tonne of feed and T2 was given combination of synthetic choline chloride@1kg/tonne (60% and biotin @ 150 mg/ton of feed. To study the effect of inclusion of herbal sources of choline and synthetic choline on hepatic lipid metabolism, serum triglycerides and cholesterol were estimated on day 21st and 42nd of experimental study. Gross pathological changes in liver were recorded on representative birds per group at the end of the study. It was recorded that inclusion of either synthetic choline or herbal source of choline exerted a hypocholesterolemic effect and also decreased the level of triglycerides as compared to untreated control thus minimizing the incidence of fatty liver, however the two treatment do not differ significantly. Gross pathological study also revealed no significant changes in the architecture of liver as compared to control. It can be concluded that the herbal supplements can successfully replace their synthetic analogues from broiler ration. [Veterinary World 2010; 3(7.000: 318-320

  20. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008312 Impact of hepatitis B virus infection on the activity of hematopoietic stem cell.SHI Yanmei(石雁梅),et al.Dept Infect Dis,1st Clin Coll,Harbin Med Univ,Harbin 150001.Chin J Infect Dis 2008;26(4):197-201.Objective To study the impact of hepatitis B virus (HBV)infection on the activity of cord hematopoieticstem cells.Methods CD34+cells were isolated from healthy human cord blood by mini MACS.Cells were

  1. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism

    Science.gov (United States)

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  2. Basis of aggravated hepatic lipid metabolism by chronic stress in high-fat diet-fed rat.

    Science.gov (United States)

    Han, Ying; Lin, Min; Wang, Xiaobin; Guo, Keke; Wang, Shanshan; Sun, Mengfei; Wang, Jiao; Han, Xiaoyu; Fu, Ting; Hu, Yang; Fu, Jihua

    2015-03-01

    Our previous study has demonstrated that long-term stress, known as chronic stress (CS), can aggravate nonalcoholic fatty liver disease in high-fat diet (HFD)-fed rat. In this study, we tried to figure out which lipid metabolic pathways were impacted by CS in the HFD-fed rat. Male Sprague-Dawley rats (6 weeks of age, n = 8 per group) were fed with either standard diet or HFD with or without CS exposure for 8 weeks. Hepatic lipidosis, biochemical, hormonal, and lipid profile markers in serum and liver, and enzymes involved in de novo lipogenesis (DNL) of fatty acids (FAs) and cholesterol, β-oxidation, FAs uptake, triglycerides synthesis, and very low-density lipoprotein (VLDL) assembly in the liver were detected. CS exposure reduced hepatic lipidosis but further elevated hepatic VLDL content with aggravated dyslipidemia in the HFD-fed rats. There was a synergism between CS and HFD on VLDL production and dyslipidemia. PCR and western blot assays showed that CS exposure significantly promoted hepatic VLDL assembly in rats, especially in the HFD-fed rats, while it had little impact on DNL, β-oxidation, FAs uptake, and triglycerides synthesis in the HFD-fed rats. This phenomenon was in accordance with elevated serum glucocorticoid level. The critical influence of CS exposure on hepatic lipid metabolism in the HFD-fed rats is VLDL assembly which might be regulated by glucocorticoid.

  3. Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp -/- mice.

    Science.gov (United States)

    Newberry, Elizabeth P; Kennedy, Susan M; Xie, Yan; Luo, Jianyang; Crooke, Rosanne M; Graham, Mark J; Fu, Jin; Piomelli, Daniele; Davidson, Nicholas O

    2012-04-01

    The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp(-/-) mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp(-/-) mice. Here we show that the lean phenotype in L-Fabp(-/-) mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not intestinal, fatty acid amide metabolism. L-Fabp(-/-) mice exhibited short-term changes in feeding behavior with decreased food intake, which was associated with reduced abundance of key signaling fatty acid ethanolamides, including oleoylethanolamide (OEA, an agonist of PPARα) and anandamide (AEA, an agonist of cannabinoid receptors), in the liver. These reductions were associated with increased expression and activity of hepatic fatty acid amide hydrolase-1, the enzyme that degrades both OEA and AEA. Moreover, L-Fabp(-/-) mice demonstrated attenuated responses to OEA administration, which was completely reversed with an enhanced response after administration of a nonhydrolyzable OEA analog. These findings demonstrate a role for L-Fabp in attenuating obesity and hepatic steatosis, and they suggest that hepatic fatty acid amide metabolism is altered in L-Fabp(-/-) mice.

  4. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008449 A cross-sectional survey of occult hepatitis B virus infection in HIV-infected patients. MA Jianxin(马建新), et al.Dept Infect Dis, Shanghai Public Health Clin Center, Shanghai 201508. Chin J Intern Med 2008;47(7):574-577. Objective To assess the prevalence of occult HBV infection in HIV-infected patients.

  5. Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets.

    Science.gov (United States)

    Cai, Demin; Jia, Yimin; Lu, Jingyu; Yuan, Mengjie; Sui, Shiyan; Song, Haogang; Zhao, Ruqian

    2014-11-14

    To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.

  6. Xenobiotic organic compounds in wastewater

    DEFF Research Database (Denmark)

    Eriksson, Eva; Baun, Anders; Henze, Mogens

    2002-01-01

    Information regarding the contents of xenobiotic organic compounds (XOCs) in wastewater is limited, but it has been shown that at least 900 different compounds / compound groups could potentially be present in grey wastewater. Analyses of Danish grey wastewater revealed the presence of several...... hundred of XOCs, among them mainly originating from hygiene products: chlorophenols, detergents and phthalates. Several compounds not deriving from hygiene products were also identified e.g. flame-retardants and drugs. A environmental hazard identification showed that a large number of compounds with high...... aquatic toxicity were present and that data for environmental fate could only be retrieved for about half of the compounds....

  7. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis.

    Directory of Open Access Journals (Sweden)

    Xuan Xia

    Full Text Available Berberine (BBR is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French. It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK and Glucose-6-phosphatase (G6Pase, were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1, sterol regulatory element-binding protein 1c (SREBP1 and carbohydrate responsive element-binding protein (ChREBP were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

  8. Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Hui Cao

    2017-07-01

    Full Text Available Dangguiliuhuang decoction (DGLHD is a traditional Chinese medicine (TCM formula, which mainly consists of angelica, radix rehmanniae, radix rehmanniae praeparata, scutellaria baicalensis, coptis chinensis, astragalus membranaceus, and golden cypress, and used for the treatment of diabetes and some autoimmune diseases. In this study, we explored the potential mechanism of DGLHD against insulin resistance and fatty liver in vivo and in vitro. Our data revealed that DGLHD normalized glucose and insulin level, increased the expression of adiponectin, diminished fat accumulation and lipogenesis, and promoted glucose uptake. Metabolomic analysis also demonstrated that DGLHD decreased isoleucine, adenosine, and cholesterol, increased glutamine levels in liver and visceral adipose tissue (VAT of ob/ob mice. Importantly, DGLHD promoted the shift of pro-inflammatory to anti-inflammatory cytokines, suppressed T lymphocytes proliferation, and enhanced regulatory T cells (Tregs differentiation. DGLHD also inhibited dendritic cells (DCs maturation, attenuated DCs-stimulated T cells proliferation and secretion of IL-12p70 cytokine from DCs, and promoted the interaction of DCs with Tregs. Further studies indicated that the changed PI3K/Akt signaling pathway and elevated PPAR-γ expression were not only observed with the ameliorated glucose and lipid metabolism in adipocytes and hepatocytes, but also exhibited in DCs and T cells by DGLHD. Collectively, our results suggest that DGLHD exerts anti-insulin resistant and antisteatotic effects by improving abnormal immune and metabolic homeostasis. And DGLHD may be a novel approach to the treatment of obesity-related insulin resistance and hepatic steatosis.

  9. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy?

    Directory of Open Access Journals (Sweden)

    Lim TR

    2014-12-01

    Full Text Available TR Lim Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK Abstract: Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy. Keywords: HCV, genotype 3, metabolic syndrome, steatosis, directly acting antiviral agents

  10. Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

    Institute of Scientific and Technical Information of China (English)

    Quan Zhou; Tong-Wei Yao; Su Zeng

    2001-01-01

    AIM: To study the influence of inducers of drug metabolism enzyme, β-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots.Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubstion of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R ( - ) isomer was observed in metabolism st Iow substrate concentrations of racemic propafenone, but lost the stereoselectivity st high substrate concentrations.However; in control group, no stereeselectivity was observed. The enzyme kinetic parameters were: ① Km.Control group: R( - ) 83 ± 6, S( + ) 94 ± 7; BNF group: R (-)105 ± 6, S( + )128 ± 14; DEX group: R( - ) 86± 11, S( + ) 118 ± 16; ② vmax. Control group: R( - ) 0.75 ± 0.16, S( + ) 0.72±0.07; BNF group: R( - )1.04± 0.15, S( + )1.07±14; DEX group: R( - ) 0.93 ± 0.06, S( + ) 1.04 ± 0.09; (③)Clint. Control group: R( - ) 8.9± 1.1, S( + ) 7.6±0.7; BNFgroup: R( - )9.9±0.9, S( + )8.3±0.7; DEX group: R( - )10.9± 0.8, S( + ) 8.9 ± 0.9. The enantiomeric differences in Km and Clint were both significant, but not in Vmax, in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group.Furthermore, Km and Umax were both significantly less than those in BNF or DEX group. In the rat liver microsorne induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at Iow substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereo.selective with R

  11. Hepatic biotransformation pathways and ruminal metabolic stability of the novel anthelmintic monepantel in sheep and cattle.

    Science.gov (United States)

    Ballent, M; Virkel, G; Maté, L; Viviani, P; Lanusse, C; Lifschitz, A

    2016-10-01

    Monepantel (MNP) is a new amino-acetonitrile derivative anthelmintic drug used for the treatment of gastrointestinal (GI) nematodes in sheep. The present work investigated the main enzymatic pathways involved in the hepatic biotransformation of MNP in sheep and cattle. The metabolic stability in ruminal fluid of both the parent drug and its main metabolite (monepantel sulphone, MNPSO2 ) was characterized as well. Additionally, the relative distribution of both anthelmintic molecules between the fluid and particulate phases of the ruminal content was studied. Liver microsomal fractions from six (6) rams and five (5) steers were incubated with a 40 μm of MNP. Heat pretreatment (50 °C for 2 min) of liver microsomes was performed for inactivation of the flavin-monooxygenase (FMO) system. Additionally, MNP was incubated in the presence of 4, 40, and 80 μm of methimazole (MTZ), a FMO inhibitor, or equimolar concentrations of piperonyl butoxide (PBx), a well-known general cytochrome P450 (CYP) inhibitor. In both ruminant species, MNPSO2 was the main metabolite detected after MNP incubation with liver microsomes. The conversion rate of MNP into MNPSO2 was fivefold higher (P MNP oxidation in cattle liver microsomes. On the other hand, PBx inhibited the production of MNPSO2 in liver microsomes of both sheep (58 to 98%, in a dose-dependent manner) and cattle (almost 100%, independently of the PBx concentration added). The incubation of MNP and MNPSO2 with ruminal contents of both species showed a high chemical stability without evident metabolism and/or degradation as well as an extensive degree of adsorption (83% to 90%) to the solid phase of the ruminal content. Overall, these results are a further contribution to the understanding of the metabolic fate of this anthelmintic drug in ruminants.

  12. D-pinitol attenuates the impaired activities of hepatic key enzymes in carbohydrate metabolism of streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Sivakumar, Selvaraj; Subramanian, Sorimuthu P

    2009-09-01

    During diabetes mellitus, endogenous hepatic glucose production is increased as a result of impaired activities of the key enzymes of carbohydrate metabolism, which leads to the condition known as hyperglycemia. D-pinitol, a bioactive constituent isolated from soybeans, has been shown to reduce hyperglycemia in experimental diabetes. We therefore designed this study to investigate the effect of oral administration of D-pinitol (50 mg/kg b. w. for 30 days) on the activities of key enzymes in carbohydrate and glycogen metabolism in the liver tissues of streptozotocin-induced diabetic rats. The efficacy was compared with glyclazide, a standard hypoglycemic drug. Oral administration of D-pinitol to diabetic group of rats showed a marked decrease in the levels of blood glucose, glycosylated hemoglobin and an increase in plasma insulin and body weight. The activities of the hepatic enzymes such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glycogen synthase and hepatic glycogen content were significantly (p pinitol. The results suggest that alterations in the activities of key metabolic enzymes of carbohydrate metabolism could be one of the biochemical rationale by which D-pinitol attenuates the hyperglycemic effect in diabetic rats.

  13. Hepatitis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008079 Relationship of HBV genotype and bcp and pc mutations with HBV DNA rebound after lamivudine therapy. SU Minghua(苏明华), et al. Dept Infect Dis Clin Hosp, Guangxi Med Univ, Nanning 530027. World Chin J Digestol 2007;15(33):3507-3513. Objective To investigate the relationship of HBV gene mutations with HBV DNA rebound after lamivudine therapy. Methods Twenty-seven hepatitis B patients with HBV DNA rebound after

  14. Concentrations, patterns and metabolites of organochlorine pesticides in relation to xenobiotic phase I and II enzyme activities in ringed seals (Phoca hispida) from Svalbard and the Baltic Sea

    Energy Technology Data Exchange (ETDEWEB)

    Routti, Heli, E-mail: heli.routti@npolar.n [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway); Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, 20014 Turku (Finland); Bavel, Bert van [MTM Research Centre, Orebro University, 70182 Orebro (Sweden); Letcher, Robert J. [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Arukwe, Augustine [Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim (Norway); Chu Shaogang [Wildlife Toxicology and Disease Program, Wildlife and Landscape Science Directorate, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario K1A 0H3 (Canada); Gabrielsen, Geir W. [Norwegian Polar Institute, Polar Environmental Centre, 9296 Tromso (Norway)

    2009-08-15

    The present study investigates the concentrations and patterns of organochlorine pesticides (OCPs) and their metabolites in liver and plasma of two ringed seal populations (Phoca hispida): lower contaminated Svalbard population and more contaminated Baltic Sea population. Among OCPs, p,p'-DDE and sum-chlordanes were the highest in concentration. With increasing hepatic contaminant concentrations and activities of xenobiotic-metabolizing enzymes, the concentrations of 3-methylsulfonyl-p,p'-DDE and the concentration ratios of pentachlorophenol/hexachlorobenzene increased, and the toxaphene pattern shifted more towards persistent Parlar-26 and -50 and less towards more biodegradable Parlar-44. Relative concentrations of the chlordane metabolites, oxychlordane and -heptachlorepoxide, to sum-chlordanes were higher in the seals from Svalbard compared to the seals from the Baltic, while the trend was opposite for cis- and trans-nonachlor. The observed differences in the OCP patterns in the seals from the two populations are probably related to the catalytic activity of xenobiotic-metabolizing enzymes, and also to differences in dietary exposure. - Contrasting patterns of organochlorine pesticides in two ringed seal populations.

  15. Prediction of bacterial growth on xenobiotics

    DEFF Research Database (Denmark)

    Brock, Andreas Libonati; Kästner, Matthias; Trapp, Stefan

    method, we evaluated it with both simple substrates (e.g. acetate, methanol, and glyoxylate) and xenobiotics (e.g 2,4-D, linuron, carbofuran, carbon tetrachloride, and toluene). Experimental data for the simple substrates were taken from [4], for xenobiotics from [6] and own experimental data. For simple...

  16. α-Mangostin Mediated Pharmacological Modulation of Hepatic Carbohydrate Metabolism in Diabetes Induced Wistar Rat

    Directory of Open Access Journals (Sweden)

    Vikas Kumar

    2016-09-01

    Full Text Available Garcinia mangostana L. (Fruit has been commonly used as folklore drug in the treatment of various types of diseases. The present experiment was designed to evaluate the potential effect of α-mangostin mediated pharmacological modulation of hepatic carbohydrate metabolism in streptozotocin (STZ induced diabetic rats. Oral glucose tolerance test (OGTT was performed in normoglycemic rats. Single intraperitoneal injection of STZ (60 mg/kg, body weight was used for induction the diabetes in Swiss albino (Wistar strain rats. The rats were divided into different groups. Blood glucose level, body weight, insulin, glycated hemoglobin and hemoglobin levels were recorded at regular intervals. Biochemical parameters, liver enzymes, lipid profile, antioxidant parameters and inflammatory cytokine mediators were also scrutinized. Histopathology study of kidney, pancreas and liver were performed. The result of OGTT study depicted the better utilization of glucose in experimental rats. STZ induced diabetic rats treated with α-mangostin (25, 50 and 100 mg/kg, p.o. and glibenclamide depicted the decline in the level of blood glucose; enhanced body weight and showed the better utilization of glucose by different organs. STZ induced diabetic rats treated with α-mangostin illustrated the increased level of plasma insulin, hemoglobin, hexokinase, HDL, total protein, SOD, CAT, GSH and declined level of glycated hemoglobin, fructose-1-6-biphosphatase, glucose-6-Phosphatase, TC, TG, LDL, VLDL, CRE, BUN, SGOT, SGPT, ALP and LPO at effective dose dependent manners. Histological study showed the inflamed blood vessels in diabetic kidney, which was less in α-mangostin treated rats; diabetic pancreatic showed the complete damage of β cells, islets, aciini and producing necrosis, but all damage was less obvious in α-mangostin treating group rats; diabetic liver showed the damage of hepatocytes as well as central vein but was less in treated groups. Considering the

  17. Alisol A 24-Acetate Prevents Hepatic Steatosis and Metabolic Disorders in HepG2 Cells

    Directory of Open Access Journals (Sweden)

    Lu Zeng

    2016-11-01

    Full Text Available Background: Non-alcoholic fatty liver disease (NAFLD is closely associated with metabolic disorders including hepatic lipid accumulation and inflammation. Alisol A 24-acetate, a triterpene from Alismatis rhizome, has multiple biologic activities such as hypolipidemic, anti-inflammatory and anti-diabetic. Thus we hypothesized that Alisol A 24 -acetate would have effect on NAFLD. The present study was conducted to investigate the therapeutic effects and potential mechanisms of Alisol A 24-acetate against hepatic steatosis in a free fatty acids (FFAs induced NAFLD cell model. Methods: This study was divided into four groups including Control group, Model group (FFA group, Alisol A 24-acetate (FFA+A group, Fenofibrate (FFA+F group. Preventive role of Alisol A 24-acetate was evaluated using 10µM Alisol A 24-acetate plus 1 mM FFA (oleate:palmitate=2:1 incubated with HepG2 cells for 24 h, which was determined by Oil Red O Staining, Oil Red O based colorimetric assay and intracellular triglyceride (TG content. Besides, the inflammatory cytokines tumor necrosis factor (TNF- α, interleukin (IL-6 levels as well as the protein and mRNA expressions that were involved in fatty acid synthesis and oxidation including Adiponectin, AMP-activated protein kinase (AMPK α, peroxisome proliferator-activated receptor (PPAR α, sterol regulatory element binding protein 1c (SREBP-1c, acetyl-CoA carboxylase (ACC, fatty acid synthase (FAS, carnitine palmitoyltransferase 1 (CPT1 and acyl coenzyme A oxidase 1 (ACOX1 were detected. Results: Alisol A 24-acetate significantly decreased the numbers of lipid droplets, Oil Red O lipid content, and intracellular TG content. Besides, inflammatory cytokines TNF-α, IL-6 levels were markedly inhibited by Alisol A 24-acetate. Furthermore, Alisol A 24-acetate effectively increased the protein and mRNA expressions of Adiponectin, the phosphorylation of AMPKα, CPT1 and ACOX1, whereas decreased SREBP-1c, the phosphorylation of ACC and

  18. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

    Science.gov (United States)

    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus.

  19. Anti-hepatitis C virus seropositivity is not associated with metabolic syndrome irrespective of age, gender and fibrosis.

    Science.gov (United States)

    Cheng, Yuan-Lung; Wang, Yuan-Chen; Lan, Keng-Hsin; Huo, Teh-Ia; Huang, Yi-Hsiang; Su, Chien-Wei; Lin, Han-Chieh; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

    2015-01-01

    Although many studies have tried to clarify the association between hepatitis C virus (HCV) infection and metabolic syndrome, few studies have comprehensively assessed their relationship stratified by different demographic characteristics. We aimed to investigate the correlation between metabolic syndrome and anti-HCV seropositivity in Taiwan. This study enrolled consecutive subjects who had received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Metabolic syndrome was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention. Among the 30616 subjects enrolled in this study, the prevalence of positive anti-HCV serology was 2.7%, and 28.8% were diagnosed with metabolic syndrome. By multivariate analysis, metabolic syndrome was associated with higher body mass index, older age, male sex, a higher level of alanine aminotransferase, gamma-glutamyltransferase, platelet count and the presence of fatty liver whereas anti-HCV seropositivity was not an independent variable for metabolic syndrome. Further stratifying the subjects by age and sex, and there was still no significant difference in HCV status between those with and without metabolic syndrome. Moreover, the stage of liver fibrosis represented by aspartate aminotransferase to platelet ratio index was also not correlated with metabolic syndrome in the subjects with anti-HCV seropositivity. In conclusion, although subjects with anti-HCV seropositivity had higher fasting glucose levels and lower cholesterol and triglyceride levels compared to those with negative anti-HCV test, anti-HCV seropositivity was not associated with metabolic syndrome based on the current diagnostic criteria irrespective of age, gender and the stage of hepatic fibrosis.

  20. Overview of Extracellular Microvesicles in Drug Metabolism

    Science.gov (United States)

    Conde-Vancells, Javier; Gonzalez, Esperanza; Lu, Shelly C.; Mato, Jose M.; Falcon-Perez, Juan M.

    2010-01-01

    Importance of the field Liver is the major body reservoir for enzymes involved in the metabolism of endogenous and xenobiotic compounds. Recently, it has been shown that hepatocytes release exosome-like vesicles to the extracellular medium, and the proteomic characterization of these hepatocyte-secreted exosomes has revealed the presence of several of these enzymes on them. Areas covered in this review A systematic bibliographic search focus on two related aspects: 1) xenobiotic-metabolizing enzymes that have been detected in microvesicles, and 2) microvesicles which are in the blood stream or secreted by cell-types with clear interactions with this fluid. What the reader will gain A discussion of these hepatocyte-secreted vesicles along with others microvesicles as enzymatic carriers in the context of extrahepatic drug-metabolizing systems. Take home message The contribution of many tissues including the liver to the microvesicles plasma population is supported by several reports. On the other hand, many enzymes involved in the metabolism of drugs have been detected in microvesicles. Together, these observations argue positively through a role of hepatic-microvesicles in spreading the liver metabolizing activities through the body contributing in this manner to extrahepatic drug metabolism systems what could be relevant for body homeostasis and pharmaceutical interests. PMID:20192903

  1. Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism

    Directory of Open Access Journals (Sweden)

    Kalhan Satish C

    2005-11-01

    Full Text Available Abstract Background The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function. Methods The gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP (EC 4.1.1.32 (PEPCK-C was deleted in mice by homologous recombination (PEPCK-C-/- mice and the metabolic consequences assessed. Results PEPCK-C-/- mice became severely hypoglycemic by day two after birth and then died with profound hypoglycemia (12 mg/dl. The mice had milk in their stomachs at day two after birth and the administration of glucose raised the concentration of blood glucose in the mice but did not result in an increased survival. PEPCK-C-/- mice have two to three times the hepatic triglyceride content as control littermates on the second day after birth. These mice also had an elevation of lactate (2.5 times, β-hydroxybutyrate (3 times and triglyceride (50% in their blood, as compared to control animals. On day two after birth, alanine, glycine, glutamine, glutamate, aspartate and asparagine were elevated in the blood of the PEPCK-C-/- mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-14C]-acetate, and [5-14C]-glutamate to 14CO2 by liver slices from PEPCK-C-/- mice at two days of age was greatly reduced, as was the rate of fatty acid synthesis from acetate and glucose. As predicted by the lack of PEPCK-C, the concentration of malate in the livers of the PEPCK-C-/- mice was 10 times that of controls. Conclusion We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for cataplerosis (i.e. the removal of citric acid cycle anions and that the failure of this process in the livers of PEPCK-C-/- mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.

  2. Trans-10,cis-12-CLA dysregulate lipid and glucose metabolism and induce hepatic NR4A receptors.

    Science.gov (United States)

    Navarro, Maria A; Badimon, Lina; Rodriguez, Cristina; Arnal, Carmen; Noone, Enda J; Roche, Helen M; Osada, Jesus; Martinez-Gonzalez, Jose

    2010-01-01

    Our aim was to assess the effect of two isomers of conjugated linoleic acids (CLA), cis-9,trans-11-CLA (c9,t11-CLA) and trans-10,cis-12-CLA (t10,c12-CLA), on glucose metabolism and hepatic expression of NR4A receptors, key transcription factors regulating gluconeogenesis. ApoE-deficient mice were fed isocaloric, isonitrogenous westernized diets enriched with c9,t11-CLA, t10,c12-CLA or linoleic acid (control diet). Plasma glucose, NEFA, triglyceride and cholesterol concentrations were significantly higher in the t10,c12-CLA group compared with c9,t11-CLA or control group. Plasma insulin concentrations were lowered by c9,t11-CLA compared with either control or t10,c12-CLA group. Hepatic expression of NR4A receptors (Nur77, Nurr1 and NOR-1) was induced by t10,c12-CLA while c9,t11-CLA had not effect. Consistently t10,c12-CLA up-regulated key genes involved in gluconeogenesis including glucose-6-phosphatase, enolase, phosphoenolpyruvate carboxykinase and pyruvate carboxylase. Hepatic expression of NR4A receptors correlated with plasma NEFA, with the expression of their target gene fatty acid transporter (FAT)/CD36 and with the accumulation of fat in the liver. These results suggest that t10,c12-CLA promote dysregulation of lipid and glucose metabolism, at least in part, by an isomer-specific modulation of hepatic expression of NR4A receptors.

  3. Isocaloric high-fat feeding directs hepatic metabolism to handling of nutrient imbalance promoting liver fat deposition

    KAUST Repository

    Díaz-Rúa, R.

    2016-03-22

    Background/Objectives: Consumption of fat-rich foods is associated with obesity and related alterations. However, there is a group of individuals, the metabolically obese normal-weight (MONW) subjects, who present normal body weight but have metabolic features characteristic of the obese status, including fat deposition in critical tissues such as liver, recognized as a major cause for the promotion of metabolic diseases. Our aim was to better understand metabolic alterations present in liver of MONW rats applying whole genome transcriptome analysis. Methods: Wistar rats were chronically fed a high-fat diet isocaloric relative to Control animals to avoid the hyperphagia and overweight and to mimic MONW features. Liver transcriptome analysis of both groups was performed. Results: Sustained intake of an isocaloric high-fat diet had a deep impact on the liver transcriptome, mainly affecting lipid metabolism. Although serum cholesterol levels were not affected, circulating triacylglycerols were lower, and metabolic adaptations at gene expression level indicated adaptation toward handling the increased fat content of the diet, an increased triacylglycerol and cholesterol deposition in liver of MONW rats was observed. Moreover, gene expression pointed to increased risk of liver injury. One of the top upregulated genes in this tissue was Krt23, a marker of hepatic disease in humans that was also increased at the protein level.Conclusion:Long-term intake of a high-fat diet, even in the absence of overweight/obesity or increase in classical blood risk biomarkers, promotes a molecular environment leading to hepatic lipid accumulation and increasing the risk of suffering from hepatic diseases.

  4. Musa Paradisiaca flower extract improves carbohydrate metabolism in hepatic tissues of streptozotocin-induced experimental diabetes in rats

    Institute of Scientific and Technical Information of China (English)

    Shanmuga Sundaram.C; Subramanian.S

    2012-01-01

    Objective: Musa Paradisiaca, commonly known as plantains have been traditionally used for various medicinal purposes. In the absence of an ideal drug to alleviate the primary and secondary complications of diabetes mellitus, search for novel drugs without side effects, preferably from plant origin continues. Recently, we have reported the presence of biologically active phytochemicals as well as the hypoglycemic activity of Musa paradisiaca tepals extract in STZ induced experimental diabetes in rats. The present study was aimed to evaluate the role of tepals, an integrated part of Musa paradisiaca flowers on carbohydrate metabolism in hepatic tissues of experimental diabetic rats. Methods: Streptozotocin-induced diabetic rats were treated with ethanolic extract of tepals at a concentration of 200mg/kg body weight/day for 30 days. The levels of fasting blood glucose, plasma insulin and glycosylated hemoglobin were estimated. The activities of key enzymes in carbohydrate metabolism such as glucokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in hepatic tissues were assayed. The levels of glycogen in hepatic tissues were also estimated. Results: Oral administration ofMusa paradisiaca tepals extract significantly improved the altered levels of blood glucose, plasma insulin, glycosylated hemoglobin and modulated the activities of carbohydrate metabolizing enzymes. The glycogen content in hepatic tissues was significantly increased in diabetic rats treated with tepals extract. Conclusions: The results of the present study clearly indicate that the tepals extract plays pivotal role to maintain normoglycemia in diabetes by modulating the activities of carbohydrate metabolic enzymes.

  5. The Effects of Chloroquine-Resistant and Chloroquine-Sensitive Strains of Berghei on Rodent Hepatic Drug-Metabolizing Enzymes

    Science.gov (United States)

    1993-10-14

    Dipetolllonema M<’I:stomys 42.94 106 58.46 viteolle Schistosollloll mansoni S . I1\\I!lnsoni Fasciola hepatica matalensis Mi ce (SWiss) Mice (Swiss...infected with Fasciola hepatica (Table 4). This may be due to direct residence of the parasites in their host’s liver and severe injury of the liver...vitro drug- metabolizing activity of the hepatic mixed function oxidase system in rats infected experimentally with Fasciola hepatica

  6. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

    Science.gov (United States)

    Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

    2016-02-01

    Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

  7. Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition

    Directory of Open Access Journals (Sweden)

    Malaisse WJ

    2008-12-01

    Full Text Available Abstract Background There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA depletion on hepatic metabolism. Results n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPARγ, and an increased β-oxidation (CPT1, PPARα and PGC1α without modification of fatty acid esterification (DGAT2, GPAT1, secretion (MTTP or intracellular transport (L-FABP. Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice. Conclusion n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between β-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.

  8. Interspecies variation in phase I metabolism of bufalin in hepatic microsomes from mouse, rat, dog, minipig, monkey, and human.

    Science.gov (United States)

    Ning, Jing; Hou, Jie; Wang, Ping; Wu, Jing-Jing; Dai, Zi-Ru; Zou, Li-Wei; Li, Wei; Ge, Guang-Bo; Ma, Xiao-Chi; Yang, Ling

    2015-01-01

    1. Bufalin (BF), one of the major bioactive compounds in traditional Chinese medicine (TCM) Chansu, has been found with various pharmacological and toxicological effects. This study aims to investigate the species differences in phase I metabolism of BF in hepatic microsomes from human and five common experimental animals. 2. Metabolite profiling demonstrated that two major metabolites were formed in liver microsomes from human and animal species in NADPH-generating system. Two major metabolites were identified as 5β-hydroxyl-bufalin and 3-keto-bufalin, with the help of authentic standards. CYP3A was assigned as the main isoform involved in both 5β-hydroxylation and 3-oxidation in all studied liver microsomes. The apparent kinetic parameters including substrate affinity and catalytic efficiency for 5β-hydroxylation and 3-oxidation of BF were also determined. 3. In summary, CYP3A mediated 5β-hydroxylation and 3-oxidation were two major metabolic pathways of BF in hepatic microsomes from human and five studied animals, but kinetic analysis demonstrated that the intrinsic clearances of these two metabolic pathways were much different among various species. The qualitative and quantitative interspecies study indicated that minipig exhibited the similar metabolic profile, kinetic behaviors and intrinsic metabolic clearances of BF phase I biotransformation in comparison with that of human.

  9. The suppression of hepatic glucose production improves metabolism and insulin sensitivity in subcutaneous adipose tissue in mice.

    Science.gov (United States)

    Casteras, Sylvie; Abdul-Wahed, Aya; Soty, Maud; Vulin, Fanny; Guillou, Hervé; Campana, Mélanie; Le Stunff, Hervé; Pirola, Luciano; Rajas, Fabienne; Mithieux, Gilles; Gautier-Stein, Amandine

    2016-12-01

    Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals. Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L-G6pc (-/-) mice). Morphological and metabolic changes in the adipose tissues were characterised by histological analyses, gene expression and protein content. Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver. Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.

  10. Hepatic lipid metabolism changes in short-and long-term prehepatic portal hypertensive rats

    Institute of Scientific and Technical Information of China (English)

    Maria-Angeles Aller; Elena Vara; Cruz García; Maria-Paz Nava; Alejandra Angulo; Fernando Sánchez-Patán; Ana Calderón; Patri Vergara; Jaime Arias

    2006-01-01

    AIM:To verify the impairment of the hepatic lipid metabolism in prehepatic portal hypertension.METHODS:The concentrations of free fatty acids,diacylglycerol, triglycerides, and phospholipids were assayed by using D-[U-14C] glucose incorporation in the different lipid fractions and thin-layer chromatography and cholesterol was measured by spectrophotometry,in liver samples of Wistar rats with partial portal vein ligation at short- (1 mo) and long-term (1 year) (i.e.portal hypertensive rats) and the control rats.RESULTS:In the portal hypertensive rats, liver phospholipid synthesis significantly decreased (7.42 ±0.50 vs 4.70 ± 0.44 nCi/g protein; P < 0.01) and was associated with an increased synthesis of free fatty acids (2.08 ± 0.14 vs 3.36 ± 0.33 nCi/g protein; P < 0.05),diacylglycerol (1.93 ± 0.2 vs 2.26 ± 0.28 nCi/g protein),triglycerides (2.40 ± 0.30 vs 4.49 ± 0.15 nCi/g protein)and cholesterol (24.28 ± 2.12 vs 57.66 ± 3.26 mg/gprotein; P < 0.01).CONCLUSION:Prehepatic portal hypertension in rats impairs the liver lipid metabolism. This impairment consists in an increase in lipid deposits (triglycerides,diacylglycerol and cholesterol) in the liver, accompanied by a decrease in phospholipid synthesis.

  11. Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling

    Science.gov (United States)

    Li, Zhi-qin; Gu, Xin-yu; Hu, Jin-xing; Ping, Yu; Li, Hua; Yan, Jing-ya; Li, Juan; Sun, Ran; Yu, Zu-jing; Zhang, Yi

    2016-01-01

    It has been suggested that Hepatitis C virus (HCV) core protein is associated with metabolic disorders of liver cell. However, the precise mechanism is still unclear. The aim of the present study was to explore the impact of HCV core protein on hepatocyte metabolism by HepG2 and the possible involvement of long non-coding (lnc) RNAs in this process. The effect of HCV core protein on lncRNAs expression was examined with quantitative RT-PCR (qRT-PCR). Manipulation of HVC core protein and lncRNA HOTAIR was to evaluate the role of interaction between them on cell metabolism-related gene expression and cellular metabolism. The potential downstream Sirt1 signal was examined by western blotting and qRT-PCR. Our data suggested that suppression of HOTAIR abrogates HCV core protein-induced reduction in Sirt1 and differential expression of glucose- and lipid-metabolism-related genes. Also it benefits for metabolic homoeostasis of hepatocyte indicated by restoration of cellular reactive oxygen species (ROS) level and NAD/NADH ratio. By manipulation of HOTAIR, we concluded that HOTAIR negatively regulates Sirt1 expression through affecting its promotor methylation. Moreover, overexpression of Sirt1 reverses pcDNA-HOTAIR-induced glucose- and lipid-metabolism-related gene expression. Our study suggests that HCV core protein causes dysfunction of glucose and lipid metabolism in liver cells through HOTAIR-Sirt1 signalling pathway. PMID:27129296

  12. Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency.

    Science.gov (United States)

    Korman, Stanley H; Waterham, Hans R; Gutman, Alisa; Jakobs, Cornelis; Wanders, Ronald J A

    2005-11-01

    Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorder.

  13. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.

    Science.gov (United States)

    Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc

    2003-11-13

    Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

  14. Current knowledge of detoxification mechanisms of xenobiotic in honey bees.

    Science.gov (United States)

    Gong, Youhui; Diao, Qingyun

    2017-01-01

    The western honey bee Apis mellifera is the most important managed pollinator species in the world. Multiple factors have been implicated as potential causes or factors contributing to colony collapse disorder, including honey bee pathogens and nutritional deficiencies as well as exposure to pesticides. Honey bees' genome is characterized by a paucity of genes associated with detoxification, which makes them vulnerable to specific pesticides, especially to combinations of pesticides in real field environments. Many studies have investigated the mechanisms involved in detoxification of xenobiotics/pesticides in honey bees, from primal enzyme assays or toxicity bioassays to characterization of transcript gene expression and protein expression in response to xenobiotics/insecticides by using a global transcriptomic or proteomic approach, and even to functional characterizations. The global transcriptomic and proteomic approach allowed us to learn that detoxification mechanisms in honey bees involve multiple genes and pathways along with changes in energy metabolism and cellular stress response. P450 genes, is highly implicated in the direct detoxification of xenobiotics/insecticides in honey bees and their expression can be regulated by honey/pollen constitutes, resulting in the tolerance of honey bees to other xenobiotics or insecticides. P450s is also a key detoxification enzyme that mediate synergism interaction between acaricides/insecticides and fungicides through inhibition P450 activity by fungicides or competition for detoxification enzymes between acaricides. With the wide use of insecticides in agriculture, understanding the detoxification mechanism of insecticides in honey bees and how honeybees fight with the xenobiotis or insecticides to survive in the changing environment will finally benefit honeybees' management.

  15. Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

    Institute of Scientific and Technical Information of China (English)

    Hong-xia GUO; Dai-hua LIU; Ying MA; Jin-feng LIU; Ying WANG; Zhiyan DU; Xin WANG; Jing-kangSHEN; Hong-li PENG

    2009-01-01

    Aim: Baicalin, one of the major flavonoids in Scutellaria baicalensis, possesses antioxidant and anti-inflammatory properties. However, the effects of baicalin on metabolic disorders and hepatic steatosis have not been investigated.Methods: Body weight was examined in high-fat diet (HFD)-fed rats with or without baicalin treatment. At the end of the experiment, serum biochemical parameters, liver histology and lipid profile were analyzed to assess whether the animals were suffering from metabolic disorders or hepatic steatosis. In the liver, the phosphorylation of AMP activated protein kinase (AMPK) and acetyl-CoA carboxy-lase (ACC) and the gene expression of some enzymes involved in lipogenesis were examined. The effects of baicalin on the phosphorylation of AMPK and lipid accumulation induced by high glucose in human hepatoma HepG2 cells were also examined. Results: Baicalin (80 mg/kg) administered ip for 16 weeks suppressed body weight gain in HFD-fed rats. Weight reduction was accompanied by the reduction of visceral fat mass. Baicalin significantly decreased the elevated serum cholesterol, free fatty acid and insulin concentrations caused by the HFD. Baicalin also suppressed systemic inflammation by reducing the serum level of tumor necrosis factor a. Baicalin reduced hepatic lipid accumulation, enhanced the phosphorylation of AMPK and ACC and down-regulated genes involved in lipogenesis, including fatty acid synthase and its upstream regulator SREBP-1c. In HepG2 cells, baicalin (5 and 10 μmol/L) increased the phosphorylation of AMPK and decreased lipid accumulation following the addition of high glucose. Conclusion: Our study suggests that baicalin might have beneficial effects on the development of hepatic steatosis and obesity-related disorders by targeting the hepatic AMPK.

  16. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation.

    Science.gov (United States)

    Schwarz, Jean-Marc; Mulligan, Kathleen; Lee, Jeongae; Lo, Joan C; Wen, Michael; Noor, Mustafa A; Grunfeld, Carl; Schambelan, Morris

    2002-02-01

    We recently reported that treatment with a pharmacologic dose of recombinant human growth hormone (GH) resulted in a significant loss of body fat and gain in lean tissue in HIV-infected patients with syndromes of fat accumulation. However, insulin-mediated glucose disposal decreased transiently after one month of GH therapy. The present paper focuses on the changes of hepatic carbohydrate and fat metabolism associated with GH treatment in the same subjects. We assessed hepatic insulin sensitivity under both fasting and hyperinsulinemic-euglycemic clamp conditions prior to and after one and six months of GH treatment (3 mg/day) in five patients using stable isotope tracer techniques. Indirect calorimetry, and measurements of lipid concentrations. Fasting endogenous glucose production (EGP) increased significantly at one month (12.0 +/- 0.7 to 14.9 +/- 0.9 micromol/kg/min, P glucogenesis (GNG) (3.5 +/- 0.9 to 5.2 +/- 0.9 and 5.8 +/-1.2 micromol/kg/min, n = 4, P < 0.01 and P < 0.01 at one and six months, respectively); small changes in hepatic glycogenolysis also contributed. Sustained increases in lipolysis and progressive decreases in hepatic fractional de novo lipogenesis (DNL) and triglyceride concentrations occurred with GH treatment. These changes were accompanied by an improved lipid profile with a significant increase in HDL cholesterol and significant decreases in total and LDL cholesterol and triglyceride levels, the latter consistent with the decrease in hepatic DNL. During a hyperinsulinemic-euglycemic glucose clamp, EGP and GNG were markedly suppressed compared to the corresponding time points under fasting conditions, albeit less so when measured after one month of GH treatment. Thus, in HIV-infected patients with abnormal fat distribution, pharmacologic doses of GH improved the overall lipid profile, but worsened glucose homeostasis under both fasting and hyperinsulinemic conditions. The combined implications of these positive and negative metabolic

  17. The effect of beta-naphthoflavone on the metabolism of amiodarone by hepatic and extra-hepatic microsomes.

    Science.gov (United States)

    Elsherbiny, Marwa E; El-Kadi, Ayman O S; Brocks, Dion R

    2010-06-02

    Amiodarone is a potent antiarrhythmic drug with several limiting side effects, some of which have been correlated with increased levels of its more toxic metabolite, desethylamiodarone. Elevated serum desethylamiodarone to amiodarone ratios are associated with a risk of amiodarone-induced pulmonary toxicity. Polycyclic aromatic hydrocarbons such as beta-naphthoflavone are known to increase desethylamiodarone levels in rat in vivo. In this article we investigated if this increase was solely due to increased formation as a result of cytochrome P450 (CYP) 1A1 and 1A2 induction in different rat hepatic and extra-hepatic tissues. Additionally, the effect of amiodarone treatment on CYP1A1 and 1A2 gene expression and activity was investigated. In rats, beta-naphthoflavone was found to increase desethylamiodarone forming activity in lung and kidney microsomes. Amiodarone increased beta-naphthoflavone mediated induction of CYP1A1 gene expression in liver, lung and kidney. However, there was no significant change in CYP1A activity. As expected, the data indicated that the increase in desethylamiodarone levels in vivo was partly due to increased formation through CYP1A1 induction, although increased formation was only evident in some extra-hepatic tissues. Amiodarone treatment did not affect basal or induced CYP1A activity.

  18. Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model.

    Science.gov (United States)

    Zheng, Ze; Xu, Xiaohua; Zhang, Xuebao; Wang, Aixia; Zhang, Chunbin; Hüttemann, Maik; Grossman, Lawrence I; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong

    2013-01-01

    Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diametersliver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis. Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM(2.5) for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM(2.5) exposure promotes liver pathogenesis. Mice exposed to PM(2.5) for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM(2.5) exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM(2.5) led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM(2.5) exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver. Our study suggests that PM(2.5) exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  19. Ursodeoxycholic acid treatment of hepatic steatosis: a (13)C NMR metabolic study.

    Science.gov (United States)

    Nunes, Patrícia M; Jones, John G; Rolo, Anabela P; Palmeira, Carlos M M; Carvalho, Rui A

    2011-11-01

    Ursodeoxycholic acid (UDCA) is commonly used for the treatment of hepatobiliary disorders. In this study, we tested whether a 4-week treatment with this bile acid (12-15 mg/kg/day) could improve hepatic fatty acid oxidation in obese Zucker rats - a model for nonalcoholic fatty liver disease and steatosis. After 24 h of fasting, livers were perfused with physiological concentrations of [U-(13) C]nonesterified fatty acids and [3-(13) C]lactate/[3-(13) C]pyruvate. Steatosis was associated with abundant intracellular glucose, lactate, alanine and methionine, and low concentrations of choline and betaine. Steatotic livers also showed the highest output of glucose and lactate. Glucose and glycolytic products were mostly unlabeled, indicating active glycogenolysis and glycolysis after 24 h of fasting. UDCA treatment resulted in a general amelioration of liver metabolic abnormalities with a decrease in intracellular glucose and lactate, as well as their output. Hepatic betaine and methionine were also normalized after UDCA treatment, suggesting the amelioration of anti-oxidative defenses. Choline levels were not affected by the bile acid, which may indicate a deficient synthesis of very-low-density lipoproteins. The percentage contribution of [U-(13) C]nonesterified fatty acids to acetyl-coenzyme A entering the tricarboxylic acid (TCA) cycle was significantly lower in livers from Zucker obese rats relative to control rats: 23.1 ± 4.9% versus 44.1 ± 2.7% (p  0.05), comparable with control group values. The TCA cycle activity subsequent to fatty acid oxidation was reduced in steatotic livers and improved when UDCA was administered (0.24 ± 0.04 versus 0.37 ± 0.05, p = 0.05). We further suggest that the mechanism of action of UDCA is either related to the activity of the farnesoid receptor, or to the amelioration of the anti-oxidative defenses and cell nicotinamide adenine dinucleotide (NAD(+) /NADH) ratio, favoring TCA cycle activity and β-oxidation.

  20. t-10, c-12 CLA dietary supplementation inhibits atherosclerotic lesion development despite adverse cardiovascular and hepatic metabolic marker profiles.

    Science.gov (United States)

    Mitchell, Patricia L; Karakach, Tobias K; Currie, Deborah L; McLeod, Roger S

    2012-01-01

    Animal and human studies have indicated that fatty acids such as the conjugated linoleic acids (CLA) found in milk could potentially alter the risk of developing metabolic disorders including diabetes and cardiovascular disease (CVD). Using susceptible rodent models (apoE(-/-) and LDLr(-/-) mice) we investigated the interrelationship between mouse strain, dietary conjugated linoleic acids and metabolic markers of CVD. Despite an adverse metabolic risk profile, atherosclerosis (measured directly by lesion area), was significantly reduced with t-10, c-12 CLA and mixed isomer CLA (Mix) supplementation in both apoE(-/-) (pCLA supplemented animals having distinct patterns, suggestive of hepatic insulin resistance, regardless of mouse strain. The effect of CLA supplementation on hepatic lipid and fatty acid composition was explored in the LDLr(-/-) strain. Dietary supplementation with t-10, c-12 CLA significantly increased liver weight (pCLA also increased the ratio of 18∶1 to 18∶0 fatty acid in the liver suggesting an increase in the activity of stearoyl-CoA desaturase. Changes in plasma adiponectin and liver weight with t-10, c-12 CLA supplementation were evident within 3 weeks of initiation of the diet. These observations provide evidence that the individual CLA isomers have divergent mechanisms of action and that t-10, c-12 CLA rapidly changes plasma and liver markers of metabolic syndrome, despite evidence of reduction in atherosclerosis.

  1. Potential for anaerobic conversion of xenobiotics

    DEFF Research Database (Denmark)

    Mogensen, Anders Skibsted; Dolfing, J.; Haagensen, Frank

    2003-01-01

    This review covers the latest research on the anaerobic biodegradation of aromatic xenobiotic compounds, with emphasis on surfactants, polycyclic aromatic hydrocarbons, phthalate esters, polychlorinated biphenyls, halogenated phenols, and pesticides. The versatility of anaerobic reactor systems...

  2. A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD

    Science.gov (United States)

    Ashworth, William B.; Bogle, I. David L.

    2016-01-01

    In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the

  3. A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD.

    Directory of Open Access Journals (Sweden)

    William B Ashworth

    2016-09-01

    Full Text Available In non-alcoholic fatty liver disease (NAFLD, lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation

  4. Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι.

    Science.gov (United States)

    Sajan, Mini P; Nimal, Sonali; Mastorides, Stephen; Acevedo-Duncan, Mildred; Kahn, C Ronald; Fields, Alan P; Braun, Ursula; Leitges, Michael; Farese, Robert V

    2012-04-01

    Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small-molecule PKC-ι/λ inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-λ, in which partial deficiency of muscle PKC-λ impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)], binds to the substrate-binding site of PKC-λ/ι, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PB1-binding domains of aPKC-λ/ι/ζ and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKC-dependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-ι in obesity, the metabolic syndrome, and type 2 diabetes mellitus and suggest that 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)] and aurothiomalate or similar agents that

  5. Metabolic effects of a novel bioartificial liver on serum from severe hepatitis patients: an in vitro study

    Institute of Scientific and Technical Information of China (English)

    闫峰; 赵军; 马建仓; 李宗芳; 苏清华

    2003-01-01

    Objective To establish a novel bioartificial liver (BAL) consisting of spheroids of porcine hepatocytes in a hollow-fiber bioreactor, and to perform an in vitro study on its metabolic effects on the serum from severe hepatitis B patients.Methods Hepatocytes were isolated from pup pigs and cultured as aggregate spheroids through rotation and vibration. Phase-contrast microscopy, transmission electron microscopy, and scanning electron microscopy were used for morphological detection of hepatocyte spheroids. The hepatocyte spheroids were then transferred into the shell of a polysulfone hollow-fiber bioreactor, creating a novel BAL. Diluted serum samples of severe hepatitis B patients were circulated for 3 hours each into the bioreactor, by using an extracorporeal circulatory system. Every half hour, including both before and after perfusion, serum samples were collected to assay total bilirubin (TBIL), total protein (TP), albumin (ALB), and globulin (GLB) concentrations in order to judge the metabolic effects of this novel BAL. Results Most hepatocytes had formed spheroids with high viability after 24 hours in culture. After 3 hours of perfusion, when compared with the control group, the serum concentration of TBIL in the treatment group decreased significantly (P<0.01), but the serum concentrations of TP and ALB increased significantly (P<0.05). Conclusions Hepatocytes can be conveniently cultured as aggregate spheroids through a rotation and vibration method. The novel BAL is efficient in removing bilirubin from the serum of severe hepatitis B patients, and in supplying the serum with ALB. Thus, the BAL might provide effective therapy for patients with severe hepatitis B.The extracorporeal bioartificial liver support system (EBLSS) has been established to compensate for hepatic function in patients with severe hepatopathy, and to provide supportive therapy for these patients. EBLSS has an important status in the research of artificial organs. At present, the study

  6. Hepatic metabolism affects the atropselective disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice.

    Science.gov (United States)

    Wu, Xianai; Barnhart, Christopher; Lein, Pamela J; Lehmler, Hans-Joachim

    2015-01-06

    To understand the role of hepatic vs extrahepatic metabolism in the disposition of chiral PCBs, we studied the disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) and its hydroxylated metabolites (HO-PCBs) in mice with defective hepatic metabolism due to the liver-specific deletion of cytochrome P450 oxidoreductase (KO mice). Female KO and congenic wild type (WT) mice were treated with racemic PCB 136, and levels and chiral signatures of PCB 136 and HO-PCBs were determined in tissues and excreta 3 days after PCB administration. PCB 136 tissue levels were higher in KO compared to WT mice. Feces was a major route of PCB metabolite excretion, with 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol being the major metabolite recovered from feces. (+)-PCB 136, the second eluting PCB 136 atropisomers, was enriched in all tissues and excreta. The second eluting atropisomers of the HO-PCBs metabolites were enriched in blood and liver; 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol in blood was an exception and displayed an enrichment of the first eluting atropisomers. Fecal HO-PCB levels and chiral signatures changed with time and differed between KO and WT mice, with larger HO-PCB enantiomeric fractions in WT compared to KO mice. Our results demonstrate that hepatic and, possibly, extrahepatic cytochrome P450 (P450) enzymes play a role in the disposition of PCBs.

  7. Alternative splicing interference by xenobiotics.

    Science.gov (United States)

    Zaharieva, Emanuela; Chipman, J Kevin; Soller, Matthias

    2012-06-14

    The protein coding sequence of most eukaryotic genes (exons) is interrupted by non-coding parts (introns), which are excised in a process termed splicing. To generate a mature messenger RNA (mRNA) hundreds of combinatorial protein-protein and RNA-protein interactions are required to splice out often very large introns with high fidelity and accuracy. Inherent to splicing is the use of alternative splice sites generating immense proteomic diversity from a limited number of genes. In humans, alternative splicing is a major mode of regulating gene expression, occurs in over 90% of genes and is particularly abundant in the brain. Only recently, it has been recognized that the complexity of the splicing process makes it susceptible to interference by various xenobiotics. These compounds include antineoplastic substances, commonly used drugs and food supplements and cause a spectrum of effects ranging from deleterious inhibition of general splicing to highly specific modifications of alternative splicing affecting only certain genes. Alterations in splicing have been implicated in numerous diseases such as cancer and neurodegeneration. Splicing regulation plays an important role in the execution of programmed cell death. The switch between anti- and pro-apoptotic isoforms by alternative splice site selection and misregulation of a number of splicing factors impacts on cell survival and disease. Here, our current knowledge is summarized on compounds interfering with general and alternative splicing and of the current methodology to study changes in these processes relevant to the field of toxicology and future risk assessments.

  8. Nonalcoholic hepatic steatosis: association with metabolic syndrome and cardiovascular risk factors in obese adolescents

    Directory of Open Access Journals (Sweden)

    Wener Barbosa Resende

    2014-03-01

    Full Text Available Objective: To evaluate the association between nonalcoholic hepatic steatosis (NAHS, metabolic syndrome (MS and cardiovascular risk factors (CRF in obese adolescents. Methods: Cross-sectional observational study with a quantitative approach, carried out from June to August 2011. The volunteers were randomly selected and referred to clinical evaluation in the endocrinology and cardiology units at the clinics hospital of the Federal University of Uberlândia, being included 34 adolescents of 14-19 years above the 95th percentile of the growth curve. NAHS was assessed by ultrasonography. The MS and CRF were diagnosed by the International Diabetes Federation criteria. Results: The sample consisted of 14 male and 20 female patients aged 16.8 ± 1.6 and body mass index (BMI of 35.7 ± 3.9. The occurrence of NAHS and MS was 76.5% and 50%, respectively. Males had a higher incidence of NAHS (78.6%, SM (64.3% and association of NAHS with MS (50%. Regarding the CRF, 100% (n=34, 61.8% (n=21 and 52.9% (n=18 of the adolescents had elevated values of waist circumference (WC, low-density lipoprotein cholesterol (LDL-C and systolic blood pressure (SBP, respectively, and 52.9% (n=18 showed low levels of high-density lipoprotein cholesterol (HDL-C. There were correlations between MS and triglycerides; systolic and diastolic blood pressure and HDL-C; and between NAHS and BMI and WC. Conclusion: A high occurrence of NAHS, SM and CRF was observed in obese adolescents. A strong correlation was observed between MS and NAHS, and between FRC and NAHS and SM. doi:10.5020/18061230.2014.p131

  9. Brief maternal deprivation of rats reduces hepatic mixed function oxidase activities

    Energy Technology Data Exchange (ETDEWEB)

    Vesell, E.S. (Pennsylvania State Univ., Hershey (USA)); Heubel, F.; Netter, K.J. (Philipps-Universitaet, Lahnberge (Germany, F.R.))

    1989-01-01

    Deprivation of pups from mother and sibs for 3 min daily from day 5 today 41 of life reduced activities of 4 hepatic mixed function oxidases (MFO) expressed per mg protein in male rats compared to unhandled control rats. These decreases, though generally small, 22.4% and under, reached statistical significance for the substrates aminopyrine, benzphetamine and ethoxycoumarin. This handling procedure did not consistently affect the inductive response to phenobarbital. Previously ignored as a source of variability in response to xenobiotics, handling appears from these results to merit further investigation as such a factor in uninduced rats. Differences among rats in handling could contribute to large day-to-day variations in their metabolism of xenobiotics.

  10. Evaluation of the intestinal toxicity and transport of xenobiotics utilizing precision-cut slices

    NARCIS (Netherlands)

    Niu, Xiaoyu; de Graaf, Inge A. M.; Groothuis, Geny M. M.

    1. The precision-cut intestinal slice (PCIS) technology is a relatively new addition to the battery of in vitro assays for evaluation of xenobiotic toxicity, metabolism, and transport. 2. The intestine is an important target for drug-induced toxicity due to its high exposure after oral

  11. Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans

    DEFF Research Database (Denmark)

    Jürgens, Gesche; Christensen, Hanne Rolighed; Brøsen, Kim;

    2002-01-01

    Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.......Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes....

  12. Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

    Science.gov (United States)

    Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-08-01

    Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns.

  13. Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.

    Science.gov (United States)

    Sopasakis, Victoria Rotter; Liu, Pixu; Suzuki, Ryo; Kondo, Tatsuya; Winnay, Jonathon; Tran, Thien T; Asano, Tomoichiro; Smyth, Graham; Sajan, Mini P; Farese, Robert V; Kahn, C Ronald; Zhao, Jean J

    2010-03-03

    The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110alpha in liver results in markedly blunted insulin signaling with decreased generation of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110beta. As a result, mice with hepatic knockout of p110alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110alpha in liver did not respond to metformin treatment. Together, these data indicate that the p110alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism. 2010 Elsevier Inc. All rights reserved.

  14. Maternal high-fat diet during pregnancy and lactation affects hepatic lipid metabolism in early life of offspring rat

    Indian Academy of Sciences (India)

    YANHONG HUANG; TINGTING YE; CHONGXIAO LIU; FANG FANG; YUANWEN CHEN; YAN DONG

    2017-06-01

    We investigated whether maternal over-nutrition during pregnancy and lactation affects the offspring’s lipidmetabolism at weaning by assessing liver lipid metabolic gene expressions and analysing its mechanisms on thedevelopment of metabolic abnormalities. Female Sprague–Dawley rats were fed with standard chow diet (CON)or high-fat diet (HFD) for 8 weeks, and then continued feeding during gestation and lactation. The offspringwhose dams were fed with HFD had a lower birth weight but an increased body weight with impaired glucosetolerance, higher serum cholesterol, and hepatic steatosis at weaning. Microarray analyses showed that there were120 genes differently expressed between the two groups. We further verified the results by qRT-PCR. Significantincrease of the lipogenesis (Me1, Scd1) gene expression was found in HFD (P<0.05), and up-regulated expressionof genes (PPAR-α, Cpt1α, Ehhadh) involved in β-oxidation was also observed (P<0.05), but the Acsl3 gene wasdown-regulated (P<0.05). Maternal over-nutrition could not only primarily induce lipogenesis, but also promotelipolysis through an oxidation pathway as compensation, eventually leading to an increased body weight,impaired glucose tolerance, elevated serum cholesterol and hepatic steatosis at weaning. This finding may providesome evidence for a healthy maternal diet in order to reduce the risk of metabolic diseases in the early life of theoffspring.

  15. Effects of guar gum and cellulose on glucose absorption, hormonal release and hepatic metabolism in the pig

    Science.gov (United States)

    Nunes, C. S.; Malmlof, K.

    1992-01-01

    Six Large White pigs (mean body-weight 59 (SE 1.7) kg) were surgically fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein, as well as with electromagnetic flow probes around the portal vein and the hepatic artery, and allowed to recover. The non-anaesthetized animals were given a basal non-fibre diet (diet A) alone or together with 60 g guar gum/kg (diet B) or 150 g purified cellulose/kg (diet C) by substitution for mica. The diets were given for weekly periods and according to a replicated 3 x 3 Latin square design. On the last day of each such adaptation period, test meals of 800 g were given before blood sampling. Sampling was continued for 8 h. Guar gum strongly reduced glucose apparent absorption without changing the absorption and the hepatic uptake profiles. Production rates of insulin, gastric inhibitory polypeptide and insulin-like growth factor-1 (IGF-1) were lowest after guar gum ingestion. However, the reductions in peripheral blood insulin levels caused by guar gum were not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly secreted by the gut, whereas the liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut-produced IGF-1. Guar gum ingestion appeared also to decrease glucagon secretion. Cellulose at the level consumed had very few effects on the variables considered. It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the metabolic effects described.

  16. Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

    Science.gov (United States)

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

  17. Side effects of budesonide in liver cirrhosis due to chronic autoimmune hepatitis: Influence of hepatic metabolism versus portosystemic shunts on a patient complicated with HCC

    Institute of Scientific and Technical Information of China (English)

    Andreas Geier; Carsten Gartung; Christoph G.Dietrich; Hermann E. Wasmuth; Patrick Reinatz; Siegfried Matern

    2003-01-01

    AIM: To investigate the systemic availability of budesonide in a patient with Child A cirrhosis due to autoimmune hepatitis (AIH) and primary hepatocellular carcinoma, who developed serious side effects.METHODS: Serum levels of budesonide, 6β-OH-budesonide and 16α-OH-prednisolon were measured by HPLC/MS/MS;portosystemic shunt-index (SI) was determined by 99mTc nuclear imaging. All values were compared with a matched control patient without side effects.RESULTS: Serum levels of budesonide were 13-fold increased in the index patient. The ratio between serum levels of the metabolites 6β-OH-budesonide and 16α-OHprednisolone, respectively, and serum levels of budesonide was diminished (1.0 vs. 4.0 for 6β-OH-budesonide, 4.2 vs.10.7 for 16α-OH-prednisolone). Both patients had portosystemic SI (5.7 % and 3.1%) within the range of healthy subjects.CONCLUSION: Serum levels of budesonide vary up to 13-fold in AIH patients with Child A cirrhosis in the absence of relevant portosystemic shunting. Reduced hepatic metabolism, as indicated by reduced metabolite-to-drug ratio, rather than portosystemic shunting may explain systemic side effects of this drug in cirrhosis.

  18. Influence of dietary macronutrients on induction of hepatic drug metabolizing enzymes by Coleus forskohlii extract in mice.

    Science.gov (United States)

    Yokotani, Kaori; Chiba, Tsuyoshi; Sato, Yoko; Nakanishi, Tomoko; Murata, Masatsune; Umegaki, Keizo

    2013-01-01

    From studies in mice, we have reported that Coleus forskohlii extract (CFE), a popular herbal weight-loss ingredient, markedly induced hepatic drug metabolizing enzymes, especially cytochrome P450 (CYP), and interacted with co-administered drugs. This study was designed to examine how the induction of drug metabolizing enzymes by CFE was influenced by different levels of macronutrients in the diet. Mice were fed a non-purified diet or semi-purified diet with and without CFE (0.3-0.5%) for 14-18 d, and changes in the ratio of liver weight to body weight, an indicator of hepatic CYP induction, and hepatic drug metabolizing enzymes were analyzed. The ratio of liver weight to body weight, content and activities of CYPs, and activity of glutathione S-transferase were higher in a semi-purified standard diet (AIN93G formula) group than in high sucrose (62.9%) and high fat (29.9%) diet groups. Different levels of protein (7%, 20%, and 33%) in the diets did not influence CFE-induced CYP induction or increase the ratio of liver weight to body weight. The effect of CFE on the ratio of liver weight to body weight was higher with a semi-purified diet than with a non-purified diet, and was similar between dietary administration and intragastric gavage when the CFE dose and the diet were the same. There was a positive correlation between CFE-induced CYP induction and the content of starch in the diets, suggesting that dietary starch potentiates CFE-induced CYP induction in mice. The mechanism of enhanced CYP induction remains unclear.

  19. Interactions of Orthosiphon stamineus and Morinda citrifolia with hepatic aminopyrine metabolism by CYP3A in rats

    Directory of Open Access Journals (Sweden)

    J H Chin

    2009-01-01

    Full Text Available Herb-drug interaction studies have getting attention recently due to the increasingly use of herbal products worldwide. The porpose of the present study was to examine the in vitro effect of methanol leaf extract of Orthosiphon stamineus and Morinda citrofolia fruit juice extract on hepatic aminopyrine metabolism by CYP 3A in different age of normal and STZ-induced diabetic Sprague Dawley (SD rats. Isolated rat hepatocytes were prepared using the collagenase perfusion technique. Aminopyrine was used as a probe substrate to determine the hepatic levels of CYP 3A by measuring the activity of N-demethylation of aminopyrine in rat hepatocytes according to the method described by Nash. Results obtained showed that aminopyrine N-demethylase activity measured from all diabetic rat hepatocytes was not affected by 0. stamineus and M. citrifolia extract. A significant decrease in the aminopyrine N-demethylase activity was observed in the normal old male SD rat hepatocytes preincubated with 0.1 mg/kg (P< 0.01 of methanol extract of 0. stamineus when compared to the respective control group. M. citrifolia juice extract at 0.1 mg/ml (P< 0.01 significantly increased aminopyrine N-demethylase activity in normal adult male SD rat hepatocytes as compared to the control group. For conclusion, both M. citrifolia and 0. stamineus extract could affect the in vitro metabolism of aminopyrine by CYP3A in normal rat hepatocytes. No significant change in the hepatic aminopyrine metabolism was observed in the diabetic rats after incubating with different concentrations of M. citrifolia and 0. stamineus extracts. The observed herb-drug interactions in the present study was age- and disease-dependent.

  20. Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

    Science.gov (United States)

    Almatrafi, Manal Mused; Vergara-Jimenez, Marcela; Murillo, Ana Gabriela; Norris, Gregory H.; Blesso, Christopher N.; Fernandez, Maria Luz

    2017-01-01

    To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver. PMID:28640194

  1. Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Manal Mused Almatrafi

    2017-06-01

    Full Text Available To investigate the mechanisms by which Moringa oleifera leaves (ML modulate hepatic lipids, guinea pigs were allocated to either control (0% ML, 10% Low Moringa (LM or 15% High Moringa (HM diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH and triglyceride (TG metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG with the lowest concentrations in the HM group (p < 0.001, consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL-1β and interferon-γ, were lowest in the HM group (p < 0.005. Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01. This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.

  2. Virgin coconut oil improves hepatic lipid metabolism in rats--compared with copra oil, olive oil and sunflower oil.

    Science.gov (United States)

    Arunima, S; Rajamohan, T

    2012-11-01

    Effect of virgin coconut oil (VCO) on lipid levels and regulation of lipid metabolism compared with copra oil (CO), olive oil (OO), and sunflower oil (SFO) has been reported. Male Sprague-Dawley rats were fed different oils at 8% level for 45 days along with synthetic diet. Results showed that VCO feeding significantly lowered (P VCO than other groups. Hepatic lipogenesis was also down regulated in VCO fed rats, which was evident from the decreased activities of enzymes viz., HMG CoA reductase, glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase and malic enzyme. In addition, VCO significantly (P VCO by regulating the synthesis and degradation of lipids.

  3. Disruption of the Acyl-CoA binding protein gene delays hepatic adaptation to metabolic changes at weaning

    DEFF Research Database (Denmark)

    Neess, Ditte; Marcher, Ann-Britt; Bloksgaard, Maria;

    -CoA esters between different enzymatic systems. However, little is known about the in vivo function in mammalian cells. We have generated mice with targeted disruption of ACBP (ACBP-/-). These mice are viable and fertile and develop normally. However, around weaning the ACBP-/- mice show decreased growth...... to target sites in chromatin. In conclusion, lack of ACBP causes elevated levels of plasma and hepatic lipids during weaning, which interferes with the normal metabolic adaptation to weaning by delaying induction of the lipogenic gene programs in the liver....

  4. The impact of obesity and metabolic syndrome on chronic hepatitis B and drug-induced liver disease.

    Science.gov (United States)

    Pais, Raluca; Rusu, Elena; Ratziu, Vlad

    2014-02-01

    Steatosis and insulin resistance (IR) are no more frequent in chronic hepatitis B (CHB) than in the general population. Although experimental studies suggest that the HBx protein induces liver fat, human studies have shown that steatosis and IR are related to coexistent metabolic risk factors, thus epidemiologically linked rather than virally induced. Diabetes and obesity are associated with advanced fibrosis and increased risk of hepatocellular carcinoma in CHB. Despite abundant experimental data showing that fatty liver is more susceptible to liver injury, drug-induced liver disease seems no more frequent in NAFLD patients, except, possibly, a higher incidence but not severity of acetaminophen hepatotoxicity.

  5. Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring.

    Science.gov (United States)

    Clayton, Zoe E; Vickers, Mark H; Bernal, Angelica; Yap, Cassandra; Sloboda, Deborah M

    2015-01-01

    Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing.

  6. Association between Leptin, Metabolic Factors and Liver Histology in Patients with Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Robert P Myers

    2007-01-01

    Full Text Available BACKGROUND: Steatosis is common in hepatitis C virus (HCV-infected patients and likely accelerates fibrosis progression. Leptin, the peptide product of the obesity gene (ob, has been implicated in hepatic fibrogenesis; circulating levels of leptin correlate with body fat mass. The objective of the present study was to determine the clinical and histological correlates of serum leptin in HCV-infected patients, and to determine its utility in predicting liver histological lesions.

  7. Estimation of aerial deposition and foliar uptake of xenobiotics: Assessment of current models

    Energy Technology Data Exchange (ETDEWEB)

    Link, S.O.; Fellows, R.J.; Cataldo, D.A.; Droppo, J.G.; Van Voris, P.

    1987-10-01

    This report reviews existing mathematical and/or computer simulation models that estimate xenobiotic deposition to and transport through (both curricular and stomatal) vegetative surfaces. The report evaluates the potential for coupling the best of those models to the existing Uptake, Translocation, Accumulation, and Biodegradation model to be used for future xenobiotic exposure assessments. Here xenobiotic compounds are defined as airborne contaminants, both organic and gaseous pollutants, that are introduced into the environment by man. Specifically this document provides a detailed review of the state-of-the-art models that addressed aerial deposition of particles and gases to foliage; foliar and cuticular transport, metabolism, and uptake of organic xenobiotics; and stomatal transport of gaseous and volatile organic xenobiotic pollutants. Where detailed information was available, parameters for each model are provided on a chemical by chemical as well as species by species basis. Sufficient detail is provided on each model to assess the potential for adapting or coupling the model to the existing UTAB plant exposure model. 126 refs., 6 figs., 10 tabs.

  8. Hepatitis A

    Science.gov (United States)

    ... inflammation of the liver.” This inflammation can be caused by a wide variety of toxins, drugs, and metabolic diseases, as well as infection. There are at least 5 hepatitis viruses. Hepatitis A is contracted when a child eats food or drinks water that is contaminated with the virus or has ...

  9. t-10, c-12 CLA dietary supplementation inhibits atherosclerotic lesion development despite adverse cardiovascular and hepatic metabolic marker profiles.

    Directory of Open Access Journals (Sweden)

    Patricia L Mitchell

    Full Text Available Animal and human studies have indicated that fatty acids such as the conjugated linoleic acids (CLA found in milk could potentially alter the risk of developing metabolic disorders including diabetes and cardiovascular disease (CVD. Using susceptible rodent models (apoE(-/- and LDLr(-/- mice we investigated the interrelationship between mouse strain, dietary conjugated linoleic acids and metabolic markers of CVD. Despite an adverse metabolic risk profile, atherosclerosis (measured directly by lesion area, was significantly reduced with t-10, c-12 CLA and mixed isomer CLA (Mix supplementation in both apoE(-/- (p<0.05, n = 11 and LDLr(-/- mice (p<0.01, n = 10. Principal component analysis was utilized to delineate the influence of multiple plasma and tissue metabolites on the development of atherosclerosis. Group clustering by dietary supplementation was evident, with the t-10, c-12 CLA supplemented animals having distinct patterns, suggestive of hepatic insulin resistance, regardless of mouse strain. The effect of CLA supplementation on hepatic lipid and fatty acid composition was explored in the LDLr(-/- strain. Dietary supplementation with t-10, c-12 CLA significantly increased liver weight (p<0.05, n = 10, triglyceride (p<0.01, n = 10 and cholesterol ester content (p<0.01, n = 10. Furthermore, t-10, c-12 CLA also increased the ratio of 18∶1 to 18∶0 fatty acid in the liver suggesting an increase in the activity of stearoyl-CoA desaturase. Changes in plasma adiponectin and liver weight with t-10, c-12 CLA supplementation were evident within 3 weeks of initiation of the diet. These observations provide evidence that the individual CLA isomers have divergent mechanisms of action and that t-10, c-12 CLA rapidly changes plasma and liver markers of metabolic syndrome, despite evidence of reduction in atherosclerosis.

  10. Drug and xenobiotic biotransformation in the blood-brain barrier: A neglected issue.

    Directory of Open Access Journals (Sweden)

    José A.G. Agúndez

    2014-10-01

    Full Text Available Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to BBB as a drug-metabolizing barrier. The presence of drug metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying the drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

  11. 14C-labeled propionate metabolism in vivo and estimates of hepatic gluconeogenesis relative to Krebs cycle flux.

    Science.gov (United States)

    Landau, B R; Schumann, W C; Chandramouli, V; Magnusson, I; Kumaran, K; Wahren, J

    1993-10-01

    Purposes of this study were 1) to estimate in humans, using 14C-labeled propionate, the rate of hepatic gluconeogenesis relative to the rate of Krebs cycle flux; 2) to compare those rates with estimates previously made using [3-14C]lactate and [2-14C]acetate; 3) to determine if the amount of ATP required for that rate of gluconeogenesis could be generated in liver, calculated from that rate of Krebs cycle flux and splanchnic balance measurements, previously made, and 4) to test whether hepatic succinyl-CoA is channeled during its metabolism through the Krebs cycle. [2-14C]propionate, [3-14C]-propionate, and [2,3-14C]succinate were given along with phenyl acetate to normal subjects, fasted 60 h. Distributions of 14C were determined in the carbons of blood glucose and of glutamate from excreted phenylacetylglutamine. Corrections to the distributions for 14CO2 fixation were made from the specific activities of urinary urea and the specific activities in glucose, glutamate, and urea previously found on administering [14C]-bicarbonate. Uncertainties in the corrections and in the contributions of pyruvate and Cori cyclings limit the quantitations. The rate of gluconeogenesis appears to be two or more times the rate of Krebs cycle flux and pyruvate's decarboxylation to acetyl-CoA, metabolized in the cycle, less than one-twenty-fifth the rate of its decarboxylation. Such estimates were previously made using [3-14C]lactate. The findings support the use of phenyl acetate to sample hepatic alpha-ketoglutarate. Ratios of specific activities of glucose to glutamate and glucose to urinary urea and expired CO2 indicate succinate's extensive metabolism when presented in trace amounts to liver. Utilizations of the labeled compounds by liver relative to other tissues were in the order succinate = lactate > propionate > acetate. ATP required for gluconeogenesis and urea formation was approximately 40% of the amount of ATP generated in liver. There was no channeling of succinyl-CoA in

  12. Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor

    Science.gov (United States)

    Garten, Antje; Popkova, Yulia; Penke, Melanie; Franke, Christin; Ricken, Albert; Schulz, Angela; Kiess, Wieland; Huster, Daniel; Schöneberg, Torsten; Schiller, Jürgen

    2017-01-01

    Obesity is often associated with dyslipidemia and hepatosteatosis. A number of animal models of non-alcoholic fatty liver disease (NAFLD) are established but they significantly differ in the molecular and biochemical changes depending on the genetic modification and diet used. Mice deficient for melanocortin type 4 receptor (Mc4rmut) develop hyperphagia, obesity, and subsequently NAFLD already under regular chow and resemble more closely the energy supply-driven obesity found in humans. This animal model was used to assess the molecular and biochemical consequences of hyperphagia-induced obesity on hepatic lipid metabolism. We analyzed transcriptome changes in Mc4rmut mice by RNA sequencing and used high resolution 1H magic angle spinning NMR spectroscopy and MALDI-TOF mass spectrometry to assess changes in the lipid composition. On the transcriptomic level we found significant changes in components of the triacylglycerol metabolism, unsaturated fatty acids biosynthesis, peroxisome proliferator-activated receptor signaling pathways, and lipid transport and storage compared to the wild-type. These findings were supported by increases in triacylglycerol, monounsaturated fatty acid, and arachidonic acid levels. The transcriptome signatures significantly differ from those of other NAFLD mouse models supporting the concept of hepatic subphenotypes depending on the genetic background and diet. Comparative analyses of our data with previous studies allowed for the identification of common changes and genotype-specific components and pathways involved in obesity-associated NAFLD. PMID:28207798

  13. The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Sílvia S. Chambel

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH, which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2 is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment.

  14. N-Acetylgalactosamine-Targeted Delivery of Dendrimer-Doxorubicin Conjugates Influences Doxorubicin Cytotoxicity and Metabolic Profile in Hepatic Cancer Cells.

    Science.gov (United States)

    Kuruvilla, Sibu P; Tiruchinapally, Gopinath; ElAzzouny, Mahmoud; ElSayed, Mohamed E H

    2017-03-01

    This study describes the development of targeted, doxorubicin (DOX)-loaded generation 5 (G5) polyamidoamine dendrimers able to achieve cell-specific DOX delivery and release into the cytoplasm of hepatic cancer cells. G5 is functionalized with poly(ethylene glycol) (PEG) brushes displaying N-acetylgalactosamine (NAcGal) ligands to target hepatic cancer cells. DOX is attached to G5 through one of two aromatic azo-linkages, L3 or L4, achieving either P1 ((NAcGalβ -PEGc)16.6 -G5-(L3-DOX)11.6 ) or P2 ((NAcGalβ -PEGc)16.6 -G5-(L4-DOX)13.4 ) conjugates. After confirming the conjugates' biocompatibility, flow cytometry studies show P1/P2 achieve 100% uptake into hepatic cancer cells at 30-60 × 10(-9) m particle concentration. This internalization correlates with cytotoxicity against HepG2 cells with 50% inhibitory concentration (IC50 ) values of 24.8, 1414.0, and 237.8 × 10(-9) m for free DOX, P1, and P2, respectively. Differences in cytotoxicity prompted metabolomics analysis to identify the intracellular release behavior of DOX. Results show that P1/P2 release alternative DOX metabolites than free DOX. Stable isotope tracer studies show that the different metabolites induce different effects on metabolic cycles. Namely, free DOX reduces glycolysis and increases fatty acid oxidation, while P1/P2 increase glycolysis, likely as a response to high oxidative stress. Overall, P1/P2 conjugates offer a platform drug delivery technology for improving hepatic cancer therapy.

  15. Effect of increased cardiac output on hepatic and intestinal microcirculatory blood flow, oxygenation, and metabolism in hyperdynamic murine septic shock.

    Science.gov (United States)

    Albuszies, Gerd; Radermacher, Peter; Vogt, Josef; Wachter, Ulrich; Weber, Sandra; Schoaff, Michael; Georgieff, Michael; Barth, Eberhard

    2005-10-01

    Septic shock-associated organ dysfunction is attributed to derangements of microcirculatory perfusion and/or impaired cellular oxygen utilization. The hepatosplanchnic organs are regarded to play a pivotal role in the pathophysiology of sepsis-related organ failure. In a murine model of septic shock, we tested the hypothesis whether achieving normotensive, hyperdynamic hemodynamics characterized by a sustained increase in cardiac output would allow maintenance of regional microvascular perfusion and oxygenation and, thus, hepatic metabolic capacity. Prospective, controlled, randomized animal study. University animal research laboratory. Male C57Bl/6 mice. Fifteen hours after sham operation (n = 11) or cecal ligation and puncture (CLP) (n = 9), mice were anesthetized, mechanically ventilated, and instrumented (central venous and left ventricular pressure-conductance catheter, portal vein and superior mesenteric artery ultrasound flow probes). Animals received continuous intravenous hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics, and glucose was infused to maintain normoglycemia. Measurements were recorded 18, 21, and 24 hrs post-CLP. In CLP mice, titration of hemodynamic targets were affiliated superior mesenteric artery and portal vein flow. Using a combined laser-Doppler flowmetry and remission spectrophotometry probe, we found well-maintained gut and liver capillary perfusion as well as intestinal microcirculatory hemoglobin oxygen saturation, whereas hepatic microcirculatory hemoglobin oxygen saturation was even increased. At 24 hrs post-CLP, the rate of de novo gluconeogenesis as derived from hepatic C-glucose isotope enrichment after continuous intravenous 1,2,3,4,5,6-C6-glucose infusion (condensation biosynthesis modeling after gas chromatography-mass spectrometry isotope measurements) was similar in the two experimental groups. During murine septic shock achieving normotensive hyperdynamic hemodynamics with fluid

  16. Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions.

    Science.gov (United States)

    Nikolaou, Kostas C; Moulos, Panagiotis; Harokopos, Vangelis; Chalepakis, George; Talianidis, Iannis

    2017-07-25

    H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK) activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Niclosamide reduces glucagon sensitivity via hepatic PKA inhibition in obese mice: Implications for glucose metabolism improvements in type 2 diabetes

    Science.gov (United States)

    Chowdhury, Md. Kamrul Hasan; Turner, Nigel; Bentley, Nicholas L.; Das, Abhirup; Wu, Lindsay E.; Richani, Dulama; Bustamante, Sonia; Gilchrist, Robert B.; Morris, Margaret J.; Shepherd, Peter R.; Smith, Greg C.

    2017-01-01

    Type 2 diabetes (T2D) is a global pandemic. Currently, the drugs used to treat T2D improve hyperglycemic symptom of the disease but the underlying mechanism causing the high blood glucose levels have not been fully resolved. Recently published data showed that salt form of niclosamide improved glucose metabolism in high fat fed mice via mitochondrial uncoupling. However, based on our previous work we hypothesised that niclosamide might also improve glucose metabolism via inhibition of the glucagon signalling in liver in vivo. In this study, mice were fed either a chow or high fat diet containing two different formulations of niclosamide (niclosamide ethanolamine salt - NENS or niclosamide - Nic) for 10 weeks. We identified both forms of niclosamide significantly improved whole body glucose metabolism without altering total body weight or body composition, energy expenditure or insulin secretion or sensitivity. Our study provides evidence that inhibition of the glucagon signalling pathway contributes to the beneficial effects of niclosamide (NENS or Nic) on whole body glucose metabolism. In conclusion, our results suggest that the niclosamide could be a useful adjunctive therapeutic strategy to treat T2D, as hepatic glucose output is elevated in people with T2D and current drugs do not redress this adequately. PMID:28054648

  18. Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions

    Directory of Open Access Journals (Sweden)

    Kostas C. Nikolaou

    2017-07-01

    Full Text Available H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability.

  19. The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

    Directory of Open Access Journals (Sweden)

    Jie Zhu

    2014-07-01

    Full Text Available Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm and glutathione peroxidase (GSH-Px in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP. Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM, reduced hepatocellular triglyceride (TG accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I and downregulating fatty acid synthase (FAS gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases.

  20. The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator.

    Science.gov (United States)

    Tavares, Clint D J; Sharabi, Kfir; Dominy, John E; Lee, Yoonjin; Isasa, Marta; Orozco, Jose M; Jedrychowski, Mark P; Kamenecka, Theodore M; Griffin, Patrick R; Gygi, Steven P; Puigserver, Pere

    2016-05-13

    Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1α to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1α acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1α acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1α acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1α-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1α acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo These results highlight a communication between methionine metabolism and PGC-1α-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.

  1. Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution.

    Science.gov (United States)

    Emoto, Chie; Murayama, Norie; Rostami-Hodjegan, Amin; Yamazaki, Hiroshi

    2010-10-01

    The attrition rate in drug development is being reduced by continuous advances in science and technology introduced by various academic institutions and pharmaceutical companies. This has been certainly noticeable in reducing the frequency with which unfavorable absorption, distribution, metabolism, and elimination (ADME) characteristics of any candidate drug causes failure in clinical development. Nonetheless, it is important that the objectives in reducing attrition during later stages of development are matched by information generated in the earliest stage of discovery. In this review, we summarize the methodologies employed during the early stages of drug discovery and discuss new findings in the areas of (1) drug metabolism enzymes, (2) the contribution of cytochrome P450 enzymes (P450, CYP) to hepatic metabolism, (3) prediction of hepatic intrinsic clearance, (4) reaction phenotyping, and (5) the metabolic differences between highly homologous enzymes such as CYP3A4 and CYP3A5. The total contribution of P450 and UDP-glucuronosyltransferases to drug metabolism is reported to be more than 80%; therefore, glucuronidation is increasingly recognized as an important clearance pathway in addition to that of P450 enzymes. When estimating the contribution of P450, interpreting the results of inhibition studies using a single P450 inhibitor can lead to false conclusions. For instance, 1-aminobenzotriazole and SKF-525A have a varying range of IC(50) values for inhibition of drug exidation-reaction by different CYP450 enzymes. There are disparities between methodologies at early stage drug discovery and late stage development. For example, although the drug depletion approach for the prediction of hepatic intrinsic clearance may not be desirable at late stages of development, it is suitable at the early drug discovery stage since kinetic characterization and measurement of specific drug metabolites are not required. Data from protein binding assays in plasma and

  2. Influence of dietary carbohydrate level on endocrine status and hepatic carbohydrate metabolism in the marine fish Sparus sarba.

    Science.gov (United States)

    Leung, L Y; Woo, Norman Y S

    2012-04-01

    Silver sea bream, Sparus sarba, were fed two diets of different carbohydrate levels (2 and 20% dextrin) for 4 weeks, and the effects on organ indices, liver composition, serum metabolite and hormone levels and gene expression profile of key enzymes of carbohydrate metabolism in the liver were investigated. By using real-time PCR, mRNA expression levels of carbohydrate metabolic enzymes including glucokinase (GK, glycolysis), glucose-6-phosphatase (G6Pase, gluconeogenesis), glycogen synthase (GS, glycogenesis), glycogen phosphorylase (GP, glycogenolysis) and glucose-6-phosphate dehydrogenase (G6PDH, pentose phosphate pathway) in liver of sea bream have been examined, and it was found that high dietary carbohydrate level increased mRNA level of GK but decreased mRNA levels of G6Pase and GP. However, mRNA levels of GS and G6PDH were not significantly influenced by dietary carbohydrate. Silver sea bream fed high dietary carbohydrate had higher hepatosomatic index (HSI), liver glycogen and protein, but there were no significant changes in gonadosomatic index (GSI), serum glucose and protein level, as well as liver lipid and moisture level. Pituitary growth hormone (GH) and hepatic insulin-like growth factor I (IGF-I) transcript abundance were assayed by real-time PCR, and it was found that both parameters remained unchanged in fish fed different dietary carbohydrate levels. Serum triiodothyronine (T(3)) and thyroxine (T(4)) were not significantly affected by dietary carbohydrate levels, but lower serum cortisol level was found in fish fed high dietary carbohydrate level. These results suggest that silver sea bream is able to adapt to a diet with high carbohydrate content (up to 20% dextrin), the consumption of which would lead to fundamental re-organization of carbohydrate metabolism resulting in hepatic glycogen deposition.

  3. Vascular and hepatic impact of short-term intermittent hypoxia in a mouse model of metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Wojciech Trzepizur

    Full Text Available Experimental models of intermittent hypoxia (IH have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS.Mice were fed either a standard diet or a high fat diet (HFD for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day or intermittent air (FiO2 21%. Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO release.Mice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.In a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

  4. Activation and detoxification metabolism of urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone by rat and mouse hepatic microsomes.

    Science.gov (United States)

    Stiborova, Marie; Cechova, Tereza; Borek-Dohalska, Lucie; Moserova, Michaela; Frei, Eva; Schmeiser, Heinz H; Paca, Jan; Arlt, Volker M

    2012-01-01

    2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. Understanding which enzymes are involved in metabolism of these toxicants is important in the assessment of individual susceptibility. Here, metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes containing cytochromes P450 (CYPs), their reductase (NADPH:CYP reductase), and NADH:cytochrome b5 reductase was investigated under anaerobic and aerobic conditions. In addition, using the same microsomal systems, 2-NBA and 3-NBA were evaluated to be enzymatically activated under anaerobic conditions to species generating 2-NBA- and 3-NBA-derived DNA adducts. High performance liquid chromatography (HPLC) with ultraviolet (UV) detection was employed for the separation and characterization of 2-NBA and 3-NBA metabolites formed by hepatic microsomes of rats and mice under the anaerobic and aerobic conditions. Microsomal systems isolated from the liver of the control (untreated) rats and rats pretreated with Sudan I, β-naphthoflavone (β-NF), phenobarbital (PB), ethanol and pregnenolon 16α-carbonitrile (PCN), the inducers of cytochromes P450 (CYP) 1A1, 1A1/2, 2B, 2E1 and 3A, respectively, were used in this study. Microsomes of mouse models, a control mouse line (wild-type, WT) and Hepatic Cytochrome P450 Reductase Null (HRN) mice with deleted gene of NADPH:CYP reductase in the liver, thus absenting this enzyme in their livers, were also employed. To detect and quantify the 2-NBA- and 3-NBA-derived DNA adducts, the 32P postlabeling technique was used. Both reductive metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), found to be formed predominantly under the anaerobic conditions, and two 3-NBA oxidative metabolites, whose structures have not yet been investigated, were formed by several microsomal systems used in the study. Whereas a 3-NBA reductive metabolite

  5. Potential for anaerobic conversion of xenobiotics

    DEFF Research Database (Denmark)

    Mogensen, Anders Skibsted; Dolfing, J.; Haagensen, Frank

    2003-01-01

    regarding the treatment of xenobiotics is shown with the focus on the UASB reactor, but the applicability of other reactor designs for treatment of hazardous waste is also included. Bioaugmentation has proved to be a viable technique to enhance a specific activity in anaerobic reactors and recent research...

  6. Bioavailability of Xenobiotics in the Soil Environment

    NARCIS (Netherlands)

    Katayama, A.; Bhula, R.; Burns, G.R.; Carazo, E.; Felsot, A.; Hamilton, D.; Harris, C.; Kim, Y.H.; Kleter, G.A.; Koedel, W.; Linders, J.; Peijnenburg, J.G.M.W.; Sabljic, A.; Stephenson, R.G.; Racke, D.K.; Rubin, B.; Tanaka, K.; Unsworth, J.; Wauchope, R.D.

    2010-01-01

    When synthetic, xenobiotic compounds such as agrochemicals and industrial chemicals are utilized, they eventually reach the soil environment where they are subject to degradation, leaching, volatilization, sorption, and uptake by organisms. The simplest assumption is that such chemicals in soil are

  7. Maternal Food Restriction during Pregnancy and Lactation Adversely Affect Hepatic Growth and Lipid Metabolism in Three-Week-Old Rat Offspring

    Directory of Open Access Journals (Sweden)

    Sangmi Lee

    2016-12-01

    Full Text Available Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR in three-week-old male offspring compared with controls (both p < 0.05. Offspring nursed by FR dams exhibited wider spaces between hepatic cells and a lower liver weight/body weight ratio than control offspring, and increased mTOR expression (p < 0.05. Interestingly, the significant decrease in expression of lipogenic-related genes was dependent on carbohydrate-responsive element-binding protein, despite the increased expression of sterol regulatory element-binding protein 1 (SREBP1 (p < 0.05. This study demonstrated increased expression of key metabolic regulators (mTOR and SREBP1, alterations in lipid metabolism, and deficits in hepatic growth in the offspring of FR-treated dams.

  8. Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

    Directory of Open Access Journals (Sweden)

    Jorge C. Correia

    2015-12-01

    Conclusions: Our results show that the main FXR variants in human liver (α1 and α2 reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists.

  9. Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

    Directory of Open Access Journals (Sweden)

    Caleb C. Lord

    2016-07-01

    Full Text Available Adipose triglyceride lipase (ATGL and comparative gene identification 58 (CGI-58 are critical regulators of triacylglycerol (TAG turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

  10. Associations between hepatic miRNA expression, liver triacylglycerols and gut microbiota during metabolic adaptation to high-fat diet in mice.

    Science.gov (United States)

    Blasco-Baque, Vincent; Coupé, Berengère; Fabre, Aurelie; Handgraaf, Sandra; Gourdy, Pierre; Arnal, Jean-François; Courtney, Michael; Schuster-Klein, Carole; Guardiola, Beatrice; Tercé, François; Burcelin, Rémy; Serino, Matteo

    2017-04-01

    Despite the current pandemic of metabolic diseases, our understanding of the diverse nature of the development of metabolic alterations in people who eat a high-fat diet (HFD) is still poor. We recently demonstrated a cardio-metabolic adaptation in mice fed an HFD, which was characterised by a specific gut and periodontal microbiota profile. Since the severity of hepatic disease is characterised by specific microRNA (miRNA) signatures and the gut microbiota is a key driver of both hepatic disease and miRNA expression, we analysed the expression of three hepatic miRNA and studied their correlation with hepatic triacylglycerol content and gut microbiota. Two cohorts of C57BL/6 4-week-old wild-type (WT) male mice (n = 62 and n = 96) were fed an HFD for 3 months to provide a model of metabolic adaptation. Additionally 8-week-old C57BL/6 mice, either WT or of different genotypes, with diverse gut microbiota (ob/ob, Nod1, Cd14 knockout [Cd14KO] and Nod2) or without gut microbiota (axenic mice) were fed a normal chow diet. Following which, glycaemic index, body weight, blood glucose levels and hepatic triacylglycerol levels were measured. Gut (caecum) microbiota taxa were analysed by pyrosequencing. To analyse hepatic miRNA expression, real-time PCR was performed on total extracted miRNA samples. Data were analysed using two-way ANOVA followed by the Dunnett's post hoc test, or by the unpaired Student's t test. A cluster analysis and multivariate analyses were also performed. Our results demonstrated that the expression of miR-181a, miR-666 and miR-21 in primary murine hepatocytes is controlled by lipopolysaccharide in a dose-dependent manner. Of the gut microbiota, Firmicutes were positively correlated and Proteobacteria and Bacteroides acidifaciens were negatively correlated with liver triacylglycerol levels. Furthermore, the relative abundance of Firmicutes was negatively correlated with hepatic expression of miR-666 and miR-21. In contrast, the relative

  11. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age

    Energy Technology Data Exchange (ETDEWEB)

    Keith, Dove; Finlay, Liam; Butler, Judy [Linus Pauling Institute, Oregon State University (United States); Gómez, Luis; Smith, Eric [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States); Moreau, Régis [Linus Pauling Institute, Oregon State University (United States); Hagen, Tory, E-mail: Tory.Hagen@oregonstate.edu [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States)

    2014-07-18

    Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.

  12. In vitro hepatic metabolism of cediranib, a potent vascular endothelial growth factor tyrosine kinase inhibitor: interspecies comparison and human enzymology.

    Science.gov (United States)

    Schulz-Utermoehl, Timothy; Spear, Michael; Pollard, Christopher R J; Pattison, Christine; Rollison, Helen; Sarda, Sunil; Ward, Michelle; Bushby, Nick; Jordan, Angela; Harrison, Mike

    2010-10-01

    The in vitro metabolism of cediranib (4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of all three VEGF receptors in late-stage development for the treatment of colorectal cancer and recurrent glioblastoma was investigated in hepatic proteins from preclinical species and humans using radiolabeled material. In human hepatocyte cultures, oxidative and conjugative metabolic pathways were identified, with pyrrolidine N(+)-glucuronidation being the major route. The primary oxidative pathways were di-and trioxidations and pyrrolidine N-oxidation. All metabolites with the exception of the N(+)-glucuronide metabolite were observed in rat and cynomolgus monkey hepatocyte preparations. Additional metabolism studies in liver microsomes from these or other preclinical species (CD-1 mouse, Han Wistar rat, Dunkin Hartley guinea pig, Göttingen mini-pig, New Zealand White rabbit, beagle dog, and cynomolgus and rhesus monkey) indicated that the N(+)-glucuronide metabolite was not formed in these additional species. Incubations with recombinant flavin-containing monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) enzymes and inhibition studies using the nonselective cytochrome P450 (P450) chemical inhibitor 1-aminobenzotriazole in human hepatocytes indicated that FMO1 and FMO3 contributed to cediranib N-oxidation, whereas UGT1A4 had a major role in cediranib N(+)-glucuronidation. P450 enzymes had only a minor role in the metabolism of cediranib. In conclusion, species differences in the formation of the N(+)-glucuronide metabolite of cediranib were observed. All other metabolites of cediranib found in humans were also detected in rat and cynomolgus monkey. Non-P450 enzymes are predominantly involved in the metabolism of cediranib, and this suggests that clinical drug interactions involving other coadministered drugs are unlikely.

  13. Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT).

    Science.gov (United States)

    Mortensen, Anne Skjetne; Arukwe, Augustine

    2007-04-01

    Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to

  14. Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease

    Directory of Open Access Journals (Sweden)

    Anh Le

    2014-05-01

    Full Text Available Background: Wilson disease (WD is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA (tx-j mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal to adulthood (28 weeks. Methods: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM and S-adenosylhomocysteine (SAH liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. Results: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. Conclusion: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.

  15. Postnatal treatment with dexamethasone perturbs hepatic and cardiac energy metabolism and is associated with a sustained atherogenic plasma lipid profile in suckling rats

    NARCIS (Netherlands)

    Liu, Yan; Havinga, Rick; Bloks, Vincent W.; Baller, Juul F.; Van der Leij, Feike R.; Reijngoud, Dirk-Jan; Sauer, Pieter J. J.; Kuipers, Folkert

    2007-01-01

    Early exposure to glucocorticoids (GC) has been proposed to disturb hepatic and cardiac function in later life. In the present study, we evaluated early metabolic alterations upon GC treatment that may predispose to long-term abnormalities. Rats were injected with dexamethasone (DEX) at d 1, 2, and

  16. Peculiarities of One-Carbon Metabolism in the Strict Carnivorous Cat and the Role in Feline Hepatic Lipidosis

    Directory of Open Access Journals (Sweden)

    Marica Bakovic

    2013-07-01

    Full Text Available Research in various species has indicated that diets deficient in labile methyl groups (methionine, choline, betaine, folate produce fatty liver and links to steatosis and metabolic syndrome, but also provides evidence of the importance of labile methyl group balance to maintain normal liver function. Cats, being obligate carnivores, rely on nutrients in animal tissues and have, due to evolutionary pressure, developed several physiological and metabolic adaptations, including a number of peculiarities in protein and fat metabolism. This has led to specific and unique nutritional requirements. Adult cats require more dietary protein than omnivorous species, maintain a consistently high rate of protein oxidation and gluconeogenesis and are unable to adapt to reduced protein intake. Furthermore, cats have a higher requirement for essential amino acids and essential fatty acids. Hastened use coupled with an inability to conserve certain amino acids, including methionine, cysteine, taurine and arginine, necessitates a higher dietary intake for cats compared to most other species. Cats also seemingly require higher amounts of several B-vitamins compared to other species and are predisposed to depletion during prolonged inappetance. This carnivorous uniqueness makes cats more susceptible to hepatic lipidosis.

  17. Tris(2-butoxyethyl)phosphate and triethyl phosphate alter embryonic development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations in chicken embryos

    Energy Technology Data Exchange (ETDEWEB)

    Egloff, Caroline [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Crump, Doug, E-mail: doug.crump@ec.gc.ca [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Porter, Emily; Williams, Kim L.; Letcher, Robert J.; Gauthier, Lewis T. [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Kennedy, Sean W. [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5 (Canada)

    2014-09-15

    The organophosphate flame retardants tris(2-butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP) are used in a wide range of applications to suppress or delay the ignition and spread of fire. Both compounds have been detected in the environment and TBOEP was recently measured in free-living avian species. In this study, TBOEP and TEP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 45,400 ng/g and 0 to 241,500 ng/g egg, respectively. Pipping success, development, hepatic mRNA expression of 9 target genes, thyroid hormone levels, and circulating bile acid concentrations were determined. Exposure to the highest doses of TBOEP and TEP resulted in negligible detection of the parent compounds in embryonic contents at pipping indicating their complete metabolic degradation. TBOEP exposure had limited effects on chicken embryos, with the exception of hepatic CYP3A37 mRNA induction. TEP exposure decreased pipping success to 68%, altered growth, increased liver somatic index (LSI) and plasma bile acids, and modulated genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Plasma thyroxine levels were decreased at all TEP doses, including an environmentally-relevant concentration (8 ng/g), and gallbladder hypotrophy was evident at ≥ 43,200 ng/g. Tarsus length and circulating thyroxine concentration emerged as potential phenotypic anchors for the modulation of transthyretin mRNA. The increase in plasma bile acids and LSI, gallbladder hypotrophy, and discoloration of liver tissue represented potential phenotypic outcomes associated with modulation of hepatic genes involved with xenobiotic and lipid metabolism. - Highlights: • TBOEP is not embryolethal to chicken embryos. • TEP affected embryonic viability, morphometric endpoints, and thyroid hormone levels. • TEP altered mRNA levels of xenobiotic and lipid metabolism genes. • TEP increased plasma bile acids and caused gallbladder hypotrophy

  18. Developmental changes in hepatic glucose metabolism in a newborn piglet model: A comparative analysis for suckling period and early weaning period.

    Science.gov (United States)

    Xie, Chunyan; Wang, Qinhua; Wang, Jing; Tan, Bie; Fan, Zhiyong; Deng, Ze-yuan; Wu, Xin; Yin, Yulong

    2016-02-19

    The liver glucose metabolism, supplying sufficient energy for glucose-dependent tissues, is important in suckling or weaned animals, although there are few studies with piglet model. To better understand the development of glucose metabolism in the piglets during suckling period and early weaning period, we determined the hepatic glycogen content, and investigated the relative protein expression of key enzymes of glucogenesis (GNG) and mRNA levels of some glucose metabolism-related genes. During suckling period, the protein level of G6Pase in the liver of suckling piglets progressively declined with day of age compared with that of newborn piglets (at 1 day of age), whereas the PEPCK level stabilized until day 21 of age, indicating that hepatic GNG capacity gradually weakened in suckling piglets. The synthesis of hepatic glycogen, which was consistent with the fluctuation of glycolytic key genes PFKL and PKLR that gradually decreased after birth and was more or less steady during latter suckling period, although both the mRNA levels of GCK and key glucose transporter GLUT2 presented uptrend in suckling piglets. However, early weaning significantly suppressed the hepatic GNG in the weaned piglets, especially at d 3-5 of weaning period, then gradually recovered at d 7 of weaning period. Meanwhile, PFKL, PKLR and GLUT2 showed the similar trend during weaning period. On the contrast, the hepatic glycogen reached the maximum value when the G6Pase and PEPCK protein expression were at the lowest level, although the GCK level maintained increasing through 7 days of weaning period. Altogether, our study provides evidence that hepatic GNG and glycolysis in newborn piglets were more active than other days during suckling period, and early weaning could significantly suppressed glucose metabolism in liver, but this inhibition would progressively recover at day 7 after weaning.

  19. The interaction of hepatic lipid and glucose metabolism in liver diseases

    NARCIS (Netherlands)

    Bechmann, Lars P.; Hannivoort, Rebekka A.; Gerken, Guido; Hotamisligil, Goekhan S.; Trauner, Michael; Canbay, Ali

    It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an

  20. Effects of feeding dehydroepiandrosterone (DHEA) on the hepatic metabolism of 7,12-dimethylbenzanthracene (DMBA) in rats

    Energy Technology Data Exchange (ETDEWEB)

    Prasanna, H.R.; Schwartz, A.; Hacobian, N.; Magee, P.N.

    1987-05-01

    The possibility that the anticarcinogenic action of the naturally occurring steroid DHEA could arise from its interference in the metabolic activation of DMBA was investigated. Young mature male Sprague Dawley rats were fed for 14 days with a diet containing a nontoxic dose of DHEA in the diet. Control rats were pairfed and received the same diet except DHEA. The animals were given interperitoneally 120 ..mu..Ci of (/sup 3/H)DMBA in DMSO. After 48 hours the rats were sacrificed. Liver weights at sacrifice were 11.7 +/- 0.9 g and 7.1 g +/- 0.6 g for DHEA fed and control animals respectively. Protein content of whole liver and hepatic microsomal protein was significantly higher in DHEA fed animals. Binding of DMBA to hepatic DNA was 6688 +/- 1308 and 4070 +/- 890 dpm/mg DNA for control and DHEA fed animals respectively. Furthermore the excretion of DMBA derived radioactivity in urine was 2.3 fold more in DHEA fed animals. These results suggest that DHEA could protect rats from the carcinogenic manifestations of DMBA by interfering at the biotransformation step of the carcinogen.

  1. Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood

    DEFF Research Database (Denmark)

    Santana-Farré, Ruymán; Mirecki-Garrido, Mercedes; Bocos, Carlos

    2012-01-01

    Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood......, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced...... activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver...

  2. Disruption of the acyl-coa binding protein gene delays hepatic adaptation to metabolic changes at weaning

    DEFF Research Database (Denmark)

    Neess, Ditte; Bloksgaard, Maria; Sørensen, Signe Bek;

    2011-01-01

    , little is known about the in vivo function in mammalian cells. We have generated mice with targeted disruption of ACBP (ACBP-/-). These mice are viable and fertile and develop normally. However, around weaning the ACBP-/- mice go through a crisis with overall weakness, and a slightly decreased growth...... rate. Using microarray analysis we show that the liver of ACBP-/- mice display a significantly delayed adaptation to weaning with late induction of target genes of the sterol regulatory element binding protein (SREBP) family. As a result, hepatic de novo cholesterogenesis is decreased at weaning....... The delayed induction of SREBP target genes around weaning is caused by a compromised processing and decreased expression of SREBP precursors leading to reduced binding of SREBP to target sites in chromatin. In conclusion, lack of ACBP interferes with the normal metabolic adaptation to weaning and leads...

  3. Lead Optimization in Discovery Drug Metabolism and Pharmacokinetics/Case study: The Hepatitis C Virus (HCV) Protease Inhibitor SCH 503034.

    Science.gov (United States)

    Cheng, K-C; Korfmacher, Walter A; White, Ronald E; Njoroge, F George

    2007-06-26

    Lead optimization using drug metabolism and pharmacokinetics (DMPK) parameters has become one of the primary focuses of research organizations involved in drug discovery in the last decade. Using a combination of rapid in vivo and in vitro DMPK screening procedures on a large array of compounds during the lead optimization process has resulted in development of compounds that have acceptable DMPK properties. In this review, we present a general screening paradigm that is currently being used as part of drug discovery at Schering-Plough and we describe a case study using the Hepatitis C Virus (HCV) protease inhibitor program as an example. By using the DMPK optimization tools, a potent HCV protease inhibitor, SCH 503034, was selected for development as a candidate drug.

  4. High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation.

    Science.gov (United States)

    Mock, Kaitlin; Lateef, Sundus; Benedito, Vagner A; Tou, Janet C

    2017-01-01

    High-fructose corn syrup-55 (HFCS-55) has been suggested to be more lipogenic than sucrose, which increases the risk for nonalcoholic fatty liver disease (NAFLD) and dyslipidemia. The study objectives were to determine the effects of drinking different sugar-sweetened solutions on hepatic gene expression in relation to liver fatty acid composition and risk of NAFLD. Female rats were randomly assigned (n=7 rats/group) to drink water or water sweetened with 13% (w/v) HFCS-55, sucrose or fructose for 8 weeks. Rats drinking HFCS-55 solution had the highest (P=.03) hepatic total lipid and triglyceride content and histological evidence of fat infiltration. Rats drinking HFCS-55 solution had the highest hepatic de novo lipogenesis indicated by the up-regulation of stearoyl-CoA desaturase-1 and the highest (P55 solution. The observed lipogenic effects were attributed to the slightly higher fructose content of HFCS-55 solution in the absence of differences in macronutrient and total caloric intake between rats drinking HFCS-55 and sucrose solution. Results from gene expression and fatty acid composition analysis showed that, in a hypercaloric state, some types of sugars are more detrimental to the liver. Based on these preclinical study results, excess consumption of caloric sweetened beverage, particularly HFCS-sweetened beverages, should be limited. Published by Elsevier Inc.

  5. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    Science.gov (United States)

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.

  6. Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Manwaring, John, E-mail: manwaring.jd@pg.com [Procter & Gamble Inc., Mason Business Center, Mason, OH 45040 (United States); Rothe, Helga [Procter & Gamble Service GmbH, Sulzbacher Str. 40, 65823 Schwalbach am Taunus (Germany); Obringer, Cindy; Foltz, David J.; Baker, Timothy R.; Troutman, John A. [Procter & Gamble Inc., Mason Business Center, Mason, OH 45040 (United States); Hewitt, Nicola J. [SWS, Erzhausen (Germany); Goebel, Carsten [Procter & Gamble Service GmbH, Sulzbacher Str. 40, 65823 Schwalbach am Taunus (Germany)

    2015-09-01

    Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis–Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte K{sub m} and V{sub max} values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and C{sub max} was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers. - Highlights: • An entirely in silico/in vitro approach to predict in vivo exposure to dermally applied hair dyes • Skin penetration and epidermal conversion assessed in human

  7. Effects of Liver Resection on Hepatic Short-Chain Fatty Acid Metabolism in Humans

    Science.gov (United States)

    Neis, Evelien P. J. G.; Bloemen, Johanne G.; Rensen, Sander S.; van der Vorst, Joost R.; van den Broek, Maartje A.; Venema, Koen; Buurman, Wim A.; Dejong, Cornelis H. C.

    2016-01-01

    Aim To determine whether acute loss of liver tissue affects hepatic short-chain fatty acid (SCFA) clearance. Methods Blood was sampled from the radial artery, portal vein, and hepatic vein before and after hepatic resection in 30 patients undergoing partial liver resection. Plasma SCFA levels were measured by liquid chromatography-mass spectrometry. SCFA exchange across gut and liver was calculated from arteriovenous differences and plasma flow. Liver volume was estimated by CT liver volumetry. Results The gut produced significant amounts of acetate, propionate, and butyrate (39.4±13.5, 6.2±1.3, and 9.5±2.6 μmol·kgbw-1·h-1), which did not change after partial hepatectomy (p = 0.67, p = 0.59 and p = 0.24). Hepatic propionate uptake did not differ significantly before and after resection (-6.4±1.4 vs. -8.4±1.5 μmol·kgbw-1·h-1, p = 0.49). Hepatic acetate and butyrate uptake increased significantly upon partial liver resection (acetate: -35.1±13.0 vs. -39.6±9.4 μmol·kgbw-1·h-1, p = 0.0011; butyrate: -9.9±2.7 vs. -11.5±2.4 μmol·kgbw-1·h-1, p = 0.0006). Arterial SCFA concentrations were not different before and after partial liver resection (acetate: 176.9±17.3 vs. 142.3±12.5 μmol/L, p = 0.18; propionate: 7.2±1.4 vs. 5.6±0.6 μmol/L, p = 0.38; butyrate: 4.3±0.7 vs. 3.6±0.6 μmol/L, p = 0.73). Conclusion The liver maintains its capacity to clear acetate, propionate, and butyrate from the portal blood upon acute loss of liver tissue. PMID:27835668

  8. Metabolism

    Science.gov (United States)

    ... Surgery? Choosing the Right Sport for You Shyness Metabolism KidsHealth > For Teens > Metabolism Print A A A ... food through a process called metabolism. What Is Metabolism? Metabolism (pronounced: meh-TAB-uh-lih-zem) is ...

  9. An investigation into the hepatic cytochrome P-450 catalysed metabolism of the anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether).

    Science.gov (United States)

    Marsh, J A; Ivanetich, K M; Bradshaw, J J; Harrison, G G; Webber, B L; Kaminsky, L S

    1975-01-01

    The role of the different cytochromes P-450 in the metabolism of the anaesthetic agent fluroxene, and the mechanism of production of toxic effects seen after pre-treatment of the animals with pehnobarbital prior to anaesthesia, have been investigated. Male rats were anaesthetized with fluroxene, or with 2,2,2-trifluroethyl ethyl ether, or with ethyl vinyl ether in an attempt to ascertain the in vivo toxic effects of the three anaesthetic agents. The resultant hepatic histology is reported. A study of the binding and metabolism of fluroxene by isolated rat hepatic microsomes was also made. We conclude that it is elevated levels of cytochrome P-450 which potentiate the toxicity of fluroxene anaesthesia in phenobarbital treated animals and that cytochrome P-448 does not bind or metabolize fluroxene. The potential toxicity of the fluroxene molecule is considered to reside in the trifluoroethyl moiety, while the vinyl group of fluroxene appears to play a role in the observed liver damage.

  10. Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down-Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats

    Directory of Open Access Journals (Sweden)

    Song Mu

    2017-06-01

    Full Text Available Objective: This study was initiated to investigate the effects of Roux-en-Y gastric bypass (RYGB surgery on hepatic glucose metabolism and hepatic expression of protein tyrosine phosphatase 1B (PTP1B in obese rats. Methods: Body weight, glucose, intraperitoneal glucose, insulin, and pyruvate tolerance tests were performed pre- and postoperatively, and plasma lipid, insulin and glucagon-like peptide 1 (GLP-1 were measured. The mRNA levels of G6Pase, Pepck, Gsk-3β and Gys-2, and the expression levels of PTP1B mRNA, protein, and other components of the insulin signaling pathway were measured by using RT-PCR and western blotting. The intracellular localization of PTP1B and hepatic glycogen deposition was also observed. Results: RYGB surgery-treated rats showed persistent weight loss, significantly improved glucose tolerance, pyruvate tolerance, and dyslipidemia, as well as increased insulin sensitivity, hepatic glycogen deposition and increased plasma GLP-1 in obese rats. RT-PCR analyses showed Pepck, G6Pase, and Gsk-3β mRNA to be significantly decreased, and Gys-2 mRNA to be significantly increased in liver tissue in the RYGB group (p Conclusion: RYGB can improve hepatic glucose metabolism and down-regulate PTP1B in obese rats. An increased circulating GLP-1 concentration may be correlated with the effects following RYGB in obese rats.

  11. Adaptive and specialised transcriptional responses to xenobiotic stress in Caenorhabditis elegans are regulated by nuclear hormone receptors.

    Directory of Open Access Journals (Sweden)

    Laura M Jones

    Full Text Available Characterisation of the pathways by which xenobiotics are metabolised and excreted in both target and non-target organisms is crucial for the rational design of effective and specific novel bioactive molecules. Consequently, we have investigated the induced responses of the model nematode Caenorhabditis elegans to a variety of xenobiotics which represent a range of putative modes of action. The majority of genes that were specifically induced in preliminary microarray analyses encoded enzymes from Phase I and II metabolism, including cytochrome P450s, short chain dehydrogenases, UDP-glucuronosyl transferases and glutathione transferases. Changes in gene expression were confirmed by quantitative PCR and GFP induction in reporter strains driven by promoters for transcription of twelve induced enzymes was investigated. The particular complement of metabolic genes induced was found to be highly contingent on the xenobiotic applied. The known regulators of responses to applied chemicals ahr-1, hif-1, mdt-15 and nhr-8 were not required for any of these inducible responses and skn-1 regulated GFP expression from only two of the promoters. Reporter strains were used in conjunction with systematic RNAi screens to identify transcription factors which drive expression of these genes under xenobiotic exposure. These transcription factors appeared to regulate specific xenobiotic responses and have no reported phenotypes under standard conditions. Focussing on nhr-176 we demonstrate the role of this transcription factor in mediating the resistance to thiabendazole.

  12. Magnetic resonance spectroscopy to study hepatic metabolism in diffuse liver diseases, diabetes and cancer

    Institute of Scientific and Technical Information of China (English)

    Pieter; C; Dagnelie; Susanne; Leij-Halfwerk

    2010-01-01

    This review provides an overview of the current state of the art of magnetic resonance spectroscopy (MRS) in in vivo investigations of diffuse liver disease. So far, MRS of the human liver in vivo has mainly been used as a research tool rather than a clinical tool. The liver is particularly suitable for static and dynamic metabolic studies due to its high metabolic activity. Furthermore, its relatively superfi cial position allows excellent MRS localization, while its large volume allows detection of signal...

  13. Freshwater Clam Extract Ameliorates Triglyceride and Cholesterol Metabolism through the Expression of Genes Involved in Hepatic Lipogenesis and Cholesterol Degradation in Rats

    Directory of Open Access Journals (Sweden)

    Thomas Laurent

    2013-01-01

    Full Text Available The freshwater clam (Corbicula spp. is a popular edible bivalve and has been used as a folk remedy for liver disease in Asia. As a Chinese traditional medicine, it is said that freshwater clam ameliorates alcoholic intoxication and cholestasis. In this study, to estimate the practical benefit of freshwater clam extract (FCE, we compared the effects of FCE and soy protein isolate (SPI on triglyceride and cholesterol metabolism in rats. FCE and SPI lowered serum cholesterol, and FCE tended to reduce serum triglycerides. FCE enhanced fecal sterol excretion and hepatic mRNA levels of CYP7A1 and ABCG5 more substantially than SPI; however, both diets reduced hepatic cholesterol. Both of the diets similarly suppressed liver lipids improved Δ9-desaturated fatty acid profile, and FCE was associated with a reduction in FAS and SCD1 mRNA levels. Hepatic transcriptome analysis revealed that inhibition of lipogenesis-related gene expression may contribute to downregulation of hepatic triglycerides by FCE. FCE would have better potential benefits for preventing metabolic disorders, through greater improvement of metabolism of triglycerides and cholesterol, likely through a mechanism similar to SPI.

  14. Free Radical Mechanisms of Xenobiotic Mammalian Cytotoxicities

    Science.gov (United States)

    1991-06-30

    frequent mechanism of xenobiotic liver toxicity is biotransformation by cytochrome P,5o- enzymes to toxic free radical intermediates. The primary objective...vascular cells was to incubate the cells with both the spin trapping agent methyl nitroso propane ( MNP ) and IRP chemicals to determine if free radical...gave a reasonably strong MNP -adduct signal. Figure 1 gives the MNP adduct signal for carbon tetrachloride and trichloroethylene, as well as that for

  15. Biochemical metabolic changes assessed by 31P magnetic resonance spectroscopy after radiation-induced hepatic injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    Ri-Sheng Yu; Liang Hao; Fei Dong; Jian-Shan Mao; Jian-Zhong Sun; Ying Chen; Min Lin; Zhi-Kang Wang; Wen-Hong Ding

    2009-01-01

    AIM:To compare the features of biochemical metabolic changes detected by hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) with the liver damage score (LDS) and pathologic changes in rabbits and to investigate the diagnostic value of 31P MRS in acute hepatic radiation injury.METHODS:A total of 30 rabbits received different radiation doses (ranging 5-20 Gy) to establish acute hepatic injury models.Blood biochemical tests,31P MRS and pathological examinations were carried out 24 h after irradiation.The degree of injury was evaluated according to LDS and pathology.Ten healthy rabbits served as controls.The MR examination was performed on a 1.5 T imager using a 1H/31P surface coil by the 2D chemical shift imaging technique.The relative quantities of phosphomonoesters (PME),phosphodiesters (PDE),inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured.The data were statistically analyzed.RESULTS:(1) Relative quantification of phosphorus metabolites:(a) ATP:there were significant differences (P<0.05) (LDS-groups:control group vs mild group vs moderate group vs severe group,1.83±0.33 vs 1.55±0.24 vs 1.27±0.09 vs 0.98±0.18;pathological groups:control group vs mild group vs moderate group vs severe group,1.83±0.33 vs 1.58±0.25 vs 1.32±0.07 vs 1.02 ± 0.18) of ATP relative quantification among control group,mild injured group,moderate injured group,and severe injured group according to both LDS grading and pathological grading,respectively,and it decreased progressively with the increased degree of injury (r=-0.723,P=0.000).(b) PME and Pi;the relative quantification of PME and Pi decreased significantly in the severe injured group,and the difference between the control group and severe injured group was significant (P<0.05) (PME:LDScontrol group vs LDS-severe group,0.86±0.23 vs 0.58±0.22,P=0.031;pathological control group vs pathological severe group,0.86±0.23 vs 0.60±0.21,P=0.037;Pi:LDS-control group vs LDS-severe group,0.74±0.18 vs

  16. Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet.

    Science.gov (United States)

    Coate, Katie C; Smith, Marta S; Shiota, Masakazu; Irimia, Jose M; Roach, Peter J; Farmer, Ben; Williams, Phillip E; Moore, Mary Courtney

    2013-03-01

    Net hepatic glucose uptake (NHGU) is an important contributor to postprandial glycemic control. We hypothesized that NHGU is reduced during normal pregnancy and in a pregnant diet-induced model of impaired glucose intolerance/gestational diabetes mellitus (IGT/GDM). Dogs (n = 7 per group) that were nonpregnant (N), normal pregnant (P), or pregnant with IGT/GDM (pregnant dogs fed a high-fat and -fructose diet [P-HFF]) underwent a hyperinsulinemic-hyperglycemic clamp with intraportal glucose infusion. Clamp period insulin, glucagon, and glucose concentrations and hepatic glucose loads did not differ among groups. The N dogs reached near-maximal NHGU rates within 30 min; mean ± SEM NHGU was 105 ± 9 µmol·100 g liver⁻¹·min⁻¹. The P and P-HFF dogs reached maximal NHGU in 90-120 min; their NHGU was blunted (68 ± 9 and 16 ± 17 µmol·100 g liver⁻¹·min⁻¹, respectively). Hepatic glycogen synthesis was reduced 20% in P versus N and 40% in P-HFF versus P dogs. This was associated with a reduction (>70%) in glycogen synthase activity in P-HFF versus P and increased glycogen phosphorylase (GP) activity in both P (1.7-fold greater than N) and P-HFF (1.8-fold greater than P) dogs. Thus, NHGU under conditions mimicking the postprandial state is delayed and suppressed in normal pregnancy, with concomitant reduction in glycogen storage. NHGU is further blunted in IGT/GDM. This likely contributes to postprandial hyperglycemia during pregnancy, with potential adverse outcomes for the fetus and mother.

  17. Interactions of cytosolic sulfotransferases with xenobiotics.

    Science.gov (United States)

    James, Margaret O; Ambadapadi, Sriram

    2013-11-01

    Cytosolic sulfotransferases are a superfamily of enzymes that catalyze the transfer of the sulfonic group from 3'-phosphoadenosine-5'-phosphosulfate to hydroxy or amine groups in substrate molecules. The human cytosolic sulfotransferases that have been most studied, namely SULT1A1, SULT1A3, SULT1B1, SULT1E1 and SULT2A1, are expressed in different tissues of the body, including liver, intestine, adrenal, brain and skin. These sulfotransferases play important roles in the sulfonation of endogenous molecules such as steroid hormones and neurotransmitters, and in the elimination of xenobiotic molecules such as drugs, environmental chemicals and natural products. There is often overlapping substrate selectivity among the sulfotransferases, although one isoform may exhibit greater enzyme efficiency than other isoforms. Similarly, inhibitors or enhancers of one isoform often affect other isoforms, but typically with different potency. This means that if the activity of one form of sulfotransferase is altered (either inhibited or enhanced) by the presence of a xenobiotic, the sulfonation of endogenous and xenobiotic substrates for other isoforms may well be affected. There are more examples of inhibitors than enhancers of sulfonation. Modulators of sulfotransferase enzymes include natural products ingested as part of the human diet as well as environmental chemicals and drugs. This review will discuss recent work on such interactions.

  18. PGC-1alpha Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Leone Teresa C

    2005-01-01

    Full Text Available The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha was targeted in mice. PGC-1alpha null (PGC-1alpha-/- mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha-/- mice. With age, the PGC-1alpha-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

  19. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics.

    Science.gov (United States)

    Diamond, Deborah L; Syder, Andrew J; Jacobs, Jon M; Sorensen, Christina M; Walters, Kathie-Anne; Proll, Sean C; McDermott, Jason E; Gritsenko, Marina A; Zhang, Qibin; Zhao, Rui; Metz, Thomas O; Camp, David G; Waters, Katrina M; Smith, Richard D; Rice, Charles M; Katze, Michael G

    2010-01-01

    Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.

  20. Rapid metabolite discovery, identification, and accurate comparison of the stereoselective metabolism of metalaxyl in rat hepatic microsomes.

    Science.gov (United States)

    Wang, Xinru; Qiu, Jing; Xu, Peng; Zhang, Ping; Wang, Yao; Zhou, Zhiqiang; Zhu, Wentao

    2015-01-28

    Metabolite identification and quantitation impose great challenges on risk assessment of agrochemicals, as many metabolite standards are generally unavailable. In this study, metalaxyl metabolites were identified by time-of-flight mass spectrometry and semiquantified by triple quadrupole tandem mass spectrometry with self-prepared (13)C-labeled metalaxyl metabolites as internal standards. Such methodology was employed to characterize the stereoselective metabolism of metalaxyl in rat hepatic microsomes successfully. Metabolites derived from hydroxylation, demethylation, and didemethylation were identified and semiquantified. The results indicated that (+)-S-metalaxyl eliminated preferentially as the enantiomer fraction was 0.32 after 60 min incubation. The amounts of hydroxymetalaxyl and demethylmetalaxyl derived from (-)-R-metalaxyl were 1.76 and 1.82 times higher than that of (+)-S-metalaxyl, whereas didemethylmetalaxyl derived from (+)-S-metalaxyl was 1.44 times larger than that from (-)-R-metalaxyl. This study highlights a new quantitation approach for stereoselective metabolism of chiral agrochemicals and provides more knowledge on metalaxyl risk assessment.

  1. Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics

    Science.gov (United States)

    Jacobs, Jon M.; Sorensen, Christina M.; Walters, Kathie-Anne; Proll, Sean C.; McDermott, Jason E.; Gritsenko, Marina A.; Zhang, Qibin; Zhao, Rui; Metz, Thomas O.; Camp, David G.; Waters, Katrina M.; Smith, Richard D.; Rice, Charles M.; Katze, Michael G.

    2010-01-01

    Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis. PMID:20062526

  2. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

    Directory of Open Access Journals (Sweden)

    Teresa C Leone

    2005-04-01

    Full Text Available The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha was targeted in mice. PGC-1alpha null (PGC-1alpha(-/- mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/- mice. With age, the PGC-1alpha(-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

  3. Role and mechanism of the AMPK pathway in waterborne Zn exposure influencing the hepatic energy metabolism of Synechogobius hasta

    Science.gov (United States)

    Wu, Kun; Huang, Chao; Shi, Xi; Chen, Feng; Xu, Yi-Huan; Pan, Ya-Xiong; Luo, Zhi; Liu, Xu

    2016-12-01

    Previous studies have investigated the physiological responses in the liver of Synechogobius hasta exposed to waterborne zinc (Zn). However, at present, very little is known about the underlying molecular mechanisms of these responses. In this study, RNA sequencing (RNA-seq) was performed to analyse the differences in the hepatic transcriptomes between control and Zn-exposed S. hasta. A total of 36,339 unigenes and 1,615 bp of unigene N50 were detected. These genes were further annotated to the Nonredundant protein (NR), Nonredundant nucleotide (Nt), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases. After 60 days of Zn exposure, 708 and 237 genes were significantly up- and down-regulated, respectively. Many differentially expressed genes (DEGs) involved in energy metabolic pathways were identified, and their expression profiles suggested increased catabolic processes and reduced biosynthetic processes. These changes indicated that waterborne Zn exposure increased the energy production and requirement, which was related to the activation of the AMPK signalling pathway. Furthermore, using the primary hepatocytes of S. hasta, we identified the role of the AMPK signalling pathway in Zn-influenced energy metabolism.

  4. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics.

    Directory of Open Access Journals (Sweden)

    Deborah L Diamond

    2010-01-01

    Full Text Available Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.

  5. Effect of Liver Disease on Hepatic Transporter Expression and Function.

    Science.gov (United States)

    Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R

    2017-09-01

    Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  6. Maternal undernutrition during late pregnancy in sheep. Its relationship to maternal condition, gestation length, hepatic physiology and glucose metabolism.

    Science.gov (United States)

    West, H J

    1996-04-01

    There is a paucity of information on the metabolic effects of undernutrition of the ewe carrying multiple fetuses in late pregnancy. In the present study the effects of induction of ketosis from 132 d gestation in ewes carrying twin fetuses were compared with a control group. The ewes were well fed up to 132 d. Ketotic ewes showed a loss of condition score from 3.7 (SE 0.11) at 130 d gestation to 3.0 (SE 0.15) 10 d later after clinical recovery, compared with control twin-pregnant ewes (P < 0.01). The weight loss during the same time period was from 70.6 (SE 2.7) kg at 130 d to 64.2 (SE 2.7) kg at 140.d gestation. As expected, both groups lost weight and condition score in the first 28 d of lactation. Induction of ketosis caused a significant shortening of the gestation period to 142.8 (SE 0.7) d compared with 150 (SE 0.4) d in normal twin-pregnant ewes (P < 0.001). Ewes with induced ketosis recovered clinically and showed a normal feed intake by 3.4 (SE 0.07) d; three required treatment. Induction of ketosis resulted in reduction of hepatic uptake of bromosulphthalein (P < 0.01) and its biliary excretion (P < 0.05), metabolic clearance rate (P < 0.001), fractional clearance (P < 0.001) and 15 and 30 min retention compared with control twin-pregnant ewes. Most values had returned to normal by the first week of lactation. It is thought that in human pregnancy similar changes in bromosulphthalein clearance may be related to reduced binding sites for bromosulphthalein in the liver caused by increased circulating oestrogens. Induction of ketosis resulted in a significant hypoglycaemic (P < 0.01), ketotic (P < 0.001) state compared with well-fed twin-pregnant ewes. These changes could be correlated with the severity of the clinical signs, together with a significant rise in plasma urea (P < 0.001) and NH3 (P < 0.05) concentrations. Again, the return of most of these values to normal by the first week of lactation lends support to the reversibility of hepatic lesions

  7. A Liver-Centric Multiscale Modeling Framework for Xenobiotics

    Science.gov (United States)

    Swat, Maciej; Cosmanescu, Alin; Clendenon, Sherry G.; Wambaugh, John F.; Glazier, James A.

    2016-01-01

    We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics. PMID:27636091

  8. Hormonal control of hepatic glycogen metabolism in food-deprived, continuously swimming coho salmon Oncorhynchus kisutch

    Science.gov (United States)

    Vijayan, M.M.; Maule, A.G.; Schreck, C.B.; Moon, T.W.

    1993-01-01

    The plasma cortisol concentration and liver cytosolic glucocorticoid receptor activities of continuously swimming, food-deprived coho salmon (Oncorhynchus kisutch) did not differ from those of resting, fed fish. Plasma glucose concentration was significantly higher in the exercising, starved fish, but there were no significant differences in either hepatic glycogen concentration or hepatic activities of glycogen phosphorylase, glycogen synthase, pyruvate kinase, or lactate dehydrogenase between the two groups. Total glucose production by hepatocytes did not differ significantly between the two groups; glycogen breakdown accounted for all the glucose produced in the resting, fed fish whereas it explained only 59% of the glucose production in the exercised animals. Epinephrine and glucagon stimulation of glucose production by hepatocytes was decreased in the exercised fish without significantly affecting hepatocyte glycogen breakdown in either group. Insulin prevented glycogen breakdown and enhanced glycogen deposition in exercised fish. The results indicate that food-deprived, continuously swimming coho salmon conserve glycogen by decreasing the responsiveness of hepatocytes to catabolic hormones and by increasing the responsiveness to insulin (anabolic hormone).

  9. Fructose supplementation worsens the deleterious effects of short-term high-fat feeding on hepatic steatosis and lipid metabolism in adult rats.

    Science.gov (United States)

    Crescenzo, Raffaella; Bianco, Francesca; Coppola, Paola; Mazzoli, Arianna; Tussellino, Margherita; Carotenuto, Rosa; Liverini, Giovanna; Iossa, Susanna

    2014-09-01

    The purpose of the present study was to examine the short-term effect of high-fat or high-fat-high-fructose feeding on hepatic lipid metabolism and mitochondrial function in adult sedentary rats. Adult male rats were fed a high-fat or high-fat-high-fructose diet for 2 weeks. Body and liver composition, hepatic steatosis, plasma lipid profile and hepatic insulin sensitivity, together with whole-body and hepatic de novo lipogenesis, were assessed. Hepatic mitochondrial mass, functionality, oxidative stress and antioxidant defense were also measured. Rats fed the high-fat-high-fructose diet exhibited significantly higher plasma triglycerides, non-esterified fatty acids, insulin and indexes of hepatic insulin resistance compared with rats fed a low-fat or a high-fat diet. Hepatic triglycerides and ceramide, as well as the degree of steatosis and necrosis, were significantly higher, while liver p-Akt was significantly lower, in rats fed high-fat-high-fructose diet than in rats fed high-fat diet. A significant increase in non-protein respiratory quotient and hepatic fatty acid synthase and stearoyl CoA desaturase activity was found in rats fed the high-fat-high-fructose diet compared with those fed the high-fat diet. Significantly lower mitochondrial oxidative capacity but significantly higher oxidative stress was found in rats fed high-fat and high-fat-high-fructose diets compared with rats fed low-fat diet, while mitochondrial mass significantly increased only in rats fed high-fat-high-fructose diet. In conclusion, short-term consumption of a Western diet, rich in saturated fats and fructose, is more conducive to the development of liver steatosis and deleterious to glucose homeostasis than a high-fat diet. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  10. Degradation of a recalcitrant xenobiotic compound: methyl tert-butyl ether (MTBE) metabolism by mycobacterium austroafricanum; Degradation d'un compose xenobiotique recalcitrant: metabolisme du methyl tert-butyl ether (MTBE) par mycobacterium austroafricanum IFP 2012

    Energy Technology Data Exchange (ETDEWEB)

    Francois, A.

    2002-11-01

    Methyl tert-butyl ether (MTBE) is introduced up to 15% (vol/vol) in gasoline in order to obtain a good octane number and to prevent carbon monoxide emissions. However, as a consequence of storage tanks leakage, MTBE became one of the major pollutants of aquifers because of its very low biodegradability. The present study aimed at investigating the biodegradation of MTBE by Mycobacterium austroafricanum IFP 2012. The MTBE metabolic pathway was partially elucidated owing to the identification of some intermediates (tert-butyl formate (TBF), tert-butyl alcohol (TBA), a-hydroxy-isobutyric acid and acetone) and some enzymatic activities (MTBE/TBA monooxygenase (non hemic and inducible), TBF esterase, 2-propanol: NDMA oxidoreductase and another monooxygenase involved in acetone degradation). The involvement of TBF and the requirement of cobalt could be explanations for the low natural attenuation of MTBE; whereas the methoxy group does not seem to be implicated. (author)

  11. A redox-resistant sirtuin-1 mutant protects against hepatic metabolic and oxidant stress.

    Science.gov (United States)

    Shao, Di; Fry, Jessica L; Han, Jingyan; Hou, Xiuyun; Pimentel, David R; Matsui, Reiko; Cohen, Richard A; Bachschmid, Markus M

    2014-03-14

    Sirtuin-1 (SirT1), a member of the NAD(+)-dependent class III histone deacetylase family, is inactivated in vitro by oxidation of critical cysteine thiols. In a model of metabolic syndrome, SirT1 activation attenuated apoptosis of hepatocytes and improved liver function including lipid metabolism. We show in SirT1-overexpressing HepG2 cells that oxidants (nitrosocysteine and hydrogen peroxide) or metabolic stress (high palmitate and high glucose) inactivated SirT1 by reversible oxidative post-translational modifications (OPTMs) on three cysteines. Mutating these oxidation-sensitive cysteines to serine preserved SirT1 activity and abolished reversible OPTMs. Overexpressed mutant SirT1 maintained deacetylase activity and attenuated proapoptotic signaling, whereas overexpressed wild type SirT1 was less protective in metabolically or oxidant-stressed cells. To prove that OPTMs of SirT1 are glutathione (GSH) adducts, glutaredoxin-1 was overexpressed to remove this modification. Glutaredoxin-1 overexpression maintained endogenous SirT1 activity and prevented proapoptotic signaling in metabolically stressed HepG2 cells. The in vivo significance of oxidative inactivation of SirT1 was investigated in livers of high fat diet-fed C57/B6J mice. SirT1 deacetylase activity was decreased in the absence of changes in SirT1 expression and associated with a marked increase in OPTMs. These results indicate that glutathione adducts on specific SirT1 thiols may be responsible for dysfunctional SirT1 associated with liver disease in metabolic syndrome.

  12. A New Metabolism-Related Index Correlates with the Degree of Liver Fibrosis in Hepatitis C Virus-Positive Patients

    Directory of Open Access Journals (Sweden)

    Hirayuki Enomoto

    2015-01-01

    Full Text Available Background. Only a few biomarkers based on metabolic parameters for evaluating liver fibrosis have been reported. The aim of this study was to investigate the relevance of an index obtained from three metabolic variables (glycated albumin: GA, glycated hemoglobin: HbA1c, and branched-chain amino acids to tyrosine ratio: BTR to the degree of liver fibrosis in hepatitis C virus virus- (HCV- positive patients. Methods. A total of 394 HCV-positive patients were assessed based on the values of a new index (GA/HbA1c/BTR. The index findings were used to investigate the relationship with the degree of liver fibrosis. Results. The new index showed an association with the stage of fibrosis (METAVIR scores: F0-1: 0.42 ± 0.10, F2: 0.48 ± 0.15, F3: 0.56 ± 0.22, and F4: 0.71 ± 0.30. The index was negatively correlated with three variables of liver function: the prothrombin time percentage (P<0.0001, albumin level (P<0.0001, and cholinesterase level (P<0.0001. The new index showed a higher correlation related to liver function than FIB-4 and the APRI did. In addition, the index showed a higher AUROC value than that of FIB-4 and the APRI for prediction of liver cirrhosis. Conclusion. The new metabolism-related index, GA/HbA1c/BTR value, is shown to relate to the degree of liver fibrosis in HCV-positive patients.

  13. Modulators of hepatic lipoprotein metabolism identified in a search for small-molecule inducers of tribbles pseudokinase 1 expression.

    Directory of Open Access Journals (Sweden)

    Marek M Nagiec

    Full Text Available Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1 to the risk of coronary artery disease (CAD. Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.

  14. Effects of Arctium lappa aqueous extract on lipid profile and hepatic enzyme levels of sucrose-induced metabolic syndrome in female rats

    Directory of Open Access Journals (Sweden)

    Akram Ahangarpour

    Full Text Available ABSTRACT Arctium lappa is known to have antioxidant and antidiabetic effects in traditional medicine. Objectives: The aim of this paper was to study the effects of A. lappa root extract (AE on lipid profile and hepatic enzyme levels in sucrose-induced metabolic syndrome (MS in female rats. The study used 40 adult female Wistar rats weighing 150 g-250 g randomly divided into five groups: control, metabolic syndrome (MS, metabolic syndrome+AE at 50,100, 200 mg/kg. MS was induced by administering 50% sucrose in drinking water for 6 weeks. AE was intra-peritoneally administered daily at doses of 50,100, and 200 mg/kg for two sequential weeks at the end of the fourth week in metabolic syndrome rats. Twenty-four hours after the last administration of AE, blood was collected and centrifuged, and then the serum was used for the measurement of lipid profile and hepatic enzyme. Serum glucose, insulin, fasting insulin resistance index, body weight, water intake, lipid profile, and hepatic enzymes were significantly increased although food intake was decreased in MS rats compared to the control rats. The lipids and liver enzymes were reduced by AE extracts in the MS group. This study showed that the A. lappa root aqueous extract exhibits a hypolipidemic activity of hyperlipidemic rats. This activity is practically that of a triple-impact antioxidant, hypolipidemic, and hepatoprotective.

  15. Ethoxyresorufin-O-deethylase enzyme activities and accumulation of secondary/tertiary lysosomes in rabbitfish Siganus oramin as biomarkers for xenobiotic exposures.

    Science.gov (United States)

    Fang, James K H; Au, Doris W T; Chan, Alice K Y; So, Leo K Y; Liu, Wenhua; Mok, Helen O L; Yu, Wai-Yin; Wu, Rudolf S S; Shin, Paul K S

    2010-09-15

    The sensitivities of using hepatic and intestinal ethoxyresorufin-O-deethylase (EROD) activities and hepatic accumulation of secondary/tertiary (2 degrees/3 degrees) lysosomes to detect xenobiotic exposures were assessed in the rabbitfish Siganus oramin in a metropolitan harbour, subtropical Hong Kong, over a complete seasonal cycle of one year. Additional information on the body-burden pollutants and physiological indices in S. oramin, and seasonal variables in seawater quality, were extracted from published data and re-analyzed. Under the influences of pollutant cocktail and seasonal factors, neither the hepatic nor intestinal EROD activity was indicative of total polycyclic aromatic hydrocarbons (Sigma PAH), total polychlorinated biphenyls, condition factor and hepatosomatic index (HSI) in S. oramin. However, the relative ratio of hepatic to intestinal EROD activities provided an indication to differentiate the xenobiotic intake route in the fish through diffusion via gills/skin or consumption of contaminated food. In addition, the elevated hepatic accumulation of 2 degrees/3 degrees lysosomes was closely associated with the dominant temporal trends of zinc and Sigma PAH, as well as reduced HSI, in S. oramin. Being minimally influenced by any investigated seasonal factors, the hepatic 2 degrees/3 degrees lysosomes in S. oramin was recommended as an effective biomarker of xenobiotic exposures and toxic effects for use in coastal pollution monitoring programmes.

  16. Gender and Species Differences in Triadimefon Metabolism by Rodent Hepatic Microsomes

    Science.gov (United States)

    Understanding the potential differences in metabolic capacity and kinetics between various common laboratory species as well as between genders is an important facet of chemical risk assessment that is often overlooked, particularly for chemicals which undergo non-cytochrome P450...

  17. Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs

    Science.gov (United States)

    New generation lipid emulsions comprised of fish oil or blends of soybean/fish/medium chain triglyceride/olive oil are emerging that result in favorable clinical metabolic outcomes in pediatric populations. Our aim was to characterize the lipidodomic, metabolomic, and transcriptomic profiles these ...

  18. Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs.

    NARCIS (Netherlands)

    van Beusekom, C.D.; Schipper, L.; Fink-Gremmels, J.

    2010-01-01

    This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities

  19. The influence of starvation upon hepatic drug metabolism in rats, mice, and guinea pigs.

    Science.gov (United States)

    Furner, R. L.; Feller, D. D.

    1971-01-01

    Male rats, mice, and guinea pigs were starved for 1, 2, or 3 days, and the metabolism of ethylmorphine, p-nitroanisole, and aniline was studied. Results suggest that the oxidative enzyme systems studied are not interdependent, and the pathways studied appear to be species dependent.

  20. Maternal nutrition during the first 50 days of gestation alters bovine fetal hepatic metabolic transcriptome

    Science.gov (United States)

    We hypothesized that maternal nutrition during the first 50 d of gestation would alter the metabolic transcriptome of the bovine fetal liver. Fourteen beef heifers were estrus synchronized and assigned to 2 treatments at breeding (CON, 100% of requirements to gain 0.45kg/d; RES, 60% of CON). Heifers...

  1. Leaf Epidermal Cells: A Trap for Lipophilic Xenobiotics

    Institute of Scientific and Technical Information of China (English)

    Zhiqian Liu

    2006-01-01

    Plant surfaces are covered by a layer of cuticle, which functions as a natural barrier to protect plants from mechanical damage, desiccation, and microbial invasion. Results presented in this report show that the epicuticular wax and the cuticle of plant leaves also play an important role in resisting xenobiotic invasion.Although the epicuticular wax is impermeableto hydrophilic xenobiotics, the cuticle not only restricts the penetration of hydrophilic compounds into leaf cells, but also traps lipophilic ones. The role of the epidermal cells of plant leaves in resisting xenobiotic invasion has been neglected until now. The present study shows, for the first time, that the epidermal cells may reduce or retard the transport of lipophilic xenobiotics into the internal tissues through vacuolar sequestration. Although the guard cells appear to be an easy point of entry for xenobiotics, only a very small proportion of xenobiotics present on the leaf surface actually moves into leaf tissues via the guard cells.

  2. Evolutions of microbial degradation pathways for parent xenobiotic and for its metabolites follow different schemes.

    Science.gov (United States)

    Chong, Nyuk-Min; Chang, Chun-Shuo; Tsai, Shiu-Ching

    2012-09-01

    The pathways used by microorganisms for the metabolism of every xenobiotic substrate are specific. The catabolism of a xenobiotic goes through a series of intermediate steps and lower intermediates (metabolites) appear in sequence. The structure of the metabolites can be similar to the parents due to kinship. The purposes of this study were to examine if the degradation pathways that were developed for a parent xenobiotic are effective to degrade the parent's lower metabolites, and if the reverse is true. The xenobiotic substrates, 2,4-dichlorophenoxyacetic acid (2,4-D, the parent xenobiotic) and its metabolite 2,4-dichlorophenol (2,4-DCP), were independently subjected to acclimation and degradation tests by the biomasses of mixed-culture activated sludge and a pure culture of Arthrobacter sp. Activated sludge and Arthrobacter sp. that were acclimated to 2,4-D effectively degraded 2,4-D and the lower metabolites of 2,4-D, typically 2,4-DCP. During the degradation of 2,4-D, accumulations of the lower metabolites of 2,4-D were not found. The degradation pathways acquired from acclimation to 2,4-D are effective for all the metabolites of 2,4-D. However, pathways acquired from acclimation to 2,4-DCP are not effective in the degradation of the parent 2,4-D. Microorganisms acclimated to 2,4-D evolve their degradation pathways by a scheme that is different from the scheme the microorganisms employ when they are acclimated to the metabolites of 2,4-D.

  3. Hepatitis C virus core protein induces energy metabolism disorders of hepatocytes by down-regulation of silent mating type information regulation 2 homolog-1 and adenosine monophosphate-acti vated protein kinase signaling pathway

    Institute of Scientific and Technical Information of China (English)

    于建武

    2013-01-01

    Objective To study the role of silent mating type information regulation2homotog-1(SIRT1)-adenosine monophosphate(AMP)-activated protein kinase(AMPK) signaling pathway in hepatitis C virus core protein(HCV-core)induced energy metabolism disorders

  4. Correlation of serum leptin levels with anthropometric and metabolic parameters and biochemical liver function in Chinese patients with chronic hepatitis C virus infection

    Institute of Scientific and Technical Information of China (English)

    Zheng-Wen Liu; Ni Zhang; Qun-Ying Han; Jun-Tao Zeng; Yong-Lie Chu; Jian-Ming Qiu; Ya-Wen Wang; Lie-Ting Ma; Xiao-Qin Wang

    2005-01-01

    AIM: To determine serum leptin levels and investigate their correlations with anthropometric and metabolic parameters and biochemical liver function in patients with chronic hepatitis C virus (HCV) infection and their potential clinical implications.METHODS: Forty-two chronic HCV-infected patients without anti-viral treatment were enrolled in this study, 30 patients had chronic hepatitis C, 10 had cirrhosis, and 2 had hepatocellular carcinoma (HCC). Thirty age- and sex-matched healthy individuals served as controls. Serum leptin levels were determined by ELISA. The biochemical liver function and serum lipids were determined at the same time. The height and body weight of patients and controls were measured, and body mass index (BMI) and body fat were calculated simultaneously. The correlations of serum leptin levels with anthropometric and metabolic parameters and biochemical liver function were assessed statistically.RESULTS: The mean of serum leptin levels in patients with chronic hepatitis C, HCV-associated cirrhosis, HCVassociated HCC and control groups was (6.13±3.94),(5.25±4.21), (4.17±0.28), and (3.59±3.44) ng/mL, respectively. The serum leptin level in patients with chronic hepatitis C was significantly higher than that in controls. The serum leptin levels between cirrhotic patients and controls and between male and female cirrhotic patients had no significant difference. Serum leptin levels were positively-correlated with body fat, BMI, and apolipoprotein B (Apo B) in patients with chronic HCV infection. The serum alanine aminotransferase (ALT) levels were closelycorrelated with BMI in patients with chronic hepatitis C. CONCLUSION: HCV infection interferes with fat and lipid metabolism in patients with chronic HCV infection and leptin may play a role in hepatosteatosis.

  5. Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice.

    Science.gov (United States)

    Herrema, Hilde; Derks, Terry G J; van Dijk, Theo H; Bloks, Vincent W; Gerding, Albert; Havinga, Rick; Tietge, Uwe J F; Müller, Michael; Smit, G Peter A; Kuipers, Folkert; Reijngoud, Dirk-Jan

    2008-06-01

    Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD(-/-) mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD(-/-) mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) and decreased peroxisome proliferator-activated receptor alpha (Ppar alpha) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD(-/-) mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD(-/-) mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD(-/-) mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD(-/-) mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD(-/-) mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD(-/-) mice, was mainly due to enhanced peripheral glucose uptake. Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the

  6. [Carnitine: function, metabolism and value in hepatic failure during chronic alcohol intoxication].

    Science.gov (United States)

    Kępka, Alina; Szajda, Sławomir Dariusz; Waszkiewicz, Napoleon; Płudowski, Paweł; Chojnowska, Sylwia; Rudy, Michał; Szulc, Agata; Ladny, Jerzy Robert; Zwierz, Krzysztof

    2011-10-07

    Alcoholism is one of the most frequent dependences among people, leading to damage of the liver and death of the person. Chronic alcohol consumption decreases fatty acid oxidation by interfering with carnitine metabolism and citric acid cycle activity. Block in activity of the citric acid cycle caused by alcohol and its metabolites is partially compensated by increased ketone body production, which results in ketosis. Chronic administration of alcohol induces liver injury, inflammation, cirrhosis, focal necrosis and steatosis. L-carnitine (L-3-hydroxy-4-N, N, N-trimethylaminebutyric acid) is an essential factor in fatty acid metabolism, which plays a major role in transport of activated long-chain fatty acids to sites of β-oxidation in mitochondria. Carnitine also stabilizes cell membranes by removing long-chain acyl-CoA and excess of the acyl group from the body. L-carnitine can be a useful and safe drug in the liver pathology induced by chronic ethanol exposure.

  7. Dietary fatty acids affecting hepatic metabolism and atherosclerosis - mechanisms unravelled using a proteomics approach

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez Gutierrez, G.; Roos, B. de

    2009-07-01

    Dietary fatty acids play an important role in the aetiology of coronary heart disease. The effects of dietary fatty acids on lipoprotein metabolism are well described, but additional or alternative mechanisms relating to potential influence on coronary heart disease are not known. This review describes how proteomics techniques have been used to identify proteins that are differentially regulated by dietary fatty acids. Such proteins may reveal pathways by which dietary fatty acids influence disease risk. (Author) 40 refs.

  8. Heroin Dependence Duration Influences the Metabolic Parameters Mechanisms and Consequences of Impaired Insulin Sensitivity in Hepatitis C Virus Seronegative Heroin Dependents

    OpenAIRE

    Pereska, Zanina; Bozinovska, Cvetanka; Dimitrovski, Chedo; Cakalarovski, Koco; Chibishev, Andon; Zdravkovska, Milka; Babulovska, Aleksandra; Janikevik Ivanovska, Danijela

    2012-01-01

    Objective: Carbohydrate metabolism disorder in heroin dependence is an issue with long history and contradicting results. The aim of the study was to evaluate basal insulin sensitivity in hepatitis C virus seronegative heroin dependents with normal body mass index, taking into consideration the duration of heroin dependence. Method: 78 heroin dependents and 32 healthy controls were enrolled in the cross-sectional, prospective study. The dependents were observed in 2 groups: group 1 with de...

  9. Increasing levels of dietary crystalline methionine affect plasma methionine profiles, ammonia excretion, and the expression of genes related to the hepatic intermediary metabolism in rainbow trout (Oncorhynchus mykiss)

    DEFF Research Database (Denmark)

    Rolland, Marine; Skov, Peter Vilhelm; Larsen, Bodil Katrine;

    2016-01-01

    . The diets were fed in excess for six weeks before three sampling campaigns carried out successively to elucidate (i) the hepatic expression of selected genes involved in lipid, glucose and amino acid metabolism; (ii) the postprandial ammonia excretion; and (iii) the postprandial plasma methionine...... significantly affected by the increase in dietary methionine. Changes in gene expression reflected to some extent the decrease in ammonia excretion (P=0.022) and in the hepatosomatic index (HSI; P...

  10. Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

    Science.gov (United States)

    Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui

    2014-11-05

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

  11. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.

    Science.gov (United States)

    Jung, Un Ju; Cho, Yun-Young; Choi, Myung-Sook

    2016-05-19

    Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver.

  12. Effect of betaine supplementation on changes in hepatic metabolism of sulfur-containing amino acids and experimental cholestasis induced by alpha-naphthylisothiocyanate.

    Science.gov (United States)

    Kim, Young C; Jung, Young S; Kim, Sang K

    2005-05-01

    Alterations in the hepatic metabolism of sulfur amino acids in experimental cholestasis induced by alpha-naphthylisothiocyanate (ANIT) (100 mg/kg, po) were monitored in male mice for 1 week. We also examined the effects of betaine supplementation (1% in drinking water) for 2 weeks on the hepatotoxicity and changes in the sulfur amino acid metabolism induced by ANIT treatment. Acute ANIT challenge elevated the serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities, and total bilirubin contents from 5 h after the treatment, reaching a peak at t = 48-72 h. Hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels were decreased significantly in a manner almost inversely proportional to the changes in serum parameters measured to determine the ANIT-induced toxicity. Hepatic glutathione and cysteine levels were elevated at t = 120 h after the treatment. Betaine supplementation blocked or significantly attenuated induction of the hepatotoxicity by ANIT. The decrease in SAM and SAH levels was also inhibited by betaine intake. The results indicate that betaine supplementation may antagonize the induction of experimental cholestasis and changes in the metabolism of sulfur amino acids associated with ANIT treatment. The underlying mechanism and pharmacological significance of its action are discussed.

  13. Interplay among cellular polarization, lipoprotein metabolism and hepatitis C virus entry

    Institute of Scientific and Technical Information of China (English)

    Ignacio Benedicto; Francisca Molina-Jiménez; Ricardo Moreno-Otero; Manuel López-Cabrera; Pedro L Majano

    2011-01-01

    Hepatitis C virus (HCV) infects more than three million new individuals worldwide each year. In a high percentage of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines, and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection.Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still largely unknown. In addition, increasing evidence indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition and host cell phenotype.Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process.

  14. Catechins and Caffeine Inhibit Fat Accumulation in Mice through the Improvement of Hepatic Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Chikako Sugiura

    2012-01-01

    Full Text Available To elucidate the inhibiting mechanisms of fat accumulation by catechins, caffeine, and epigallocatechin gallate (EGCG, ICR mice were fed diets containing either 0.3% catechins or 0.1% EGCG and/or 0.05% caffeine for 4 weeks. After the feeding, intraperitoneal adipose tissues weights were significantly lower in the caffeine, catechins + caffeine, and EGCG + caffeine groups compared to controls. Hepatic fatty acid synthase (FAS activity in the catechins + caffeine group was significantly lower, and the activities of acyl-CoA oxidase (ACO and carnitine palmitoyltransferase-II (CPT-II were significantly higher, compared to the control group. However, these activities were not observed in the other groups. FAS mRNA expression levels in the catechins + caffeine group were significantly lower than in the control group. ACO and CPT-II mRNA levels were not different among all of the treatment groups. These findings indicate that the inhibitory effects of fat accumulation via a combination of catechins, EGCG, or caffeine were stronger collectively than by either catechins, EGCG, or caffeine alone. Moreover, it was demonstrated that the combination of catechins and caffeine induced inhibition of fat accumulation by suppression of fatty acid synthesis and upregulation of the enzymatic activities involved in β-oxidation of fatty acid in the liver, but this result was not observed by combination of EGCG and caffeine.

  15. Catechins and Caffeine Inhibit Fat Accumulation in Mice through the Improvement of Hepatic Lipid Metabolism.

    Science.gov (United States)

    Sugiura, Chikako; Nishimatsu, Shiho; Moriyama, Tatsuya; Ozasa, Sayaka; Kawada, Teruo; Sayama, Kazutoshi

    2012-01-01

    To elucidate the inhibiting mechanisms of fat accumulation by catechins, caffeine, and epigallocatechin gallate (EGCG), ICR mice were fed diets containing either 0.3% catechins or 0.1% EGCG and/or 0.05% caffeine for 4 weeks. After the feeding, intraperitoneal adipose tissues weights were significantly lower in the caffeine, catechins + caffeine, and EGCG + caffeine groups compared to controls. Hepatic fatty acid synthase (FAS) activity in the catechins + caffeine group was significantly lower, and the activities of acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-II (CPT-II) were significantly higher, compared to the control group. However, these activities were not observed in the other groups. FAS mRNA expression levels in the catechins + caffeine group were significantly lower than in the control group. ACO and CPT-II mRNA levels were not different among all of the treatment groups. These findings indicate that the inhibitory effects of fat accumulation via a combination of catechins, EGCG, or caffeine were stronger collectively than by either catechins, EGCG, or caffeine alone. Moreover, it was demonstrated that the combination of catechins and caffeine induced inhibition of fat accumulation by suppression of fatty acid synthesis and upregulation of the enzymatic activities involved in β-oxidation of fatty acid in the liver, but this result was not observed by combination of EGCG and caffeine.

  16. Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism.

    Science.gov (United States)

    Saeedi, Ramesh; Mojebi-Mogharar, Ali; Sandhu, Supna K; Dubland, Joshua A; Ford, Jo-Ann; Yousefi, Masoud; Pudek, Morris; Holmes, Daniel T; Erb, Siegfried R; Peter Kwan, Wing; Kendler, David L; Yoshida, Eric M

    2017-01-01

    Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

  17. Effect of Breathwalk on body composition, metabolic and mood state in chronic hepatitis C patients with insulin resistance syndrome

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To identify the anthropometric, metabolic and mood state in hepatitis C virus (HCV)-infected patients from the west of Mexico and to evaluate the effect of Breathwalk (BW), a combination of walking, synchronized breathing and focussed attention, on those patients.METHODS: In an experimental study, 17 patients with serological and molecular diagnosis of HCV, not receiving pharmacological treatment, were studied. One hour sessions of BW were practiced 3 times at week for six months. Body composition was assessed by electric impedance. Biochemical profiles and insulin resistance (IR) risk was assessed by conventional methods. Mood state was evaluated with specific and open questions at the beginning and at the end of the program.RESULTS: Seventy percent of patients were overweight or obese, and 77% of the patients presented with IR at the beginning of the study. Improvements were observed at the 3rd mo, and statistically significant differences were recorded at the 6th mo using the fitness score (76 vs 83, P < 0.01), in alanine aminotransferase (ALT)(106 ± 93 U/L vs 59 ± 32 U/L, P < 0.01), total bilirubin (0.09 ± 1 mg/dL vs 0.62 ± 0.2 mg/dL, P < 0.01), ALT/AST ratio (1.04 vs 0.70, P < 0.01), triglycerides (165 ±86 mg/dL vs 124±49 mg/dL, P < 0.01) and the IR risk (4.0 vs 2.7). Most patients (88%) indicated to feel better at the end of BW (P < 0.01).CONCLUSION: Breathwalk has an important effect on body composition, lipid profile and liver enzymes. It is also easy, inexpensive and has a beneficial effect on metabolic and mood state in HCV patients.

  18. MAY ULTRASONOGRAPHY DIAGNOSED HEPATIC STEATOSIS BE PREDICTOR OF METABOLIC SYNDROME AMONG AVIATORS?

    Directory of Open Access Journals (Sweden)

    Alpaslan Tanoglu

    2015-12-01

    Results: The prevalence of HS was %16.9 (n=32 in the aviators who were performed abdominal USG as an annual routine test. BMI (26.1+/-1.9 vs 24.0+/-1.9, p<0.001, SBP (119.1+/-11.2 vs 110.7+/-7.5, p=0.001, and DBP (76.6+/-7.6 vs 70.1+/-6.9, p=0.001, FBG (97.7+/-9.1 vs 90.1+/-13.3, p=0.010, TC (219.9+/-42.3 vs 191.2+/-30.1, p=0.003, LDL-C (140.2+/-34.3 vs 117.9+/-22.2, p=0.003 and VLDL-C (32.1+/-14.5 vs 23.9+/-12.5, p=0.019, TC/HDL-C ratio (4.5+/-0.9 vs 3.9+/-0.8, p=0.011 were significantly higher in aviators with HS compared to healthy ones. Metabolic syndrome ( and #8805;3 criteria was significantly higher in aviators with HS compared to healthy ones (53.1% vs 18.8%, p=0.004. Conclusions: HS may be a reliable representative of metabolic syndrome which can be non-invasively screened among aviators. Moreover, HS may be a clinical indicator of metabolic syndrome among aviators who need further cardiovascular evaluation and also counseling for lifestyle and dietary changes, and exercise activity programming. [Dis Mol Med 2015; 3(4.000: 35-42

  19. Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice.

    Science.gov (United States)

    Dikkers, Arne; Annema, Wijtske; de Boer, Jan Freark; Iqbal, Jahangir; Hussain, M Mahmood; Tietge, Uwe J F

    2014-05-01

    Because apoB-containing lipoproteins are pro-atherogenic and their secretion by liver and intestine largely depends on microsomal triglyceride transfer protein (MTP) activity, MTP inhibition strategies are actively pursued. How decreasing the secretion of apoB-containing lipoproteins affects intracellular rerouting of cholesterol is unclear. Therefore, the aim of the present study was to determine the effects of reducing either systemic or liver-specific MTP activity on cholesterol metabolism and reverse cholesterol transport (RCT) using a pharmacological MTP inhibitor or a genetic model, respectively. Plasma total cholesterol and triglyceride levels were decreased in both MTP inhibitor-treated and liver-specific MTP knockout (L-Mttp(-/-)) mice (each P small but significant decrease in fecal bile acid excretion was observed in inhibitor-treated mice (P excretion was substantially increased by 75% (P intestinal absorption. In contrast, in L-Mttp(-/-) mice both fecal neutral sterol and bile acid excretion remained unchanged. However, while total RCT increased in inhibitor-treated mice (P < 0.01), it surprisingly decreased in L-Mttp(-/-) mice (P < 0.05). These data demonstrate that: i) pharmacological MTP inhibition increases RCT, an effect that might provide additional clinical benefit of MTP inhibitors; and ii) decreasing hepatic MTP decreases RCT, pointing toward a potential contribution of hepatocyte-derived VLDLs to RCT.

  20. Carnitine: function, metabolism and value in hepatic failure during chronic alcohol intoxication

    Directory of Open Access Journals (Sweden)

    Alina Kępka

    2011-10-01

    Full Text Available Alcoholism is one of the most frequent dependences among people, leading to damage of the liver and death of the person. Chronic alcohol consumption decreases fatty acid oxidation by interfering with carnitine metabolism and citric acid cycle activity. Block in activity of the citric acid cycle caused by alcohol and its metabolites is partially compensated by increased ketone body production, which results in ketosis. Chronic administration of alcohol induces liver injury, inflammation, cirrhosis, focal necrosis and steatosis.L-carnitine (L-3-hydroxy-4-N, N, N-trimethylaminebutyric acid is an essential factor in fatty acid metabolism, which plays a major role in transport of activated long-chain fatty acids to sites of β-oxidation in mitochondria. Carnitine also stabilizes cell membranes by removing long-chain acyl-CoA and excess of the acyl group from the body. L-carnitine can be a useful and safe drug in the liver pathology induced by chronic ethanol exposure.

  1. Irisin ameliorates hepatic glucose/lipid metabolism and enhances cell survival in insulin-resistant human HepG2 cells through adenosine monophosphate-activated protein kinase signaling.

    Science.gov (United States)

    So, Wing Yan; Leung, Po Sing

    2016-09-01

    Irisin is a newly identified myokine that promotes the browning of white adipose tissue, enhances glucose uptake in skeletal muscle and modulates hepatic metabolism. However, the signaling pathways involved in the effects on hepatic glucose and lipid metabolism have not been resolved. This study aimed to examine the role of irisin in the regulation of hepatic glucose/lipid metabolism and cell survival, and whether adenosine monophosphate-activated protein kinase (AMPK), a master metabolic regulator in the liver, is involved in irisin's actions. Human liver-derived HepG2 cells were cultured in normal glucose-normal insulin (NGNI) or high glucose-high insulin (HGHI/insulin-resistant) condition. Hepatic glucose and lipid metabolism was evaluated by glucose output and glycogen content or triglyceride accumulation assays, respectively. Our results showed that irisin stimulated phosphorylation of AMPK and acetyl-CoA-carboxylase (ACC) via liver kinase B1 (LKB1) rather than Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) in HepG2 cells. Irisin ameliorated hepatic insulin resistance induced by HGHI condition. Irisin reduced hepatic triglyceride content and glucose output, but increased glycogen content, with those effects reversed by dorsomorphin, an AMPK inhibitor. Furthermore, irisin also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and promoted cell survival in an AMPK-dependent manner. In conclusion, our data indicate that irisin ameliorates dysregulation of hepatic glucose/lipid metabolism and cell death in insulin-resistant states via AMPK activation. These findings reveal a novel irisin-mediated protective mechanism in hepatic metabolism which provides a scientific basis for irisin as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes mellitus. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Metabolic syndrome in patients with chronic hepatitis C virus genotype 1 infection who do not have obesity or type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Lucivalda Pereira Magalhães Oliveira

    2012-01-01

    Full Text Available OBJECTIVE: The individual components of metabolic syndrome may be independent predictors of mortality in patients with liver disease. We aimed to evaluate the prevalence of metabolic syndrome and its related components in hepatitis C virus-infected patients who are not obese and do not have type 2 diabetes. METHODS: This cross-sectional study included 125 patients infected with hepatitis C virus genotype 1. Metabolic syndrome was defined according to the International Diabetes Federation. Anthropometric data were measured according to standardized procedures. Bioimpedance analysis was performed on all patients. RESULTS: Metabolic syndrome was diagnosed in 21.6% of patients. Of the subjects with metabolic syndrome, 59.3% had hypertension, 77.8% had insulin resistance, 85.2% were overweight, 48.1% had a high waist circumference, 85.2% had an increased body fat percentage, and 92.3% had an elevated waist:hip ratio. In the bivariate analysis, female sex (OR 2.58; 95% CI: 1.09-6.25, elevated gamma-glutamyl transferase (γGT (OR 2.63; 95% CI: 1.04-7.29, elevated fasting glucose (OR 8.05; 95% CI: 3.17-21.32, low HDL cholesterol (OR 2.80; 95% CI: 1.07-7.16, hypertriglyceridemia (OR 7.91; 95% CI: 2.88-22.71, elevated waist circumference (OR 10.33; 95% CI: 3.72-30.67, overweight (OR 11.33; 95% CI: 3.97-41.07, and increased body fat percentage (OR 8.34; 95% CI: 2.94-30.08 were independent determinants of metabolic syndrome. Using the final multivariate regression model, similar results were observed for abdominal fat (OR 9.98; 95% CI: 2.63-44.41 and total body fat percentage (OR 8.73; 95% CI: 2.33-42.34. However, metabolic syndrome risk was also high for those with blood glucose >5.55 mmol/L or HDL cholesterol <0.9 mmol/L (OR 16.69; 95% CI: 4.64-76.35; OR 7.23; 95% CI: 1.86-32.63, respectively. CONCLUSION: Metabolic syndrome is highly prevalent among hepatitis C virus-infected patients without type 2 diabetes or obesity. Metabolic syndrome was

  3. Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia.

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    Peyta, Laure; Jarnouen, Kathleen; Pinault, Michelle; Coulouarn, Cedric; Guimaraes, Cyrille; Goupille, Caroline; de Barros, Jean-Paul Pais; Chevalier, Stephan; Dumas, Jean-François; Maillot, François; Hatch, Grant M; Loyer, Pascal; Servais, Stephane

    2015-11-01

    Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (pcachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.

  4. Obesity and Metabolic Phenotypes (Metabolically Healthy and Unhealthy Variants Are Significantly Associated with Prevalence of Elevated C-Reactive Protein and Hepatic Steatosis in a Large Healthy Brazilian Population

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    Sameer Shaharyar

    2015-01-01

    Full Text Available Background. Among the obese, the so-called metabolically healthy obese (MHO phenotype is thought to confer a lower CVD risk as compared to obesity with typical associated metabolic changes. The present study aims to determine the relationship of different subtypes of obesity with inflammatory-cardiometabolic abnormalities. Methods. We evaluated 5,519 healthy, Brazilian subjects (43±10 years, 78% males, free of known cardiovascular disease. Those with <2 metabolic risk factors (MRF were considered metabolically healthy, and those with BMI ≥ 25 kg/m2 and/or waist circumference meeting NCEP criteria for metabolic syndrome as overweight/obese (OW. High sensitivity C reactive protein (hsCRP was measured to assess underlying inflammation and hepatic steatosis (HS was determined via abdominal ultrasound. Results. Overall, 40% of OW individuals were metabolically healthy, and 12% normal-weight had ≥2 MRF. The prevalence of elevated CRP (≥3 mg/dL and HS in MHO versus normal weight metabolically healthy group was 22% versus 12%, and 40% versus 8% respectively (P<0.001. Both MHO individuals and metabolically unhealthy normal weight (MUNW phenotypes were associated with elevated hsCRP and HS. Conclusion. Our study suggests that MHO and MUNW phenotypes may not be benign and physicians should strive to treat individuals in these subgroups to reverse these conditions.

  5. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

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    Alwahsh, Salamah Mohammad; Xu, Min; Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (Pfructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and insulin resistance-accompanied liver damage.

  6. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

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    Salamah Mohammad Alwahsh

    Full Text Available Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control, liquid Lieber-DeCarli (LDC diet, LDC +30%J of ethanol (L-Et or fructose (L-Fr, and LDC combined with 30%J ethanol and 30%J fructose (L-EF. Body weight (BW and liver weight (LW were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week, whereas fructose-fed animals had higher LW than controls (P<0.05. Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group. The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on

  7. The influence of single application of paracetamol and/or N-acetylcysteine on rats subchronic exposed to trichloroethylene vapours. I. Effect on hepatic moonooxygenase system dependent of cytochrome P450

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    Andrzej Plewka

    2012-06-01

    Full Text Available Background: There is a number of factors which potentially affect occurrence of toxic change in liver after overdosing of paracetamol. Hepatic metabolism of trichloroethylene has primary impact on hepatotoxic effect of this solvent. This means that the combined exposure to these xenobiotics can be particularly harmful for human. The influence of N-acetylcysteine (NAC as a protective factor after paracetamol intoxication was studies. Materials and method: Tests were carried out on rats which were treated with trichloroethylene, paracetamol and/or N-acetylcysteine. In the hepatic microsomal fraction activity of the components of cytochrome P450- dependent monooxygenases was determined Results: Paracetamol slightly stimulated cytochrome P450 having no effect on reductase activity cooperating with it. Cytochrome b5 and its reductase were inhibited by this compound. Trichloroethylene was the inhibitor of compounds of II microsomal electron transport chain. N-acetylcysteine inhibited activity of reductase of NADH-cytochrome b5. Conclusions: Tested doses of the xenobiotics influenced on II microsomal electron transport chain. Protective influence of N-acetylcysteine was better if this compound was applied 2 hours after exposure on xenobiotics

  8. Effect of fishmeal replacement by soy protein concentrate with taurine supplementation on hepatic intermediary metabolism and antioxidant status of totoaba juveniles (Totoaba macdonaldi).

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    Bañuelos-Vargas, Isaura; López, Lus M; Pérez-Jiménez, Amalia; Peres, Helena

    2014-04-01

    The effect of dietary incorporation of soy protein concentrate (SPC) and the concomitant supplementation with taurine on hepatic intermediary metabolism and antioxidant status of totoaba (Totoaba macdonaldi) juveniles was assessed. Four isoproteic and isolipidic diets were formulated containing either 30 or 60% of SPC (diets SP30 and SP60), supplemented or not with 1% of taurine (diets SP30T and SP60T). A fish meal (FM) based diet, without SPC and taurine supplementation, was used as a control. Triplicate groups of 32 totoaba juveniles (average body mass=7.5g) were fed these diets over 45days. Results revealed that dietary FM replacement by SPC depressed the overall intermediary metabolism. Activity of key enzymes of amino acid catabolism and gluconeogenesis was significantly reduced and a trend to reduce glycolysis and glucose-6-phosphate dehydrogenase activity was observed. The incorporation of the highest level of SPC also significantly increased hepatic lipid peroxidation and the activity of superoxide dismutase. Concomitant taurine supplementation restored the activity of amino acid catabolic and gluconeogenic enzymes and hexokinase to levels similar of those of the control diet. Taurine supplementation also led to a significant increase of glucose-6-phosphate dehydrogenase and catalase activity, as well as to a significant reduction of liver lipid peroxidation. These results suggest that taurine may play an important metabolic modulation action on totoaba fed SPC based diets, contributing to the enhancement of the overall metabolism and to the reduction of liver oxidative damage.

  9. Validation of using gene expression in mononuclear cells as a marker for hepatic cholesterol metabolism

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    Dutta Amrita

    2006-08-01

    Full Text Available Abstract HMG-CoA reductase and the LDL receptor are ubiquitously expressed in major tissues. Since the liver plays a major role in regulating circulating LDL, it is usually of interest to measure the effects of drug or dietary interventions on these proteins in liver. In humans, peripheral blood mononuclear cells have been used as a surrogate for liver to assess regulation of these genes, although there is concern regarding the validity of this approach. The purpose of this study was to evaluate the relationship between liver and mononuclear cell expression of HMG-CoA reductase and the LDL receptor in guinea pigs, a well established model for human cholesterol and lipoprotein metabolism. We extracted RNA from liver and mononuclear cells of guinea pigs from a previous study where the effects of rapamycin, an immunosuppresant drug used for transplant patients, on lipid metabolism were evaluated. Guinea pigs were assigned to three different diets containing the same amount of fat (15 g/100 g and cholesterol (0.08 g/100 g for a period of 3 weeks. The only difference among diets was the concentration of rapamycin: 0, 0.0028 or 0.028 g/100 g. There were no differences in plasma LDL cholesterol (LDL-C among groups. Values were 78.4 ± 14.3, 65.8 ± 17.2 and 68.4 ± 45.4 mg/dL (P > 0.05 for guinea pigs treated with 0, low or high doses of rapamycin, respectively. The mRNA abundance for the LDL receptor and HMG-CoA reductase was measured both in liver (n = 30 and mononuclear cells (n = 22 using reverse transcriptase PCR. In agreement with the finding of no changes in plasma LDL-C, there were also no differences for the expression of HMG-CoA reductase or the LDL receptor among groups. However, a positive correlation was found between liver and mononuclear cells for both HMG-CoA reductase (r = 0.613, P

  10. Hepatitis B virus (HBV) X protein-mediated regulation of hepatocyte metabolic pathways affects viral replication.

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    Bagga, Sumedha; Rawat, Siddhartha; Ajenjo, Marcia; Bouchard, Michael J

    2016-11-01

    Chronic HBV infection is a risk factor for hepatocellular carcinoma (HCC). The HBV HBx protein stimulates HBV replication and likely influences the development of HBV-associated HCC. Whether HBx affects regulators of metabolism in normal hepatocytes has not been addressed. We used an ex vivo, cultured primary rat hepatocyte system to assess the interplay between HBV replication and mechanistic target of rapamycin complex 1 (mTORC1) signaling. HBx activated mTORC1 signaling; however, inhibition of mTORC1 enhanced HBV replication. HBx also decreased ATP levels and activated the energy-sensing factor AMP-activated protein kinase (AMPK). Inhibition of AMPK decreased HBV replication. Inhibition of AMPK activates mTORC1, and we showed that activated mTORC1 is one factor that reduces HBV replication when AMPK is inhibited. HBx activation of both AMPK and mTORC1 suggests that these activities could provide a balancing mechanism to facilitate persistent HBV replication. HBx activation of mTORC1 and AMPK could also influence HCC development. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Longitudinal Changes in Liver Aminotransferases Predict Metabolic Syndrome in Chinese Patients with Nonviral Hepatitis

    Institute of Scientific and Technical Information of China (English)

    CHEN Qi Cai; XIAO Juan; ZHANG Peng Peng; CHEN Li Li; CHEN Xiao Xiao; WANG Shu Mei

    2016-01-01

    ObjectiveThis study exploredthe correlation of longitudinal changes in serumalanine aminotransferase (ALT) and aspartate aminotransferase (AST)levels with the incidence of metabolic syndrome (Mets)based on a dynamic health examination cohort. MethodsA Mets-free dynamic cohortinvolving 4541 participants who underwent at leastthree health examinations from 2006 to 2011 was included in the study. Mets was defined according to the Chinese Medical Association Diabetes Branch definitionthat included hypertension, obesity, hyperlipidemia, and hyperglycemia. Generalized estimating equation (GEE) model was used to analyze multivariate relative risk (RR) of repeated observations ofALT and AST in quartiles for Mets or its components according to gender. ResultsIn all, 826Mets cases were reported. Adjustmentof relevant parameters indicated that time-varyingchanges in ALT and ASTlevels were positively associated with the incidenceof Mets in a dose-response manner. Positive association between high ALT levels and fatty liver was much stronger than that between high AST levels and fatty liver, particularly in maleparticipants. These associations were consistently observed in the following subgroups: participants with ALT and ASTlevels of ConclusionThese results suggested that elevated serum ALT and AST levels wereearly biomarkers of Mets or its components.

  12. Dietary fatty acids affecting hepatic metabolism and atherosclerosis - mechanisms unravelled using a proteomics approach

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    Rodríguez Gutiérrez, Guillermo

    2009-03-01

    Full Text Available Dietary fatty acids play an important role in the aetiology of coronary heart disease. The effects of dietary fatty acids on lipoprotein metabolism are well described, but additional or alternative mechanisms relating to potential influence on coronary heart disease are not known. This review describes how proteomics techniques have been used to identify proteins that are differentially regulated by dietary fatty acids. Such proteins may reveal pathways by which dietary fatty acids influence disease risk.Los ácidos grasos de la dieta cumplen un importante papel en la etiología de las enfermedades coronarias. A pesar de estar bien descrito el efecto de dichos ácidos grasos sobre el metabolismo lipoproteíco, no se conocen mecanismos alternativos que relacionen su influencia sobre posibles enfermedades coronarias. En esta revisión se describe el uso de técnicas proteómicas para