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Sample records for acid-induced fatty liver

  1. Uridine prevents fenofibrate-induced fatty liver.

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    Thuc T Le

    Full Text Available Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD and acyl-CoA oxidase 1 (ACOX1, and induces excessive accumulation of long chain fatty acids (LCFA and very long chain fatty acids (VLCFA. Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.

  2. Effects of Fatty Liver Induced by Excess Orotic Acid on B-Group Vitamin Concentrations of Liver, Blood, and Urine in Rats.

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    Shibata, Katsumi; Morita, Nobuya; Kawamura, Tomoyo; Tsuji, Ai; Fukuwatari, Tsutomu

    2015-01-01

    Fatty liver is caused when rats are given orotic acid of the pyrimidine base in large quantities. The lack of B-group vitamins suppresses the biosynthesis of fatty acids. We investigated how orotic acid-induced fatty liver affects the concentrations of liver, blood, and urine B-group vitamins in rats. The vitamin B6 and B12 concentrations of liver, blood, and urine were not affected by orotic acid-induced fatty liver. Vitamin B2 was measured only in the urine, but was unchanged. The liver, blood, and urine concentrations of niacin and its metabolites fell dramatically. Niacin and its metabolites in the liver, blood, and urine were affected as expected. Although the concentrations of vitamin B1, pantothenic acid, folate, and biotin in liver and blood were decreased by orotic acid-induced fatty liver, these urinary excretion amounts showed a specific pattern toward increase. Generally, as for the typical urinary excretion of B-group vitamins, these are excreted when the body is saturated. However, the ability to sustain vitamin B1, pantothenic acid, folate, and biotin decreased in fatty liver, which is hypothesized as a specific phenomenon. This metabolic response might occur to prevent an abnormally increased biosynthesis of fatty acids by orotic acid.

  3. Sulfur Amino Acids in Diet-induced Fatty Liver: A New Perspective Based on Recent Findings

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    John I. Toohey

    2014-06-01

    Full Text Available The relationship of sulfur amino acids to diet-induced fatty liver was established 80 years ago, with cystine promoting the condition and methionine preventing it. This relationship has renewed importance today because diet-induced fatty liver is relevant to the current epidemics of obesity, non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes. Two recent papers provide the first evidence linking sulfane sulfur to diet-induced fatty liver opening a new perspective on the problem. This review summarizes the early data on sulfur amino acids in fatty liver and correlates that data with current knowledge of sulfur metabolism. Evidence is reviewed showing that the lipotropic effect of methionine may be mediated by sulfane sulfur and that the hepatosteatogenic effect of cystine may be related to the removal of sulfane sulfur by cysteine catabolites. Possible preventive and therapeutic strategies are discussed.

  4. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

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    Sathish Kumar Natarajan

    2018-01-01

    Full Text Available Acute fatty liver of pregnancy (AFLP, a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD. The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency.

  5. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

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    Ibdah, Jamal A.

    2018-01-01

    Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. PMID:29361796

  6. ω-3 Fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease.

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    Chen, Yi; Xu, Chengfu; Yan, Tianlian; Yu, Chaohui; Li, Youming

    2015-01-01

    The aim of this study was to evaluate the effect of ω-3 fatty acids on nonalcoholic fatty liver disease concerning hepatocyte lipid accumulation as well as apoptosis induced by free fatty acids (FFAs) and to explore the underlying mechanism involving autophagy. Hepatocytes were incubated with a mixture of free fatty acids (FFAs) to mimic in vitro lipotoxicity in the pathogenesis of nonalcoholic fatty liver disease, presented by lipid accumulation and cellular apoptosis. Chemical inhibitor or inducer of autophagy and genetic deficit cells, as well as ω-3 fatty acids were used as intervention. The autophagic role of ω-3 fatty acids was investigated using Western blot and immunofluorescence. The underlying mechanism of ω-3 fatty acids involving autophagy was preliminarily explored by quantitative real-time polymerase chain reaction and Western blot. FFAs induce lipid accumulation and apoptosis in hepatocytes. Inhibition or genetic defect of autophagy increases lipid accumulation induced by FFA, whereas induction acts inversely. ω-3 Fatty acids reduced lipid accumulation and inhibited apoptosis induced by FFA. ω-3 Fatty acids induced autophagy by downregulating stearoyl-CoA desaturase 1 expression in hepatocytes. ω-3 Fatty acids exert protective effects on hepatocytes against lipotoxicity through induction of autophagy, as demonstrated by inhibition of lipid accumulation and apoptosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.

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    Lanaspa, Miguel A; Sanchez-Lozada, Laura G; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y; Johnson, Richard J

    2012-11-23

    Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Rather than a consequence, uric acid induces fatty liver Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.

  8. Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

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    Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

    2007-12-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

  9. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

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    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C

    2017-01-01

    advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid...

  10. Curcumin improves alcoholic fatty liver by inhibiting fatty acid biosynthesis.

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    Guo, Chang; Ma, Jingfan; Zhong, Qionghong; Zhao, Mengyuan; Hu, Tianxing; Chen, Tong; Qiu, Longxin; Wen, Longping

    2017-08-01

    Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy. Copyright © 2017. Published by Elsevier Inc.

  11. Dietary intake of ain-93 standard diet induces Fatty liver with altered hepatic fatty acid profile in Wistar rats.

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    Farias Santos, Juliana; Suruagy Amaral, Monique; Lima Oliveira, Suzana; Porto Barbosa, Júnia; Rego Cabral, Cyro; Sofia Melo, Ingrid; Bezerra Bueno, Nassib; Duarte Freitas, Johnatan; Goulart Sant'ana, Antônio; Rocha Ataíde, Terezinha

    2015-05-01

    There are several standard diets for animals used in scientific research, usually conceived by scientific institutions. The AIN-93 diet is widely used, but there are some reports of fatty liver in Wistar rats fed this diet. We aimed to evaluate the hepatic repercussions of the AIN-93 diet intake in Wistar rats. Forty newly-weaned 21-day-old male Wistar rats were fed either the AIN-93 diet or a commercial diet for either 1 month or 4 months. Weight gain, serum biochemistry, hepatic histology, and hepatic fatty acid profile were analyzed. Hepatic steatosis was observed, especially in the group fed the AIN-93 diet. Serum blood glucose, absolute and relative liver weight and hepatic levels of oleic, palmitoleic, stearic, and palmitic fatty acids were related to the observed steatosis, while lipidogram and serum markers of liver function and injury were not. AIN-93 diet induced acute hepatic steatosis in Wistar rats, which may compromise its use as a standard diet for experimental studies with rodents. The hepatic fatty acid profile was associated with steatosis, with possible implications for disease prognosis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  12. Protective effect of bicyclol on tetracycline-induced fatty liver in mice

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    Yu, Hong-Yan; Wang, Bao-Lian; Zhao, Jing; Yao, Xiao-Min; Gu, Yu; Li, Yan

    2009-01-01

    Peroxisome proliferators-activated receptor α (PPARα) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids β-oxidation regulated by PPARα. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARα and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1 h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARα and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARα expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARα pathway and ameliorating mitochondrial function.

  13. Enhanced Amelioration of High-Fat Diet-Induced Fatty Liver by Docosahexaenoic Acid and Lysine Supplementations

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    Hsin-Yu Lin

    2014-01-01

    Full Text Available Fatty liver disease is the most common pathological condition in the liver. Here, we generated high-fat diet-(HFD- induced nonalcoholic fatty liver disease (NAFLD in mice and tested the effects of docosahexaenoic acid (DHA and lysine during a four-week regular chow (RCfeeding. Our results showed that 1% lysine and the combination of 1% lysine + 1% DHA reduced body weight. Moreover, serum triglyceride levels were reduced by 1% DHA and 1% lysine, whereas serum alanine transaminase activity was reduced by 1% DHA and 1% DHA + 0.5% lysine. Switching to RC reduced hepatic lipid droplet accumulation, which was further reduced by the addition of DHA or lysine. Furthermore, the mRNA expressions of hepatic proinflammatory cytokines were suppressed by DHA and combinations of DHA + lysine, whereas the mRNA for the lipogenic gene, acetyl-CoA carboxylase 1 (ACC1, was suppressed by DHA. In the gonadal adipose tissues, combinations of DHA and lysine inhibited mRNA expression of lipid metabolism-associated genes, including ACC1, fatty acid synthase, lipoprotein lipase, and perilipin. In conclusion, the present study demonstrated that, in conjunction with RC-induced benefits, supplementation with DHA or lysine further ameliorated the high-fat diet-induced NAFLD and provided an alternative strategy to treat, and potentially prevent, NAFLD.

  14. Keap1-knockdown decreases fasting-induced fatty liver via altered lipid metabolism and decreased fatty acid mobilization from adipose tissue.

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    Jialin Xu

    Full Text Available AIMS: The purpose of this study was to determine whether Nrf2 activation, via Keap1-knockdown (Keap1-KD, regulates lipid metabolism and mobilization induced by food deprivation (e.g. fasting. METHODS AND RESULTS: Male C57BL/6 (WT and Keap1-KD mice were either fed ad libitum or food deprived for 24 hours. After fasting, WT mice exhibited a marked increase in hepatic lipid accumulation, but Keap1-KD mice had an attenuated increase of lipid accumulation, along with reduced expression of lipogenic genes (acetyl-coA carboxylase, stearoyl-CoA desaturase-1, and fatty acid synthase and reduced expression of genes related to fatty acid transport, such as fatty acid translocase/CD36 (CD36 and Fatty acid transport protein (FATP 2, which may attribute to the reduced induction of Peroxisome proliferator-activated receptor (Ppar α signaling in the liver. Additionally, enhanced Nrf2 activity by Keap1-KD increased AMP-activated protein kinase (AMPK phosphorylation in liver. In white adipose tissue, enhanced Nrf2 activity did not change the lipolysis rate by fasting, but reduced expression of fatty acid transporters--CD36 and FATP1, via a PPARα-dependent mechanism, which impaired fatty acid transport from white adipose tissue to periphery circulation system, and resulted in increased white adipose tissue fatty acid content. Moreover, enhanced Nrf2 activity increased glucose tolerance and Akt phosphorylation levels upon insulin administration, suggesting Nrf2 signaling pathway plays a key role in regulating insulin signaling and enhanced insulin sensitivity in skeletal muscle. CONCLUSION: Enhanced Nrf2 activity via Keap1-KD decreased fasting-induced steatosis, pointing to an important function of Nrf2 on lipid metabolism under the condition of nutrient deprivation.

  15. Aspects of the regulation of long-chain fatty acid oxidation in bovine liver

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    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-01-01

    Factors involved in regulation of bovine hepatic fatty acid oxidation were examined using liver slices. Fatty acid oxidation was measured as the conversion of l-[ 14 C] palmitate to 14 CO 2 and total [ 14 C] acid-soluble metabolites. Extended (5 to 7 d) fasting of Holstein cows had relatively little effect on palmitate oxidation to acid-soluble metabolites by liver slices, although oxidation to CO 2 was decreased. Feeding a restricted roughage, high concentrate ration to lactating cows resulted in inhibition of palmitate oxidation. Insulin, glucose, and acetate inhibited palmitate oxidation by bovine liver slices. The authors suggest the regulation of bovine hepatic fatty acid oxidation may be less dependent on hormonally induced alterations in enzyme activity as observed in rat liver and more dependent upon action of rumen fermentation products or their metabolites on enzyme systems involved in fatty acid oxidation

  16. Studies on lipids and fatty acids in rats with streptozotocin-induced insulin deficiency II. Incorporation of 1-(14)C-sodium acetate into lipids and fatty acids of liver slices and whole blood cells

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    三宅,寛治

    1988-01-01

    In order to study the lipid and fatty acid metabolism in the insulin deficient state, the in vitro incorporation of 1-(14)C-sodium acetate into major lipid fractions and fatty acids of liver slices and whole blood cells was determined. Rats were studied one week, one month and three months after insulin deficiency was induced by administration of streptozotocin.The net incorporation of (14)C into lipid fractions and total fatty acids of liver slices significantly decreased after one week. On ...

  17. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

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    Diane DeZwaan-McCabe

    2017-05-01

    Full Text Available The unfolded protein response (UPR, induced by endoplasmic reticulum (ER stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

  18. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.

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    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C; Guo, Deng-Fu; Gansemer, Erica R; Kaufman, Randal J; Rahmouni, Kamal; Gillum, Matthew P; Taylor, Eric B; Teesch, Lynn M; Rutkowski, D Thomas

    2017-05-30

    The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Docosahexaenoic acid prevents trans-10, cis-12 conjugated linoleic acid-induced non-alcoholic fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation

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    Background: Concomitant supplementation with docosahexaenoic acid (22:6 n-3; DHA) prevented t10, c12- conjugated linoleic acid (CLA)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Effective dose of DHA and mechanisms involved are poorly understood. Methods: We examined abi...

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

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    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

  1. PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid -Hydroxylase (CYP4 Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

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    James P. Hardwick

    2009-01-01

    Full Text Available Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis, due to a decrease in mitochondria -oxidation with an increase in both peroxisomal -oxidation, and microsomal -oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs. How steatosis increases PPAR activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid -oxidation and -oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA, monounsaturated (MUFA, or saturated (SFA may be determined by the interplay of PPARs and HNF4 with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the -oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPAR. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid -hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA CYP4A and long-chain fatty acid (LCFA CYP4F -hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to

  2. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

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    Karina Reyes-Gordillo

    2016-01-01

    Full Text Available Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA that primarily regulates PGC1α and soy protein (SP that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1 and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK. Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.

  3. Chlorpromazine-induced perturbations of bile acids and free fatty acids in cholestatic liver injury prevented by the Chinese herbal compound Yin-Chen-Hao-Tang.

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    Yang, Qiaoling; Yang, Fan; Tang, Xiaowen; Ding, Lili; Xu, Ying; Xiong, Yinhua; Wang, Zhengtao; Yang, Li

    2015-04-16

    Yin-Chen-Hao-Tang (YCHT), a commonly used as a traditional chinese medicine for liver disease. Several studies indicated that YCHT may improving hepatic triglyceride metabolism and anti-apoptotic response as well as decreasing oxidative stress .However, little is known about the role of YCHT in chlorpromazine (CPZ) -induced chlolestatic liver injury. Therefore, we aimed to facilitate the understanding of the pathogenesis of cholestatic liver injury and evaluate the effect of Yin-Chen-Hao-Tang (YCHT) on chlorpromazine (CPZ)-induced cholestatic liver injury in rats based on the change of bile acids (BAs) and free fatty acids (FFAs) alone with the biochemical indicators and histological examination. We conducted an experiment on CPZ-induced cholestatic liver injury in Wistar rats with and without YCHT for nine consecutive days. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C) were measured to evaluate the protective effect of YCHT against chlorpromazine (CPZ)-induced cholestatic liver injury. Histopathology of the liver tissue showed that pathological injuries were relieved after YCHT pretreatment. In addition, ultra-performance lipid chromatography coupled with quadrupole mass spectrometry (UPLC-MS) and gas chromatography coupled with mass spectrometry (GC-MS) was applied to determine the content of bile acids, free fatty acids, respectively. Obtained data showed that YCHT attenuated the effect of CPZ-induced cholestatic liver injury, which was manifested by the serum biochemical parameters and histopathology of the liver tissue. YCHT regulated the lipid levels as indicated by the reversed serum levels of TC, TG, and LDL-C. YCHT also regulated the disorder of BA and FFA metabolism by CPZ induction. Results indicated that YCHT exerted a protective effect on CPZ-induced cholestasis liver injury. The variance of

  4. Impact of dietary fatty acids on muscle composition, liver lipids, milt composition and sperm performance in European eel

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    Butts, Ian; Baeza, R.; Støttrup, Josianne

    2015-01-01

    of dietary regime on muscle composition, and liver lipids prior to induced maturation, and the resulting sperm composition and performance. To accomplish this fish were reared on three "enhanced" diets and one commercial diet, each with different levels of fatty acids, arachidonic acid (ARA......), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Neutral lipids from the muscle and liver incorporated the majority of the fatty acid profile, while phospholipids incorporated only certain fatty acids. Diet had an effect on the majority of sperm fatty acids, on the total volume of extractable milt...... induced medium milt volumes but had the highest sperm motility. EPA also seems important for sperm quality parameters since diets with higher EPA percentages had a higher volume of milt and higher sperm motility. In conclusion, dietary fatty acids had an influence on fatty acids in the tissues of male eel...

  5. Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats.

    Science.gov (United States)

    Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Nubret, Esther; Sarfati, Gilles; Bergheim, Ina; De Bandt, Jean-Pascal

    2015-10-01

    Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis. We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD. Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g · kg(-1) · d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined. Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator-activated receptor α (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls. In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved

  6. Fatty acid composition in serum correlates with that in the liver and non-alcoholic fatty liver disease activity scores in mice fed a high-fat diet.

    Science.gov (United States)

    Wang, Xing-He; Li, Chun-Yan; Muhammad, Ishfaq; Zhang, Xiu-Ying

    2016-06-01

    In this study, we investigated the correlation between the serum fatty acid composition and hepatic steatosis, inflammation, hepatocellular ballooning scores, and liver fatty acids composition in mice fed a high-fat diet. Livers were collected for non-alcoholic fatty liver disease score analysis. Fatty acid compositions were analysed by gas chromatography. Correlations were determined by Pearson correlation coefficient. Exposed to a high-fat diet, mice developed fatty liver disease with varying severity without fibrosis. The serum fatty acid variation became more severe with prolonged exposure to a high-fat diet. This variation also correlated significantly with the variation in livers, with the types of fatty acids corresponding to liver steatosis, inflammation, and hepatocellular ballooning scores. Results of this study lead to the following hypothesis: the extent of serum fatty acid variation may be a preliminary biomarker of fatty liver disease caused by high-fat intake. Copyright © 2016. Published by Elsevier B.V.

  7. Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

    Science.gov (United States)

    Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Cicerchi, Christina; Li, Nanxing; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Le, Myphuong; Garcia, Gabriela E.; Thomas, Jeffrey B.; Rivard, Christopher J.; Andres-Hernando, Ana; Hunter, Brandi; Schreiner, George; Rodriguez-Iturbe, Bernardo; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. PMID:23112875

  8. Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Myoung-Su; Kim, Daeyoung; Jo, Keunae [Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Hwang, Jae-Kwan, E-mail: jkhwang@yonsei.ac.kr [Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Translational Research Center for Protein Function Control, Yonsei University, 262 Seongsanno, Seodaemun-gu, Seoul 120-749 (Korea, Republic of)

    2010-10-08

    Research highlights: {yields} NDGA decreases high-fat diet-induced body weight gain and adiposity. {yields} NDGA reduces high-fat diet-induced triglyceride accumulation in liver. {yields} NDGA improves lipid storage in vitro through altering lipid regulatory proteins. {yields} Inhibition of lipid storage in vivo and in vitro is mediated by AMPK activation. -- Abstract: Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200 mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR){alpha}, PPAR{gamma} coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD.

  9. Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice

    International Nuclear Information System (INIS)

    Lee, Myoung-Su; Kim, Daeyoung; Jo, Keunae; Hwang, Jae-Kwan

    2010-01-01

    Research highlights: → NDGA decreases high-fat diet-induced body weight gain and adiposity. → NDGA reduces high-fat diet-induced triglyceride accumulation in liver. → NDGA improves lipid storage in vitro through altering lipid regulatory proteins. → Inhibition of lipid storage in vivo and in vitro is mediated by AMPK activation. -- Abstract: Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200 mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)α, PPARγ coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD.

  10. Fatty acid biosynthesis VII. Substrate control of chain-length of products synthesised by rat liver fatty acid synthetase

    DEFF Research Database (Denmark)

    Hansen, Heinz Johs. Max; Carey, E.M.; Dils, R.

    1970-01-01

    - 1. Gas-liquid and paper chromatography have been used to determine the chain-lengths of fatty acids synthesised by purified rat liver fatty acid synthetase from [1-14C]acetyl-CoA, [1,3-14C2]malonyl-CoA and from [1-14C]acetyl-CoA plus partially purified rat liver acetyl-CoA carboxylase. - 2....... A wide range (C4:0–C18:0) of fatty acids was synthesised and the proportions were modified by substrate concentrations in the same manner as for purified rabbit mammary gland fatty acid synthetase. - 3. The relative amount of radioactivity incorporated from added acetyl-CoA and malonyl-CoA depended...... of long-chain fatty acids was synthesised from carboxylated acetyl-CoA than from added malonyl-CoA. - 5. It is suggested that acetyl-CoA carboxylase may carboxylate acetate bound to fatty acid synthetase....

  11. Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

    Directory of Open Access Journals (Sweden)

    Jieun Lee

    2017-07-01

    Full Text Available The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD, we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2L−/− mice. Paradoxically, Cpt2L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

  12. Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

    Energy Technology Data Exchange (ETDEWEB)

    Anders, Lisanne C [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Cave, Matt [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); Arteel, Gavin E [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); McClain, Craig J [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); and others

    2016-11-15

    Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE

  13. Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

    International Nuclear Information System (INIS)

    Anders, Lisanne C; Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N; Cave, Matt; Arteel, Gavin E; McClain, Craig J

    2016-01-01

    Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE

  14. Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.

    Science.gov (United States)

    Scorletti, Eleonora; Byrne, Christopher D

    2018-03-22

    For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised

  15. Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

    Science.gov (United States)

    Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

    2016-06-01

    Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  16. Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance.

    Science.gov (United States)

    Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S; Zhao, Liang; Hartung, Thomas; Scafidi, Susanna; Riddle, Ryan C; Wolfgang, Michael J

    2017-07-18

    The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2 L-/- mice). Paradoxically, Cpt2 L-/- mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Lipocalin-2 in Fructose-Induced Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jessica Lambertz

    2017-11-01

    Full Text Available The intake of excess dietary fructose most often leads to non-alcoholic fatty liver disease (NAFLD. Fructose is metabolized mainly in the liver and its chronic consumption results in lipogenic gene expression in this organ. However, precisely how fructose is involved in NAFLD progression is still not fully understood, limiting therapy. Lipocalin-2 (LCN2 is a small secreted transport protein that binds to fatty acids, phospholipids, steroids, retinol, and pheromones. LCN2 regulates lipid and energy metabolism in obesity and is upregulated in response to insulin. We previously discovered that LCN2 has a hepatoprotective effect during hepatic insult, and that its upregulation is a marker of liver damage and inflammation. To investigate if LCN2 has impact on the metabolism of fructose and thereby arising liver damage, we fed wild type and Lcn2−/− mice for 4 or 8 weeks on diets that were enriched in fructose either by adding this sugar to the drinking water (30% w/v, or by feeding a chow containing 60% (w/w fructose. Body weight and daily intake of food and water of these mice was then measured. Fat content in liver sections was visualized using Oil Red O stain, and expression levels of genes involved in fat and sugar metabolism were measured by qRT-PCR and Western blot analysis. We found that fructose-induced steatosis and liver damage was more prominent in female than in male mice, but that the most severe hepatic damage occurred in female mice lacking LCN2. Unexpectedly, consumption of elevated fructose did not induce de novo lipogenesis or fat accumulation. We conclude that LCN2 acts in a lipid-independent manner to protect the liver against fructose-induced damage.

  18. Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver.

    Science.gov (United States)

    Osman, Rashid H; Liu, Long; Xia, Lili; Zhao, Xing; Wang, Qianqian; Sun, Xiaoxian; Zhang, Yihui; Yang, Biao; Zheng, Yun; Gong, Daoqing; Geng, Tuoyu

    2016-07-01

    Global prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes a threat to human health. Goose is a unique model of NAFLD for discovering therapeutic targets as its liver can develop severe steatosis without overt injury. Fatty acid desaturase (Fads) is a potential therapeutic target as Fads expression and mutations are associated with liver fat. Here, we hypothesized that Fads was promoted to provide a protection for goose fatty liver. To test this, goose Fads1 and Fads2 were sequenced. Fads1/2/6 expression was determined in goose liver and primary hepatocytes by quantitative PCR. Liver fatty acid composition was also analyzed by gas chromatography. Data indicated that hepatic Fads1/2/6 expression was gradually increased with the time of overfeeding. In contrast, trans-C18:1n9 fatty acid (Fads inhibitor) was reduced. However, enhanced Fads capacity for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis was not sufficient to compensate for the depleted LC-PUFAs in goose fatty liver. Moreover, cell studies showed that Fads1/2/6 expression was regulated by fatty liver-associated factors. Together, these findings suggest Fads1/2 as protective components are promoted to meet instant need for LC-PUFAs in goose fatty liver, and we propose this is required for severe hepatic steatosis without liver injury.

  19. Changes of α-glycerophosphate dehydrogenase activity in fatty liver of rats by amino acid imbalance

    International Nuclear Information System (INIS)

    Ogura, Masaji; Katsunuma, Eiichi; Akabane, Tomoko; Ogawa, Seiichi

    1976-01-01

    The previous study on the lipogenesis in the fatty livers of rats, which was induced by feeding the diet with imbalanced amino acid, revealed that the induction of this type of fatty livers was due mainly to the acceleration of triglyceride synthesis by the increase in both synthesis and esterification of fatty acid in the livers. Although many studies have been carried out on the dietary control of α-glycerophosphate dehydrogenase activity in rat livers, the enzyme change in amino acid imbalance has not been reported. In the present study, in order to elucidate the difference in the supply of glycerol moiety of triglyceride due to the imbalance, the change of the α-glycerophosphate dehydrogenase activity in livers was investigated. The experimental diets were 8% casein basal diet and basal + 0.3% DL-methionine imbalanced diet. 5 rats of each group were killed after 0.5 and 10 days on the diet, and the analysis of the lipid content in the livers and the determination of the α-glycerophosphate dehydrogenase activity were carried out. The linear response of the enzyme activity to time and protein concentration was obtained. The development of fatty livers was observed in the imbalanced diet group in the feeding period of 10 days. It was found that the specific activity of the imbalanced diet group increased significantly in 5 and 10 days as compared with that of the basal diet group. The elevation in the enzyme activity may suggest that the supply of α-glycerophosphate for triglyceride synthesis is also increased in this type of fatty livers. (Kako, I.)

  20. Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis

    International Nuclear Information System (INIS)

    Das, Kaberi P.; Wood, Carmen R.; Lin, Mimi T.; Starkov, Anatoly A.; Lau, Christopher; Wallace, Kendall B.; Corton, J. Christopher; Abbott, Barbara D.

    2017-01-01

    Highlights: • Structurally diverse PFAAs induced fatty liver and increased TG accumulation in mouse. • Genes of lipid synthesis and degradation were increased after exposure to PFAAs. • PFAAs did not inhibit either mitochondrial fatty acid transport or β-oxidation directly. - Abstract: Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated. Currently, two major hypotheses are that PFAAs interfere with mitochondrial beta-oxidation of fatty acids and/or they affect the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) in liver. To determine the ability of structurally-diverse PFAAs to cause steatosis, as well as to understand the underlying molecular mechanisms, wild-type (WT) and PPARα-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), or perfluorohexane sulfonate (PFHxS), by oral gavage for 7 days, and their effects were compared to that of PPARα agonist WY-14643 (WY), which does not cause steatosis. Increases in liver weight and cell size, and decreases in DNA content per mg of liver, were observed for all compounds in WT mice, and were also seen in PPARα-null mice for PFOA, PFNA, and PFHxS, but not for WY. In Oil Red O stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARα-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARα-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARα-null mice only by PFNA. In vitro β-oxidation of palmitoyl carnitine by isolated rat

  1. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Steven D Kunkel

    Full Text Available Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II, blood vessel recruitment (Vegfa and autocrine/paracrine IGF-I signaling (Igf1. As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

  2. Chemoprotective effect of omega-3 fatty acids on thioacetamide induced hepatic fibrosis in male rats

    Directory of Open Access Journals (Sweden)

    Atef M. Al-Attar

    2017-05-01

    Full Text Available The current study was designed to investigate the possible protective effect of omega-3 fatty acids from fish oil on hepatic fibrosis induced by thioacetamide (TAA in male rats. The experimental animals were divided into four groups. The first group was received saline solution and served as control. The second group was given 250 mg/kg body weight of TAA. The third group was treated with omega-3 fatty acids and TAA. The fourth group was given saline solution and supplemented with omega-3 fatty acids. Treatment of rats with TAA for three and six weeks resulted in a significant decrease in body weight gain, while the value of liver/body weight ratio was statistically increased. Furthermore, the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and total bilirubin were significantly increased. After three weeks of exposure to only TAA, liver sections showed an abnormal morphology characterized by noticeable fibrosis with the extracellular matrix collagen contents and damage of liver cells’ structure. Liver sections from rats treated with only TAA for six weeks revealed an obvious increase in extracellular matrix collagen content and bridging fibrosis. Treating TAA-intoxicated rats with omega-3 fatty acids significantly attenuated the severe physiological and histopathological changes. Finally, the present investigation suggests that omega-3 fatty acids could act against hepatic fibrosis induced by TAA due to its antioxidant properties, thus supporting its use in hepatic fibrosis therapy.

  3. Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.

    Science.gov (United States)

    Takahara, Ikuko; Akazawa, Yuko; Tabuchi, Maiko; Matsuda, Katsuya; Miyaaki, Hisamitsu; Kido, Youko; Kanda, Yasuko; Taura, Naota; Ohnita, Ken; Takeshima, Fuminao; Sakai, Yusuke; Eguchi, Susumu; Nakashima, Masahiro; Nakao, Kazuhiko

    2017-01-01

    A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans.

  4. Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice.

    Science.gov (United States)

    Sun, Xue; Duan, Xingping; Wang, Changyuan; Liu, Zhihao; Sun, Pengyuan; Huo, Xiaokui; Ma, Xiaodong; Sun, Huijun; Liu, Kexin; Meng, Qiang

    2017-07-05

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside, on NAFLD induced by a high-fat diet (HFD) in mice, and further to elucidate the mechanisms underlying GA protection. GA treatment significantly reduced the relative liver weight, serum ALT, AST activities, levels of serum lipid, blood glucose and insulin. GA suppressed lipid accumulation in liver. Further mechanism investigation indicated that GA reduced hepatic lipogenesis via downregulating SREBP-1c, FAS and SCD1 expression, increased fatty acids β-oxidation via an increase in PPARα, CPT1α and ACADS, and promoted triglyceride metabolism through inducing LPL activity. Furthermore, GA reduced gluconeogenesis through repressing PEPCK and G6Pase, and increased glycogen synthesis through an induction in gene expression of PDase and GSK3β. In addition, GA increased insulin sensitivity through upregulating phosphorylation of IRS-1 and IRS-2. In conclusion, GA produces protective effect against NAFLD, due to regulation of genes involved in lipid, glucose homeostasis and insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein.

    Science.gov (United States)

    Wu, Yun-Li; Peng, Xian-E; Zhu, Yi-Bing; Yan, Xiao-Li; Chen, Wan-Nan; Lin, Xu

    2016-02-15

    Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3β-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3β and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3β, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced

  6. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis.

    Science.gov (United States)

    Koo, Seung-Hoi

    2013-09-01

    Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.

  7. Silibinin Capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation.

    Science.gov (United States)

    Cui, Chun-Xue; Deng, Jing-Na; Yan, Li; Liu, Yu-Ying; Fan, Jing-Yu; Mu, Hong-Na; Sun, Hao-Yu; Wang, Ying-Hong; Han, Jing-Yan

    2017-08-17

    Silibinin Capsules (SC) is a silybin-phospholipid complex with silybin as the bioactive component. Silybin accounts for 50-70% of the seed extract of Silybum marianum (L.) Gaertn.. As a traditional medicine, silybin has been used for treatment of liver diseases and is known to provide a wide range of hepatoprotective effects. High fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) is a worldwide health problem. This study was to investigate the role of SC in NAFLD with focusing on its underlying mechanism and likely target. Male hamsters (Cricetidae) received HFD for 10 weeks to establish NAFLD model. NAFLD was assessed by biochemical assays, histology and immunohistochemistry. Proton nuclear magnetic resonance spectroscopy and western blot were conducted to gain insight into the mechanism. Hamsters fed HFD for 10 weeks developed fatty liver accompanying with increased triglyceride (TG) accumulation, enhancing de novo lipogenesis, increase in fatty acid (FA) uptake and reducing FA oxidation and TG lipolysis, as well as a decrease in the expression of phospho-adenosine monophosphate activated protein kinase α (p-AMPKα) and Sirt 1. SC treatment at 50mg/kg silybin and 100mg/kg silybin for 8 weeks protected hamsters from development of fatty liver, reducing de novo lipogenesis and increasing FA oxidation and p-AMPKα expression, while having no effect on FA uptake and TG lipolysis. SC protected against NAFLD in hamsters by inhibition of de novo lipogenesis and promotion of FA oxidation, which was likely mediated by activation of AMPKα. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  8. Liver fatty acid binding protein is the mitosis-associated polypeptide target of a carcinogen in rat hepatocytes

    International Nuclear Information System (INIS)

    Bassuk, J.A.; Tsichlis, P.N.; Sorof, S.

    1987-01-01

    Hepatocytes in normal rat liver were found previously to contain a cytoplasmic 14,000-dalton polypeptide (p14) that is associated with mitosis and is the principal early covalent target of activated metabolites of the carcinogen N-2-fluorenylacetamide (2-acetylaminofluorene). The level of immunohistochemically detected p14 was low when growth activity of hepatocytes was low, was markedly elevated during mitosis in normal and regenerating livers, but was very high throughout interphase during proliferation of hyperplastic and malignant hepatocytes induced in rat liver by a carcinogen (N-2-fluorenylacetamide or 3'-methyl-4-dimethylaminoazobenzene). The authors report here that p14 is the liver fatty acid binding protein. The nucleotide sequence of p14 cDNA clones, isolated by screening a rat liver cDNA library in bacteriophage λgt11 using p14 antiserum, was completely identical to part of the sequence reported for liver fatty acid binding protein. Furthermore, the two proteins shared the following properties: size of mRNA, amino acid composition, molecular size according to NaDodSO 4 gel electrophoresis, and electrophoretic mobilities in a Triton X-100/acetic acid/urea gel. The two polypeptides bound oleic acid similarly. Finally, identical elevations of cytoplasmic immunostain were detected specifically in mitotic hepatocytes with either antiserum. The collected findings are suggestive that liver fatty acid binding protein may carry ligands that promote hepatocyte division and may transport certain activated chemical carcinogens

  9. Dietary Omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver

    NARCIS (Netherlands)

    Griffini, P.; Fehres, O.; Klieverik, L.; Vogels, I. M.; Tigchelaar, W.; Smorenburg, S. M.; van Noorden, C. J.

    1998-01-01

    The effects of Ohm-3 polyunsaturated fatty acids (PUFAs) and Ohm-6 PUFAs on the development of experimentally induced colon carcinoma metastasis in rat liver were investigated quantitatively in vivo. Rats mere kept on either a lon-fat diet or on a fish oil (Ohm-3 PUFAs) or safflower oil (Ohm-6

  10. Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status.

    Science.gov (United States)

    Hofacer, Rylon; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Magrisso, I Jack; Benoit, Stephen C; McNamara, Robert K

    2011-09-01

    This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress.

    Directory of Open Access Journals (Sweden)

    Wei Hua

    Full Text Available Hyperlipidemia-induced apoptosis mediated by fatty acid translocase CD36 is associated with increased uptake of ox-LDL or fatty acid in macrophages, hepatocytes and proximal tubular epithelial cells, leading to atherosclerosis, liver damage and fibrosis in obese patients, and diabetic nephropathy (DN, respectively. However, the specific role of CD36 in podocyte apoptosis in DN with hyperlipidemia remains poorly investigated.The expression of CD36 was measured in paraffin-embedded kidney tissue samples (Ctr = 18, DN = 20 by immunohistochemistry and immunofluorescence staining. We cultured conditionally immortalized mouse podocytes (MPC5 and treated cells with palmitic acid, and measured CD36 expression by real-time PCR, Western blot analysis and immunofluorescence; lipid uptake by Oil red O staining and BODIPY staining; apoptosis by flow cytometry assay, TUNEL assay and Western blot analysis; and ROS production by DCFH-DA fluorescence staining. All statistical analyses were performed using SPSS 21.0 statistical software.CD36 expression was increased in kidney tissue from DN patients with hyperlipidemia. Palmitic acid upregulated CD36 expression and promoted its translocation from cytoplasm to plasma membrane in podocytes. Furthermore, palmitic acid increased lipid uptake, ROS production and apoptosis in podocytes, Sulfo-N-succinimidyloleate (SSO, the specific inhibitor of the fatty acid binding site on CD36, decreased palmitic acid-induced fatty acid accumulation, ROS production, and apoptosis in podocytes. Antioxidant 4-hydroxy-2,2,6,6- tetramethylpiperidine -1-oxyl (tempol inhibited the overproduction of ROS and apoptosis in podocytes induced by palmitic acid.CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress might participate in the process of DN.

  12. Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects.

    Science.gov (United States)

    Hong, Ye-Ji; Ahn, Hyo-Ju; Shin, Jongdae; Lee, Joon H; Kim, Jin-Hoi; Park, Hwan-Woo; Lee, Sung Ki

    2018-02-01

    Dysregulated serum fatty acids are associated with a lipotoxic placental environment, which contributes to increased pregnancy complications via altered trophoblast invasion. However, the role of saturated and unsaturated fatty acids in trophoblastic autophagy has yet to be explored. Here, we demonstrated that prolonged exposure of saturated fatty acids interferes with the invasiveness of human extravillous trophoblasts. Saturated fatty acids (but not unsaturated fatty acids) inhibited the fusion of autophagosomes and lysosomes, resulting in the formation of intracellular protein aggregates. Furthermore, when the trophoblast cells were exposed to saturated fatty acids, unsaturated fatty acids counteracted the effects of saturated fatty acids by increasing degradation of autophagic vacuoles. Saturated fatty acids reduced the levels of the matrix metalloproteinases (MMP)-2 and MMP-9, while unsaturated fatty acids maintained their levels. In conclusion, saturated fatty acids induced decreased trophoblast invasion, of which autophagy dysfunction plays a major role. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Fatty acid-binding protein in liver and small intestine of the preruminant calf

    International Nuclear Information System (INIS)

    Jenkins, K.J.

    1986-01-01

    Cytosol obtained from differential centrifugation of homogenates from liver and small intestine mucosa was incubated with 1-[ 14 C] oleic acid or 1-[ 14 C] palmitic acid and filtered through Sephadex G-75. Elution profiles for both tissues showed radioactivity in two main peaks, the first corresponding to binding of fatty acid to high molecular weight proteins and the second to a protein fraction with a molecular weight of approximately 12,000 daltons. The low molecular weight fraction had high fatty acid-binding activity, which was greater for oleic than palmitic acid. The findings demonstrate the presence of fatty acid-binding protein in liver and intestinal mucosa of the preruminant calf

  14. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

    International Nuclear Information System (INIS)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao; Cao, Di; Yu, Weibang; Zhao, Zhongxiang; Huang, Min; Jin, Jing

    2017-01-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the hepatic

  15. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Cao, Di [School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou (China); Yu, Weibang [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Zhao, Zhongxiang [School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou (China); Huang, Min [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Jin, Jing, E-mail: jinjing@mail.sysu.edu.cn [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China)

    2017-06-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the hepatic

  16. Effects of Ramadan fasting on plasma free fatty acids in patients with non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Seyed Mostafa Arabi

    2016-09-01

    Full Text Available Introduction: Nonalcoholic fatty liver disease (NAFLD is a global disease which its prevalence is about 10-35%. Several factors are involved in the pathogenesis of the disease. The present study was conducted to evaluate the effect of fasting during Ramadan on plasma free fatty acids in patients with NAFLD.Methods: This cross-sectional study was performed during the month of Ramadan in June-July, 2014 (Islamic year: 1435 with 50 patients who were living in Mashhad, Iran. The participants were recruited from 18-65 years old patients. The inclusion criteria were 1 patients with NAFLD that diagnosed fatty liver by ultrasonography and 2 being at least 10 hours fasting. Levels of plasma free fatty acids (Palmitic, Elaidic and Oleic fatty acid were analyzed in blood sample of all patients by gas chromatography apparatus equipped with a flame ionization detector (GC-FID.Result: results indicated that there was no significant changes were observed in plasma levels of Palmitic, Elaidic and Oleic fatty acids in overweight patients (BMI 25-30 , but plasma levels of Elaidic acid significantly increased in obese patients (P

  17. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    Science.gov (United States)

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis.

    Science.gov (United States)

    Visscher, Christian; Middendorf, Lea; Günther, Ronald; Engels, Alexandra; Leibfacher, Christof; Möhle, Henrik; Düngelhoef, Kristian; Weier, Stefan; Haider, Wolfram; Radko, Dimitri

    2017-05-30

    The so-called "hepatic lipidosis" in turkeys is an acute progressive disease associated with a high mortality rate in a very short time. Dead animals show a massive fatty degeneration of the liver. The cause is still unclear. Previous findings suggest that there may be parallels to human non-alcoholic fatty liver disease. The object of the study was to examine the changes in the fat contents, the fatty acid composition and the iron content in livers of animals, which have died from hepatic lipidosis. The conspicuous livers (n = 85) were collected from 20 flocks where the phenomenon of massive increased animal losses accompanied by marked macroscopically visible pathological liver steatosis suddenly occurred. For comparison and as a reference, livers (n = 16) of two healthy flocks were taken. Healthy and diseased flocks were fed identical diets concerning official nutrient recommendations and were operating under standardized, comparable conventional conditions. Compared to livers of healthy animals, in the livers of turkeys died from hepatic lipidosis there were found massively increased fat levels (130 ± 33.2 vs. 324 ± 101 g/kg dry matter-DM). In all fatty livers, different fatty acids concentrations were present in significantly increased concentrations compared to controls (palmitic acid: 104 g/kg DM, +345%; palmitoleic acid: 18.0 g/kg DM, + 570%; oleic acid: 115 g/kg DM, +437%). Fatty acids concentrations relevant for liver metabolism and inflammation were significantly reduced (arachidonic acid: 2.92 g/kg DM, -66.6%; eicosapentaenoic acid: 0.141 g/kg DM, -78.3%; docosahexaenoic acid: 0.227 g/kg DM, -90.4%). The ratio of certain fatty acids to one another between control and case livers changed analogously to liver diseases in humans (e.g.: C18:0/C16:0 - 0.913 against 0.311; C16:1n7/C16:0 - 0.090 against 0.165; C18:1/C18:0 - 0.938 against 4.03). The iron content in the liver tissue also increased massively (271 ± 51.5 vs 712 ± 214 mg/kg DM). The hepatic

  19. Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice

    International Nuclear Information System (INIS)

    Choi, You-Jin; Lee, Kang-Yo; Jung, Seung-Hwan; Kim, Hyung Sik; Shim, Gayong; Kim, Mi-Gyeong; Oh, Yu-Kyoung; Oh, Seon-Hee; Jun, Dae Won; Lee, Byung-Hoon

    2017-01-01

    Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver. - Highlights: • Berberine increases the expression and membrane translocation of CD36 in hepatocytes. • The increase of CD36 results in enhanced fatty acid uptake and lipid accumulation. • Berberine-induced fatty liver is mediated by AMPK-ERK-C/EBPβ pathway. • CD36-specific shRNA inhibited berberine-induced lipid accumulation in liver.

  20. Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice

    Energy Technology Data Exchange (ETDEWEB)

    Choi, You-Jin; Lee, Kang-Yo; Jung, Seung-Hwan [College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742 (Korea, Republic of); Kim, Hyung Sik [School of Pharmacy, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Shim, Gayong; Kim, Mi-Gyeong; Oh, Yu-Kyoung [College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742 (Korea, Republic of); Oh, Seon-Hee [The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju 501-759 (Korea, Republic of); Jun, Dae Won [Internal Medicine, Hanyang University School of Medicine, Seoul 133-791 (Korea, Republic of); Lee, Byung-Hoon, E-mail: lee@snu.ac.kr [College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2017-02-01

    Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver. - Highlights: • Berberine increases the expression and membrane translocation of CD36 in hepatocytes. • The increase of CD36 results in enhanced fatty acid uptake and lipid accumulation. • Berberine-induced fatty liver is mediated by AMPK-ERK-C/EBPβ pathway. • CD36-specific shRNA inhibited berberine-induced lipid accumulation in liver.

  1. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Bhathena J

    2011-06-01

    Full Text Available Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology.Methods: Experiments were planned to develop a diet-induced Bio F1B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O.Results: In this study, we established a diet-induced Bio F1B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed

  2. Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice.

    Directory of Open Access Journals (Sweden)

    Yasuyo Urasaki

    Full Text Available Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration.

  3. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Qiang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); The First Affiliated Hospital of Xiamen University, Xiamen (China); Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); Yu, Chundong, E-mail: cdyu@xmu.edu.cn [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China)

    2011-06-17

    Highlights: {yields} Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. {yields} FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. {yields} FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. {yields} FGFR4-ECD reduced tetracycline-induced fatty liver in mice. {yields} FGFR4-ECD partially restored tetracycline-repressed PPAR{alpha} expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  4. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Chen, Qiang; Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang; Yu, Chundong

    2011-01-01

    Highlights: → Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. → FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. → FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. → FGFR4-ECD reduced tetracycline-induced fatty liver in mice. → FGFR4-ECD partially restored tetracycline-repressed PPARα expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor α (PPARα), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  5. Alternation of plasma fatty acids composition and desaturase activities in children with liver steatosis.

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    Man-Chin Hua

    Full Text Available The aim of this study was to investigate changes in plasma fatty acids proportions and estimated desaturase activities for variable grading of liver steatosis in children.In total, 111 schoolchildren (aged 8-18 years were included in the analysis from March 2015 to August 2016. Anthropometric evaluation, liver ultrasound examination and scoring for nonalcoholic fatty liver disease (NAFLD score = 0-6, and biochemical and plasma fatty acids analysis were performed. We compared the composition ratio of fatty acids between children with high-grade liver steatosis (NAFLD score = 4-6, low-grade liver steatosis (NAFLD score = 1-3, and healthy controls (NAFLD score = 0. In addition, correlation coefficients (r between NAFLD score, metabolic variables, and estimated activity of desaturase indices (stearoyl-coenzyme A desaturase-1 (SCD1, delta-5 and delta-6 desaturase were calculated.Compared with healthy controls, children with liver steatosis showed a higher proportion of monounsaturated fatty acids (21.16 ± 2.81% vs. 19.68 ± 2.71%, p = 0.024. In addition, children with high- grade liver steatosis exhibited higher proportions of palmitic acid (C16:0, palmitoleic acid (C16:1n-7, dihomo-γ-linolenic acid (C20:3n-6, adrenic acid (C22:4n-6, and docosapentaenoic acid (C22:5n-6; and lower proportions of eicosapentaenoic acid (C20:5n-3 (P< 0.05. In all subjects, the NAFLD score was positively correlated with body mass index (BMI (kg/m2 (r = 0.696, homeostasis model of assessment ratio-index (HOMA-IR (r = 0.510, SCD1(16 (r = 0.273, and the delta-6 index (r = 0.494; and inversely associated with the delta-5 index (r = -0.443.Our current data suggested that children with liver steatosis was highly associated with obesity, and insulin resistance. In addition, increased endogenous lipogenesis through altered desaturase activity may contribute to the progression of liver steatosis in children.

  6. Mice Lacking Free Fatty Acid Receptor 1 (GPR40/FFAR1) are Protected Against Conjugated Linoleic Acid-Induced Fatty Liver but Develop Inflammation and Insulin Resistance in the Brain.

    Science.gov (United States)

    Sartorius, Tina; Drescher, Andrea; Panse, Madhura; Lastovicka, Petr; Peter, Andreas; Weigert, Cora; Kostenis, Evi; Ullrich, Susanne; Häring, Hans-Ulrich

    2015-01-01

    Conjugated linoleic acids (CLAs) affect body fat distribution, induce insulin resistance and stimulate insulin secretion. The latter effect is mediated through the free fatty acid receptor-1 (GPR40/FFAR1). This study examines whether GPR40/FFAR1 interacts with tissue specific metabolic changes induced by CLAs. After chronic application of CLAs C57BL/6J wild type (WT) and GPR40/FFAR1 (Ffar1(-/-)) knockout mice developed insulin resistance. Although CLAs accumulated in liver up to 46-fold genotype-independently, hepatic triglycerides augmented only in WT mice. This triglyceride deposition was not associated with increased inflammation. In contrast, in brain of CLA fed Ffar1(-/-) mice mRNA levels of TNF-α were 2-fold higher than in brain of WT mice although CLAs accumulated genotype-independently in brain up to 4-fold. Concomitantly, Ffar1(-/-) mice did not respond to intracerebroventricular (i.c.v.) insulin injection with an increase in cortical activity while WT mice reacted as assessed by radiotelemetric electrocorticography (ECoG) measurements. In vitro incubation of primary murine astrocytes confirmed that CLAs stimulate neuronal inflammation independent of GPR40/FFAR1. This study discloses that GPR40/FFAR1 indirectly modulates organ-specific effects of CLAs: the expression of functional GPR40/FFAR1 counteracts CLA-induced inflammation and insulin resistance in the brain, but favors the development of fatty liver. © 2015 S. Karger AG, Basel.

  7. Correlation of secretory phospholipase-A2 activity and fatty acids in cerebrospinal fluid with liver enzymes tests

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    Sepideh Ghodoosifar

    2016-02-01

    Full Text Available Introduction: The aim was to determine whether secretory phospholipase-A2 (sPLA2 activity and fatty acids in cerebrospinal fluid (CSF are correlated with liver enzymes tests. Methods: CSF and serum samples were collected from 49 patients (age 18-65 as part of routine diagnostic testing. Along with serum liver enzymes aspartate aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, the fatty acid composition of CSF was measured by gas liquid chromatography. CSF enzyme activities of sPLA2 were measured using the standard assay with diheptanoyl thio-phosphatidylcholin as substrate. Results: The saturated fatty acids (SFAs including palmitic acid and stearic acid were positively, and the unsaturated fatty acids including oleic acid and linoleic acid were negatively correlated with liver enzymes tests. In regression analysis with adjustment for body mass index (BMI, the elevated liver enzymes tests were positively associated with activity of sPLA2 (β > 0.31, P 0.38, P < 0.010 and negatively with total monounsaturated fatty acids (MUFAs (β < -0.40, P < 0.001 contents of CSF. Conclusion: CSF activity of sPLA2 and fatty acids may be linked to peripheral markers of liver function, suggesting an indirect impact of central fatty acids on hepatocytes function and metabolism.

  8. Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

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    Shim Eugene

    2011-10-01

    Full Text Available Abstract Background Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO, olive oil (OO, and beef tallow (BT on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Methods Male Sprague-Dawley rats were fed 15% (wt/wt CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg, samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Results Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Conclusions Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

  9. Brain and liver fatty acid composition changes upon consumption of Lactobacillus rhamnosus LA68.

    Science.gov (United States)

    Ivanovic, Nevena; Minic, Rajna; Djuricic, Ivana; Dimitrijevic, Ljiljana; Sobajic, Sladjana; Zivkovic, Irena; Djordjevic, Brizita

    2015-02-01

    Recent reports suggest that the metabolic activity of the enteric microbiota may influence the fatty acid composition of the host tissue. There are many studies dealing with the influence of lactobacilli on various pathological conditions, and some of the effects are strain-specific. This study was designed to test the effects of a particular Lactobacillus strain, Lactobacillus rhamnosus LA68 on fatty acid composition of the liver and the brain of C57BL/6 mice in the absence of an underlying pathological condition. Female mice were supplemented with live L. rhamnosus LA68 bacteria for the duration of 1 month. Serum biochemistry was analyzed and liver and brain fatty acid composition was assessed by gas-liquid chromatography. Significant changes in liver and brain fatty acid composition were detected. In the liver tissue we detected an increase in palmitoleic acid (p = 0.038), while in the brain compartment we found an increase in palmitic (p = 0.042), stearic (p = 0.017), arachidonic acid (p = 0.009) and docosahexaenoic acid (p = 0.004) for control versus experimental group. These results show discrete changes caused by LA68 strain consumption. Even short duration of administration of LA68 influences the fatty acid composition of the host which adds to the existing knowledge about Lactobacillus host interaction, and adds to the growing knowledge of metabolic intervention possibilities.

  10. Interactions between fatty acid synthesis, oxidation, and esterification in the production of triglyceride-rich lipoproteins by the liver.

    Science.gov (United States)

    Fukuda, N; Ontko, J A

    1984-08-01

    In a series of experiments with male rat livers perfused with or without 5-tetradecyloxy-2-furoic acid (TOFA) in the presence and absence of oleate, the relationships between fatty acid synthesis, oxidation, and esterification from newly synthesized and exogenous fatty acid substrates have been examined. When livers from fed rats were perfused without exogenous fatty acid substrate, 20% of the triglyceride secreted was derived from de novo fatty acid synthesis. Addition of TOFA caused immediate and nearly complete inhibition of fatty acid synthesis, measured by incorporation of 3H2O into fatty acids. Concurrently, ketone body production increased 140% and triglyceride secretion decreased 84%. These marked reciprocal alterations in fatty acid synthesis and oxidation in the liver almost completely abolished the production of very low density lipoproteins (VLDL). Cholesterol synthesis was also depressed by TOFA, suggesting that this drug also inhibited lipid synthesis at a site other than acetyl-CoA carboxylase. When livers from fed rats were supplied with a continuous infusion of [1-14C]oleate as exogenous substrate, similar proportions, about 45-47%, of both ketone bodies and triglyceride in the perfusate were derived from the infused [1-14C]oleate. The production of ketone bodies was markedly increased by TOFA; the secretion of triglyceride and cholesterol were decreased. Altered conversion of [1-14C]oleate into these products occurred in parallel. While TOFA decreased esterification of oleate into triglyceride, incorporation of [1-14C]oleate into liver phospholipid was increased, indicating that TOFA also affected glycerolipid synthesis at the stage of diglyceride processing. The decreased secretion of triglyceride and cholesterol following TOFA treatment was localized almost exclusively in VLDL. The specific activities of 3H and of 14C fatty acids in triglyceride of the perfusate were greater than those of liver triglyceride, indicating preferential secretion of

  11. Effect of Whole-Body X-Irradiation of the Synthesis of Individual Fatty Acids in Liver Slices from Normal and Fasted Rats

    DEFF Research Database (Denmark)

    Hansen, Heinz Johs. Max; Hansen, Lisbeth Grænge; Faber, M.

    1965-01-01

    (1) Using (2-14C) acetate and (1-14C) butyrate as precursors, rat-liver fatty acids were synthesized in vitro and assayed by paper chromatography. (2) Whole-body x-irradiation induced a change in the synthetic pattern of hepatic fatty acids towards a relatively enhanced synthesis of palmitic acid....... (3) X-irradiation and fasting seem to have opposite effects on fatty-acid synthesis. X-irradiation counteracts the drop in total synthesis and the relatively enhanced synthesis of palmitoleic acid induced by fasting. The relative enhancement of palmitic-acid synthesis mentioned under (2) stands...... in contrast to the effect of fasting, which specifically decreases the hepatic synthesis of palmitic acid. (4) There is a general similarity between corresponding fatty-acid patterns based on synthesis from (2-14C) acetate and (1-14C) butyrate, respectively....

  12. Acetaminophen-induced Liver Injury is Attenuated in Transgenic fat-1 Mice Endogenously Synthesizing Long-chain n-3 Fatty Acids.

    Science.gov (United States)

    Feng, Ruibing; Wang, Yang; Liu, Conghui; Yan, Chunyan; Zhang, Hang; Su, Huanxing; Kang, Jing X; Shang, Chang-Zhen; Wan, Jian-Bo

    2018-04-18

    Acetaminophen (APAP) overdose-caused hepatotoxicity is the most commonly cause of drugs-induced liver failurecharacterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1) / mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) - mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.

    Science.gov (United States)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao; Cao, Di; Yu, Weibang; Zhao, Zhongxiang; Huang, Min; Jin, Jing

    2017-06-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) - extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Moro orange juice prevents fatty liver in mice.

    Science.gov (United States)

    Salamone, Federico; Li Volti, Giovanni; Titta, Lucilla; Puzzo, Lidia; Barbagallo, Ignazio; La Delia, Francesco; Zelber-Sagi, Shira; Malaguarnera, Michele; Pelicci, Pier Giuseppe; Giorgio, Marco; Galvano, Fabio

    2012-08-07

    To establish if the juice of Moro, an anthocyanin-rich orange, may improve liver damage in mice with diet-induced obesity. Eight-week-old mice were fed a high-fat diet (HFD) and were administrated water or Moro juice for 12 wk. Liver morphology, gene expression of lipid transcription factors, and metabolic enzymes were assessed. Mice fed HFD displayed increased body weight, insulin resistance and dyslipidemia. Moro juice administration limited body weight gain, enhanced insulin sensitivity, and decreased serum triglycerides and total cholesterol. Mice fed HFD showed liver steatosis associated with ballooning. Dietary Moro juice markedly improved liver steatosis by inducing the expression of peroxisome proliferator-activated receptor-α and its target gene acylCoA-oxidase, a key enzyme of lipid oxidation. Consistently, Moro juice consumption suppressed the expression of liver X receptor-α and its target gene fatty acid synthase, and restored liver glycerol-3-phosphate acyltransferase 1 activity. Moro juice counteracts liver steatogenesis in mice with diet-induced obesity and thus may represent a promising dietary option for the prevention of fatty liver.

  15. Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues.

    Science.gov (United States)

    Zhao, Yu-Ying; Yang, Rui; Xiao, Mo; Guan, Min-Jie; Zhao, Ning; Zeng, Tao

    2017-09-01

    Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl 3 ) and TNF-α antagonist (etanercept) on binge drinking-induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl 3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl 3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl 3 nor etanercept could affect binge drinking-induced decrease of PPAR-α, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl 3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-α could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-α antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking-induced fatty liver by TNF-α mediated activation of lipolysis in white adipose tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    Science.gov (United States)

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  17. Positional specificity of saturated and unsaturated fatty acids in phosphatidic acid from rat liver

    NARCIS (Netherlands)

    Possmayer, F.; Scherphof, G.L.; Dubbelman, T.M.A.R.; Golde, L.M.G. van; Deenen, L.L.M. van

    1969-01-01

    1. 1. The relative incorporation of a number of radioactive fatty acids into the different glycerolipids of rat liver microsomes has been investigated. 2. 2. Studies on the distribution of the radioactivity incorporated into phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid

  18. Total lipids and fatty acid profile in the liver of wild and farmed catla catla fish

    Energy Technology Data Exchange (ETDEWEB)

    Hassan, M.; Shaihid chatha, S. A.; Tahira, I.; Hussain, B.

    2010-07-01

    This experimental work was aimed to study the moisture content, total lipids and fatty acid profile in the liver of wild and farmed freshwater major carp Catla catla of three different weight categories designated as W{sub 1} (601-900g), W{sub 2} (901- 1200)g and W{sub 3} (1201-1500g). Seven fish specimens of each of the three weight categories of wild and farmed Catla catla were obtained from Trimu Head, Jhang and Fish Hatchery, Satiana Road and Faisalabad, respectively. The fish were dissected to remove the liver and after weighing, liver samples were prepared and subjected to chemical analysis. Wild Catla catla liver had a significantly (p <0.05) higher moisture content as compared to the farmed species. Farmed Catla catla deposited significantly (p < 0.05) higher lipid contents in liver. Proportions of saturated fatty acids varied irregularly in the lipids of the liver from both wild and farmed Catla catla. Saturated fatty acids C12:0, C14:0, C16:0, C18:0, C20:0 and C22:0 were identified with considerable percentages in the liver of Catla catla from both habitats and monounsaturated fatty acid C18:1 was found in considerable amounts in the liver of both major carp. Polyunsaturated fatty acids such as C18:3 (n-6) and C20: 2 (n-6) were detected in the liver of the wild fish of W{sub 2} and W{sub 3} and was similar in the W{sub 3} weight category of the farmed species. (Author) 22 refs.

  19. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

    2016-07-26

    Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

  20. Therapeutic Mechanisms of Bile Acids and Nor-Ursodeoxycholic Acid in Non-Alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Steinacher, Daniel; Claudel, Thierry; Trauner, Michael

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease. © 2017 S. Karger AG, Basel.

  1. Alpha linolenic acid in maternal diet halts the lipid disarray due to saturated fatty acids in the liver of mice offspring at weaning.

    Science.gov (United States)

    Shomonov-Wagner, Limor; Raz, Amiram; Leikin-Frenkel, Alicia

    2015-02-26

    Alpha linolenic acid (ALA, 18:3) in maternal diets has been shown to attenuate obesity associated insulin resistance (IR) in adult offspring in mice. The objective in the present study was to detect the early effects of maternal dietary saturated fatty acids (SFA) and their partial substitution with ω-3 ALA, docosa hexenoic acid (DHA,22:6) and eicosapentenoic acid 20:5 (EPA,20:5) on the HOMA index, liver lipids and fatty acid desaturases in the offspring at weaning. 3 month old C57Bl6/J female mice were fed diets containing normal amount of calories but rich in SFA alone or partially replaced with ALA, DHA or EPA before mating, during pregnancy and lactation. Pregnant mice fed SFA produced offspring with the highest HOMA index, liver lipids and desaturase activities. ALA prevented SFA induced lipid increase but DHA and EPA only reduced it by 42% and 31% respectively. ALA, DHA and EPA decreased HOMA index by 84%, 75% and 83% respectively. ALA, DHA and EPA decreased Δ6 and SCD1 desaturase activities about 30%. SFA feeding to mothers predisposes their offspring to develop IR and liver lipid accumulation already at weaning. ω3 fatty acids reduce IR, ALA halts lipid accumulation whereas DHA and EPA only blunt it.ALA and DHA restore the increased SCD1 to normal. These studies suggest that ω-3 fatty acids have different potencies to preclude lipid accumulation in the offspring partially by affecting pathways associated to SCD1 modulation.

  2. In vivo incorporation of labeled fatty acids in rat liver lipids after oral administration

    International Nuclear Information System (INIS)

    Leyton, J.; Drury, P.J.; Crawford, M.A.

    1987-01-01

    Striking differences were found in the compartmentalization of fatty acids into liver lipid fractions. The saturated fatty acids--lauric, myristic, palmitic and stearic--were incorporated into phosphoglycerides at faster rates with increasing chain lengths, while triglyceride incorporation was almost uniform. The degree of incorporation of the unsaturated fatty acids into phosphoglycerides (structural) compared to triglyceride (storage and energy) was the converse of their oxidation rates. The incorporation of oleic, linoleic and alpha-linolenic acids was mainly into triglyceride, whereas dihomo-gamma-linolenic acid and arachidonic acid were preferentially incorporated into phosphoglycerides. The data suggest that distribution of each fatty acid is different depending on its destination for structural or energy function

  3. Non-alcoholic Fatty Liver Disease: Beneficial Effects of Flavonoids.

    Science.gov (United States)

    Akhlaghi, Masoumeh

    2016-10-01

    Non-alcoholic fatty liver disease (NAFLD) has been known as the hepatic feature of metabolic syndrome. Extra fat depots, especially in visceral areas, develop insulin resistance as a result of mild oxidation and inflammation. Insulin resistance induces lipolysis and releases free fatty acids into the circulation, where they are transported to the liver. In the liver, free fatty acids are converted to triglycerides and accumulate, causing simple steatosis that, if left untreated, can lead to steatohepatitis, and subsequently liver necrosis and cirrhosis.Flavonoids, a group of plant compounds with incredible biological characteristics, have shown advantages in pathological conditions. Beneficial effects of flavonoids against NAFLD and its related disorders have been observed in both animal and human studies. Various mechanisms have been found for their protection. Flavonoids prevent hepatosteatosis by increasing fatty acid oxidation in the liver. They can also reduce caloric intake and decrease body weight and fat deposition in visceral tissues. Flavonoids are unique antioxidants that exert their beneficial effects through inhibition of nuclear factor κB, thereby attenuating release of inflammatory cytokines, which are triggers of insulin resistance. Finally, flavonoids have shown to increase adiponectin, improve insulin sensitivity and glucose tolerance, correct dyslipidemia, and reduce blood pressure in patients with NAFLD. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Extra Virgin Olive Oil Reduced Polyunsaturated Fatty Acid and Cholesterol Oxidation in Rodent Liver: Is This Accounted for Hydroxytyrosol-Fatty Acid Conjugation?

    Science.gov (United States)

    Lee, Yiu Yiu; Crauste, Céline; Wang, Hualin; Leung, Ho Hang; Vercauteren, Joseph; Galano, Jean-Marie; Oger, Camille; Durand, Thierry; Wan, Jennifer Man-Fan; Lee, Jetty Chung-Yung

    2016-10-17

    The effects of extra virgin olive oil (EVOO) and carbon tetrachloride (CCl 4 ) induced oxidative stress in rats were determined by the generation of isoprostanoids. These are known to be robust biomarkers to evaluate nonenzymatic and free radical related oxidation. Other oxidative stress biomarkers such as hydroxyeicosatetraenoic acid products (HETEs) and cholesterol oxidation products (COPs) were also determined. The rodents received a control diet, high-fat diet (20% w/w) composed of extra virgin olive oil (EVOO), corn oil (CO), or lard, and high-fat diets with CCl 4 insult throughout the experimental period. The EVOO diet was found to suppress the formation of isoprostanoids and COPs compared to that of the control. EVOO also had a high total phenolic content and antioxidant activity compared to those of CO and lard and may be contributed to by the hydroxytyrosol component conjugated to fatty acids (HT-FA). This is the first study to identify HT-FA in EVOO, and it was 4-fold higher than that of olive oil, whereas none was found in corn oil. Furthermore, the EVOO diet showed reduced liver lipid vesicles in CCl 4 treated rats compared to that of the control. However, liver toxicity measurements of AST (aspartate transaminase) and ALT (alanine transaminase) activities showed augmentation with CCl 4 treatment but were not alleviated by the diets given. Our findings suggest that EVOO is a daily functional food capable of enhancing the antioxidant system for liver protection; the effect is potentially attributed to the phenolic and lipophenolic (phenol conjugated by fatty acids) content.

  5. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  6. Liver transcriptome profile in pigs with extreme phenotypes of intramuscular fatty acid composition

    Directory of Open Access Journals (Sweden)

    Ramayo-Caldas Yuliaxis

    2012-10-01

    Full Text Available Abstract Background New advances in high-throughput technologies have allowed for the massive analysis of genomic data, providing new opportunities for the characterization of the transcriptome architectures. Recent studies in pigs have employed RNA-Seq to explore the transcriptome of different tissues in a reduced number of animals. The main goal of this study was the identification of differentially-expressed genes in the liver of Iberian x Landrace crossbred pigs showing extreme phenotypes for intramuscular fatty acid composition using RNA-Seq. Results The liver transcriptomes of two female groups (H and L with phenotypically extreme intramuscular fatty acid composition were sequenced using RNA-Seq. A total of 146 and 180 unannotated protein-coding genes were identified in intergenic regions for the L and H groups, respectively. In addition, a range of 5.8 to 7.3% of repetitive elements was found, with SINEs being the most abundant elements. The expression in liver of 186 (L and 270 (H lncRNAs was also detected. The higher reproducibility of the RNA-Seq data was validated by RT-qPCR and porcine expression microarrays, therefore showing a strong correlation between RT-qPCR and RNA-Seq data (ranking from 0.79 to 0.96, as well as between microarrays and RNA-Seq (r=0.72. A differential expression analysis between H and L animals identified 55 genes differentially-expressed between groups. Pathways analysis revealed that these genes belong to biological functions, canonical pathways and three gene networks related to lipid and fatty acid metabolism. In concordance with the phenotypic classification, the pathways analysis inferred that linolenic and arachidonic acids metabolism was altered between extreme individuals. In addition, a connection was observed among the top three networks, hence suggesting that these genes are interconnected and play an important role in lipid and fatty acid metabolism. Conclusions In the present study RNA-Seq was used

  7. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Michaut, Anaïs; Le Guillou, Dounia [INSERM, U991, Université de Rennes 1, Rennes (France); Moreau, Caroline [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Bucher, Simon [INSERM, U991, Université de Rennes 1, Rennes (France); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Martinais, Sophie [INSERM, U991, Université de Rennes 1, Rennes (France); Gicquel, Thomas; Morel, Isabelle [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, Rennes (France); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, Rennes (France)

    2016-02-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1

  8. Liver Fatty Acid Composition and Inflammation in Mice Fed with High-Carbohydrate Diet or High-Fat Diet.

    Science.gov (United States)

    da Silva-Santi, Lorena Gimenez; Antunes, Marina Masetto; Caparroz-Assef, Silvana Martins; Carbonera, Fabiana; Masi, Laureane Nunes; Curi, Rui; Visentainer, Jesuí Vergílio; Bazotte, Roberto Barbosa

    2016-10-29

    Both high-carbohydrate diet (HCD) and high-fat diet (HFD) modulate liver fat accumulation and inflammation, however, there is a lack of data on the potential contribution of carbohydrates and lipids separately. For this reason, the changes in liver fatty acid (FA) composition in male Swiss mice fed with HCD or HFD were compared, at the time points 0 (before starting the diets), and after 7, 14, 28 or 56 days. Activities of stearoyl-CoA desaturase-1 (SCD-1), ∆-6 desaturase (D6D), elongases and de novo lipogenesis (DNL) were estimated. Liver mRNA expression of acetyl-CoA carboxylase 1 (ACC1) was evaluated as an additional indicator of the de novo lipogenesis. Myeloperoxidase activity, nitric oxide (NO) production, and mRNA expressions of F4/80, type I collagen, interleukin (IL)-6, IL-1β, IL-10, and tumor necrosis factor-α (TNF-α) were measured as indication of the liver inflammatory state. The HCD group had more intense lipid deposition, particularly of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). This group also showed higher DNL, SCD-1, and D6D activities associated with increased NO concentration, as well as myeloperoxidase activity. Livers from the HFD group showed higher elongase activity, stored more polyunsaturated fatty acids (PUFAs) and had a lower omega-6/omega-3 fatty acid ( n -6/ n -3) ratio. In conclusion, liver lipid accumulation, fatty acids (FA) composition and inflammation were modulated by the dietary composition of lipids and carbohydrates. The HCD group had more potent lipogenic and inflammatory effects in comparison with HFD.

  9. Liver Fatty Acid Composition and Inflammation in Mice Fed with High-Carbohydrate Diet or High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Lorena Gimenez da Silva-Santi

    2016-10-01

    Full Text Available Both high-carbohydrate diet (HCD and high-fat diet (HFD modulate liver fat accumulation and inflammation, however, there is a lack of data on the potential contribution of carbohydrates and lipids separately. For this reason, the changes in liver fatty acid (FA composition in male Swiss mice fed with HCD or HFD were compared, at the time points 0 (before starting the diets, and after 7, 14, 28 or 56 days. Activities of stearoyl-CoA desaturase-1 (SCD-1, ∆-6 desaturase (D6D, elongases and de novo lipogenesis (DNL were estimated. Liver mRNA expression of acetyl-CoA carboxylase 1 (ACC1 was evaluated as an additional indicator of the de novo lipogenesis. Myeloperoxidase activity, nitric oxide (NO production, and mRNA expressions of F4/80, type I collagen, interleukin (IL-6, IL-1β, IL-10, and tumor necrosis factor-α (TNF-α were measured as indication of the liver inflammatory state. The HCD group had more intense lipid deposition, particularly of saturated fatty acids (SFAs and monounsaturated fatty acids (MUFAs. This group also showed higher DNL, SCD-1, and D6D activities associated with increased NO concentration, as well as myeloperoxidase activity. Livers from the HFD group showed higher elongase activity, stored more polyunsaturated fatty acids (PUFAs and had a lower omega-6/omega-3 fatty acid (n-6/n-3 ratio. In conclusion, liver lipid accumulation, fatty acids (FA composition and inflammation were modulated by the dietary composition of lipids and carbohydrates. The HCD group had more potent lipogenic and inflammatory effects in comparison with HFD.

  10. Fatty acid composition and development of hepatic lipidosis during food deprivation--mustelids as a potential animal model for liver steatosis.

    Science.gov (United States)

    Nieminen, Petteri; Mustonen, Anne-Mari; Kärjä, Vesa; Asikainen, Juha; Rouvinen-Watt, Kirsti

    2009-03-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome characterized by asymptomatic hepatic steatosis. It is present in most cases of human obesity but also caused e.g., by rapid weight loss. The patients have decreased n-3 polyunsaturated fatty acid (PUFA) proportions with decreased percentages of 18:3(n-3), 20:5(n-3) and 22:6(n-3) and an increased n-6/n-3 PUFA ratio in liver and/or white adipose tissue (WAT). The present study examined a new experimental model to study liver steatosis with possible future applications to NAFLD. Ten European polecats (Mustela putorius), the wild form of the domestic ferret, were food-deprived for 5 days with 10 fed animals as controls. The food-deprived animals showed micro- and macrovesicular hepatic steatosis, decreased proportions of 20:5(n-3), 22:6(n-3) and total n-3 PUFA and increased n-6/n-3 PUFA ratios in liver and WAT. At the same time, the product/precursor ratios decreased in liver. The observed effects can be due to selective fatty acid mobilization preferring n-3 PUFA over n-6 PUFA, decreased Delta5 and Delta6 desaturase activities, oxidative stress, decreased arginine availability and activation of the endocannabinoid system. Hepatic lipidosis induced by food deprivation was manifested in the fatty acid composition of the polecat with similarities to human NAFLD despite the different principal etiologies.

  11. Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis

    OpenAIRE

    Visscher, Christian; Middendorf, Lea; G?nther, Ronald; Engels, Alexandra; Leibfacher, Christof; M?hle, Henrik; D?ngelhoef, Kristian; Weier, Stefan; Haider, Wolfram; Radko, Dimitri

    2017-01-01

    Background The so-called ?hepatic lipidosis? in turkeys is an acute progressive disease associated with a high mortality rate in a very short time. Dead animals show a massive fatty degeneration of the liver. The cause is still unclear. Previous findings suggest that there may be parallels to human non-alcoholic fatty liver disease. The object of the study was to examine the changes in the fat contents, the fatty acid composition and the iron content in livers of animals, which have died from...

  12. Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids

    NARCIS (Netherlands)

    Marsman, H. A.; de Graaf, W.; Heger, M.; van Golen, R. F.; ten Kate, F. J. W.; Bennink, R.; van Gulik, T. M.

    2013-01-01

    Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. Steatosis was induced in rats by a 3-week

  13. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

    Science.gov (United States)

    Li, Songtao; Liao, Xilu; Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

  14. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

    Directory of Open Access Journals (Sweden)

    Songtao Li

    Full Text Available BACKGROUND: Non-alcoholic fatty liver disease (NAFLD is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA, an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD-induced obese non-alcoholic fatty liver disease (NAFLD rat model. METHODOLOGY/PRINCIPAL FINDINGS: Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. CONCLUSIONS/SIGNIFICANCE: These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

  15. Anti-fatty liver effects of oils from Zingiber officinale and Curcuma longa on ethanol-induced fatty liver in rats.

    Science.gov (United States)

    Nwozo, Sarah Onyenibe; Osunmadewa, Damilola Adeola; Oyinloye, Babatunji Emmanuel

    2014-01-01

    The present study is aimed at evaluating the protective effects of oils from Zingiber officinale (ginger) and Curcuma longa (turmeric) on acute ethanol-induced fatty liver in male Wistar rats. Ferric reducing antioxidant power activity and oxygen radical absorbance capacity of the oils were evaluated ex vivo. Rats were pretreated for 28 d with standard drug (Livolin Forte) and oils from Z. officinale and C. longa before they were exposed to 45% ethanol (4.8 g/kg) to induce acute fatty liver. Histological changes were observed and the degree of protection was measured by using biochemical parameters such as alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities. Serum triglyceride (TG) level, total cholesterol (TC) level and the effects of both oils on reduced gluthatione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and hepatic malondialdehyde (MDA) levels were estimated. Oils from Z. officinale and C. longa at a dose of 200 mg/kg showed hepatoprotection by decreasing the activities of serum enzymes, serum TG, serum TC and hepatic MDA, while they significantly restored the level of GSH as well as GST and SOD activities. Histological examination of rats tissues was related to the obtained results. From the results it may be concluded that oils from Z. officinale and C. longa (200 mg/kg) exhibited hepatoprotective activity in acute ethanol-induced fatty liver and Z. officinale oil was identified to have better effects than C. longa oil.

  16. Binding of acyl CoA by fatty acid binding protein and the effect on fatty acid activation

    International Nuclear Information System (INIS)

    Burrier, R.E.; Manson, C.R.; Brecher, P.

    1987-01-01

    The ability of purified rat liver and heart fatty acid binding proteins (FABPs) to bind oleoyl CoA and modulate acyl CoA synthesis by microsomal membranes was investigated. Using binding assays employing either Lipidex 1000 or multilamellar liposomes to sequester unbound ligand, rat liver but not rat heart FABP was shown to bind radiolabeled acyl CoA. Binding studies suggest that liver FABP has a single binding site for acyl CoA which is separate from the two binding sites for fatty acids. Experiments were then performed to determine how binding may influence acyl CoA metabolism by liver microsomes or heart sarcoplasmic reticulum. Using liposomes as fatty acid donors, liver FABP stimulated acyl CoA production whereas heart FABP did not stimulate production over control values. 14 C-Fatty acid-FABP complexes were prepared, incubated with membranes and acyl CoA synthetase activity was determined. Up to 70% of the fatty acid could be converted to acyl CoA in the presence of liver FABP but in the presence of heart FABP, only 45% of the fatty acid was converted. The amount of product formed was not changed by additional membrane, enzyme cofactor, or incubation time. Liver but not heart FABP bound the acyl CoA formed and removed it from the membranes. These studies suggest that liver FABP can increase the amount of acyl CoA by binding this ligand thereby removing it from the membrane and possibly aiding transport within the cell

  17. Binding of acyl CoA by fatty acid binding protein and the effect on fatty acid activation

    Energy Technology Data Exchange (ETDEWEB)

    Burrier, R.E.; Manson, C.R.; Brecher, P.

    1987-05-01

    The ability of purified rat liver and heart fatty acid binding proteins (FABPs) to bind oleoyl CoA and modulate acyl CoA synthesis by microsomal membranes was investigated. Using binding assays employing either Lipidex 1000 or multilamellar liposomes to sequester unbound ligand, rat liver but not rat heart FABP was shown to bind radiolabeled acyl CoA. Binding studies suggest that liver FABP has a single binding site for acyl CoA which is separate from the two binding sites for fatty acids. Experiments were then performed to determine how binding may influence acyl CoA metabolism by liver microsomes or heart sarcoplasmic reticulum. Using liposomes as fatty acid donors, liver FABP stimulated acyl CoA production whereas heart FABP did not stimulate production over control values. /sup 14/C-Fatty acid-FABP complexes were prepared, incubated with membranes and acyl CoA synthetase activity was determined. Up to 70% of the fatty acid could be converted to acyl CoA in the presence of liver FABP but in the presence of heart FABP, only 45% of the fatty acid was converted. The amount of product formed was not changed by additional membrane, enzyme cofactor, or incubation time. Liver but not heart FABP bound the acyl CoA formed and removed it from the membranes. These studies suggest that liver FABP can increase the amount of acyl CoA by binding this ligand thereby removing it from the membrane and possibly aiding transport within the cell.

  18. Effect of bullfrog (Rana catesbeiana oil administered by gavage on the fatty acid composition and oxidative stress of mouse liver

    Directory of Open Access Journals (Sweden)

    L.P. Silva

    2004-10-01

    Full Text Available The aim of the present study was to investigate the effects of daily intragastric administration of bullfrog oil (oleic, linoleic and palmitoleic acid-rich oil, corresponding to 0.4% of body weight for four weeks, on fatty acid composition and oxidative stress (lipid peroxidation and catalase activity in mouse liver. The activities of aspartate aminotransferase (AST, alkaline phosphatase (ALP, alanine aminotransferase (ALT, and gamma-glutamyltransferase (GGT, biomarkers of tissue injury, were determined in liver homogenates and serum. The proportions of 18:2n-6, 20:4n-6, 20:5n-3, and 22:6n-3 (polyunsaturated fatty acids, from 37 to 60% in the total fatty acid content were increased in the liver of the bullfrog oil-treated group (P < 0.05 compared to control. At the same time, a significant decrease in the relative abundance of 14:0, 16:0, and 18:0 (saturated fatty acids, from 49 to 25% was observed. The hepatic content of thiobarbituric acid reactive substances (TBARS was increased from 2.3 ± 0.2 to 12.3 ± 0.3 nmol TBA-MDA/mg protein and catalase activity was increased from 840 ± 32 to 1110 ± 45 µmol reduced H2O2 min-1 mg protein-1 in the treated group. Bullfrog oil administration increased AST and ALP activities in the liver (from 234.10 ± 0.12 to 342.84 ± 0.13 and 9.38 ± 0.60 to 20.06 ± 0.27 U/g, respectively and in serum (from 95.41 ± 6.13 to 120.32 ± 3.15 and 234.75 ± 11.5 to 254.41 ± 2.73 U/l, respectively, suggesting that this treatment induced tissue damage. ALT activity was increased from 287.28 ± 0.29 to 315.98 ± 0.34 U/g in the liver but remained unchanged in serum, whereas the GGT activity was not affected by bullfrog oil treatment. Therefore, despite the interesting modulation of fatty acids by bullfrog oil, a possible therapeutic use requires care since some adverse effects were observed in liver.

  19. Diets Rich in Polyunsaturated Fatty Acids With Different Omega-6/Omega-3 Ratio Decrease Liver Content of Saturated Fatty Acids Across Generations of Wistar Rats

    Directory of Open Access Journals (Sweden)

    Simone Halfen

    Full Text Available Our study evaluated how the consumption of diets with low (LOW group - 0.4/1 or high (CON group - 13.6/1 omega-6/omega-3 ratio across generations (F1 and F2 can modulate liver fatty acid (FA profile and blood biomarkers. Liver content of α-linolenic acid was higher in animals always fed with LOW diet than animals that changed from CON to LOW diet, which by your time was higher than animals always fed with CON diet. Liver saturated FA concentration decreased in both groups from F1 to F2. In conclusion, both diets were efficient in decreasing the saturated FA liver content across generations, the LOW ratio diet was more effective in reducing blood triglycerides and non-esterified fatty acids, and there was a multigenerational effect of the LOW ratio diet, improving the FA profile even when the offspring start receiving the CON diet.

  20. Antioxidant status, lipoprotein profile and liver lipids in rats fed on high-cholesterol diet containing currant oil rich in n-3 and n-6 polyunsaturated fatty acids.

    Science.gov (United States)

    Vecera, R; Skottová, N; Vána, P; Kazdová, L; Chmela, Z; Svagera, Z; Walterá, D; Ulrichová, J; Simánek, V

    2003-01-01

    Plant-based n-3 polyunsaturated fatty acids (PUFA) possess a prospective antiatherogenic potential. Currant oil from Ribes nigrum L. is one of the few plant oils containing PUFAn-3 (15.3 mol%) in addition to PUFAn-6 (60.5 mol%). This study was aimed at comparing the effects of currant oil with those of lard fat, rich in saturated (43.8 mol%) and monounsaturated (47.0 mol%) fatty acids, on antioxidant parameters, the lipoprotein profile and liver lipids in rats fed on 1 % (w/w) cholesterol diets containing either 10 % of currant oil (COD) or lard fat (LFD). After 3 weeks of feeding, the COD induced a significant decrease in blood glutathione (GSH) and an increase in Cu(2+) induced oxidizability of serum lipids, but did not affect liver GSH and t-butyl hydroperoxide-induced lipoperoxidation of liver microsomes. Although the COD did not cause accumulation of liver triacylglycerols as LFD, the lipoprotein profile (VLDL, LDL, HDL) was not significantly improved after COD. The consumption of PUFAn-3 was reflected in LDL as an increase in eicosapentaenoic and docosahexaenoic acid. These results suggest that currant oil affects positively the lipid metabolism in the liver, above all it does not cause the development of a fatty liver. However, adverse effects of currant oil on the antioxidant status in the blood still remain of concern.

  1. Liver phospholipids fatty acids composition in response to different types of diets in rats of both sexes.

    Science.gov (United States)

    Ranković, Slavica; Popović, Tamara; Martačić, Jasmina Debeljak; Petrović, Snježana; Tomić, Mirko; Ignjatović, Đurđica; Tovilović-Kovačević, Gordana; Glibetić, Maria

    2017-05-19

    Dietary intake influence changes in fatty acids (FA) profiles in liver which plays a central role in fatty acid metabolism, triacylglycerol synthesis and energy homeostasis. We investigated the effects of 4-weeks treatment with milk- and fish-based diet, on plasma biochemical parameters and FA composition of liver phospholipids (PL) in rats of both sexes. Adult, 4 months old, Wistar rats of both sexes, were fed with different types of diets: standard, milk-based and fish-based, during 4 weeks. Analytical characterization of different foods was done. Biochemical parameters in plasma were determined. Fatty acid composition was analyzed by gas-chromatography. Statistical significance of FA levels was tested with two-way analysis of variance (ANOVA) using the sex of animals and treatment (type of diet) as factors on logarithmic or trigonometric transformed data. Our results showed that both, milk- and fish-based diet, changed the composition and ratio of rat liver phospholipids FA, in gender-specific manner. Initially present sex differences appear to be dietary modulated. Although, applied diets changed the ratio of total saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), and effects were gender specific. Milk-based diet lowered SFA and elevated MUFA in males and increased PUFA in females vs. standard diet. The same diet decreased n-3, increased n-6 and n-6/n-3 ratio in males. Fish-based diet increased n-3, decreased n-6 and n-6/n-3 ratio vs. standard and milk-based diet in females. However, the ratio of individual FA in liver PL was also dietary-influenced, but with gender specific manner. While in females fish-based diet decreased AA (arachidonic acid) increased level of EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid) and DHA (docosahexaenoic acid), the same diet elevated only DHA levels in males. Gender related variations in FA composition of rat liver PL were observed, and results have shown that

  2. [Effects of three Wenyang Jianpi Tang on cell proliferation and apoptosis of nonalcoholic fatty liver cells].

    Science.gov (United States)

    Yang, Jia-Yao; Tao, Dong-Qing; Liu, Song; Zhang, Shu; Ma, Wei; Shi, Zhao-Hong

    2017-04-01

    To investigate the effects of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang on the cell proliferation and apoptosis of nonalcoholic fatty liver cells through the nonalcoholic fatty liver cell model established by inducing L02 cells with oleic acid. Different concentrations of oleic acid were added into L02 cells to induce the nonalcoholic fatty liver cell model. Oil red O staining was used to observe fatty droplets of fatty liver cells. Automatic biochemical analyzer was used to detect the levels of aspartic transaminase(AST), alanine aminotransferase(ALT), total cholesterol(TC), and triglyceride(TG) in the cell supernatants. There were five groups, namely normal group, model group, model and Sijunzi Tang group, model and Lizhong Tang group, and model and Fuzi Lizhong Tang group. The cell proliferation and apoptosis of the five groups were detected by MTT colorimetry test and flow cytometer. The expressions of PCNA, cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax and Bcl-2 proteins of the five groups were detected by Western blot. The oil red O staining results showed that the optimum concentration of oleic acid that was used to induce nonalcoholic fatty liver cell models was 80 mg•L-1. The levels of AST, ALT, TC and TG in the nonalcoholic fatty liver cell supernatants were higher than that in normal liver cell supernatants(PTang, Lizhong Tang and Fuzi Lizhong Tang could effectively promote the cell proliferation, and inhibit the cellular apoptosis of nonalcoholic fatty liver cells(PTang showed the best effect. Western blot results showed that Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could down-regulate the expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and Bax proteins, and up-regulate the expressions of PCNA and Bcl-2 proteins of nonalcoholic fatty liver cells. And Fuzi Lizhong Tang showed the best effect. In conclusion, all of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could effectively promote the cell

  3. Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates.

    Science.gov (United States)

    Zarei, Mahnaz; Fakher, Shima; Tabei, Seyed Mohammad Bagher; Javanbakht, Mohammad Hassan; Derakhshanian, Hoda; Farahbakhsh-Farsi, Payam; Sadeghi, Mohammad Reza; Mostafavi, Ebrahim; Djalali, Mahmoud

    2016-03-01

    This study was designed and conducted to evaluate the effects of vitamin A, C and E supplementation, and omega-3 fatty acid supplementation on the activity of paraoxonase and arylesterase in an experimental model of diabetes mellitus. A total of 64 male Sprague Dawley® rats, each weighing 250 g, were randomly distributed into four groups: (a) normal control; (b) diabetic control; (c) diabetic with vitamin A, C and E supplementation; and (d) diabetic with omega-3 fatty acid supplementation. The animals were anaesthetised after four weeks of intervention, and paraoxonase and arylesterase activity in blood plasma, and liver and heart homogenates were measured. Arylesterase activity in the heart and liver homogenates was significantly lower in the diabetic control group than in the normal control group (p Vitamin A, C and E supplementation, and omega-3 fatty acid supplementation significantly increased liver arylesterase activity (p Vitamin A, C and E, or omega-3 fatty acid supplementation were found to increase liver arylesterase activity in streptozotocin-induced diabetic rats. These supplements may be potential agents for the treatment of diabetes mellitus complications. Copyright: © Singapore Medical Association.

  4. Control of bovine hepatic fatty acid oxidation

    International Nuclear Information System (INIS)

    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-01-01

    Fatty acid oxidation by bovine liver slices and mitochondria was examined to determine potential regulatory sites of fatty acid oxidation. Conversion of 1-[ 14 C]palmitate to 14 CO 2 and total [ 14 C]acid-soluble metabolites was used to measure fatty acid oxidation. Oxidation of palmitate (1 mM) was linear in both liver slice weight and incubation time. Carnitine stimulated palmitate oxidation; 2 mM dl-carnitine produced maximal stimulation of palmitate oxidation to both CO 2 and acid-soluble metabolites. Propionate (10 mM) inhibited palmitate oxidation by bovine liver slices. Propionate (.5 to 10 mM) had no effect on palmitate oxidation by mitochondria, but malonyl Coenzyme A, the first committed intermediate of fatty acid synthesis, inhibited mitochondrial palmitate oxidation (inhibition constant = .3 μM). Liver mitochonndrial carnitine palmitoyltransferase exhibited Michaelis constants for palmitoyl Coenzyme A and l-carnitine of 11.5 μM and .59 mM, respectively. Long-chain fatty acid oxidation in bovine liver is regulated by mechanisms similar to those in rats but adapted to the unique digestive physiology of the bovine

  5. Soybean Aphid Infestation Induces Changes in Fatty Acid Metabolism in Soybean.

    Directory of Open Access Journals (Sweden)

    Charles Kanobe

    Full Text Available The soybean aphid (Aphis glycines Matsumura is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of "metabolic hijacking" by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor.

  6. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken

    Science.gov (United States)

    Zhang, Yonghong; Liu, Zhen; Liu, Ranran; Wang, Jie; Zheng, Maiqing; Li, Qinghe; Cui, Huanxian; Zhao, Guiping; Wen, Jie

    2018-01-01

    Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF) diet and a methionine choline-deficient (MCD) diet. The results showed that the dwarf Jingxing-Huang (JXH) chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL) and local Beijing-You (BJY) breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers. PMID:29642504

  7. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken.

    Science.gov (United States)

    Zhang, Yonghong; Liu, Zhen; Liu, Ranran; Wang, Jie; Zheng, Maiqing; Li, Qinghe; Cui, Huanxian; Zhao, Guiping; Wen, Jie

    2018-04-08

    Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF) diet and a methionine choline-deficient (MCD) diet. The results showed that the dwarf Jingxing-Huang (JXH) chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL) and local Beijing-You (BJY) breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism ( ACACA , FASN , SCD , ACSL5 , FADS2 , FABP1 , APOA4 and ME1 ). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.

  8. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken

    Directory of Open Access Journals (Sweden)

    Yonghong Zhang

    2018-04-01

    Full Text Available Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF diet and a methionine choline-deficient (MCD diet. The results showed that the dwarf Jingxing-Huang (JXH chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL and local Beijing-You (BJY breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1. This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.

  9. Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver

    Directory of Open Access Journals (Sweden)

    Meiyuan Zhang

    2018-06-01

    Full Text Available Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15 is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress. Keywords: Fasting, Fatty acid β-oxidation, Ketogenesis, GDF15, XBP1, NAFLD

  10. Impact of diesel exhaust exposure on the liver of mice fed on omega-3 polyunsaturated fatty acids-deficient diet.

    Science.gov (United States)

    Umezawa, Masakazu; Nakamura, Masayuki; El-Ghoneimy, Ashraf A; Onoda, Atsuto; Shaheen, Hazem M; Hori, Hiroshi; Shinkai, Yusuke; El-Sayed, Yasser S; El-Far, Ali H; Takeda, Ken

    2018-01-01

    Exposure to diesel exhaust (DE) exacerbates non-alcoholic fatty liver disease, and may systemically affect lipid metabolism. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have anti-inflammatory activity and suppresses hepatic triacylglycerol accumulation, but many daily diets are deficient in this nutrient. Therefore, the effect of DE exposure in mice fed n-3 PUFA-deficient diet was investigated. Mice were fed control chow or n-3 PUFA-deficient diet for 4 weeks, then exposed to clean air or DE by inhalation for further 4 weeks. Liver histology, plasma parameters, and expression of fatty acid synthesis-related genes were evaluated. N-3 PUFA-deficient diet increased hepatic lipid droplets accumulation and expression of genes promoting fatty acid synthesis: Acaca, Acacb, and Scd1. DE further increased the plasma leptin and the expression of fatty acid synthesis-related genes: Acacb, Fasn, and Scd1. N-3 PUFA-deficient diet and DE exposure potentially enhanced hepatic fatty acid synthesis and subsequently accumulation of lipid droplets. The combination of low-dose DE exposure and intake of n-3 PUFA-deficient diet may be an additional risk factor for the incidence of non-alcoholic fatty liver disease. The present study suggests an important mechanism for preventing toxicity of DE on the liver through the incorporation of n-3 PUFAs in the diet. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Topical Formulation Comprising Fatty Acid Extract from Cod Liver Oil: Development, Evaluation and Stability Studies.

    Science.gov (United States)

    Ilievska, Biljana; Loftsson, Thorsteinn; Hjalmarsdottir, Martha Asdis; Asgrimsdottir, Gudrun Marta

    2016-06-01

    The purpose of this study was to develop a pharmaceutical formulation containing fatty acid extract rich in free omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid for topical use. Although the health benefits of cod liver oil and other fish oils taken orally as a dietary supplement have been acknowledged and exploited, it is clear that their use can be extended further to cover their antibacterial properties. In vitro evaluation showed that 20% (v/v) fatty acid extract exhibits good activity against strains of the Gram-positive bacteria Staphylococcus aureus, Enterococcus faecalis, Streptoccoccus pyogenes and Streptoccoccus pneumonia. Therefore, free polyunsaturated fatty acids from cod liver oil or other fish oils can be used as safe and natural antibacterial agents. In this study, ointment compositions containing free fatty acids as active antibacterial agents were prepared by using various natural waxes and characterized. The effects of different waxes, such as carnauba wax, ozokerite wax, laurel wax, beeswax, rice bran wax, candelilla wax and microcrystalline wax, in the concentration range of 1% to 5% (w/w) on the ointment texture, consistency and stability were evaluated. The results showed significant variations in texture, sensory and rheological profiles. This was attributed to the wax's nature and chain composition. Microcrystalline wax gave the best results but laurel wax, beeswax and rice bran wax exhibited excellent texturing, similar sensory profiles and well-balanced rheological properties.

  12. Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

    Science.gov (United States)

    Liu, Jinyao

    2014-01-01

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease. PMID:25356030

  13. Fatty liver and drugs: the two sides of the same coin.

    Science.gov (United States)

    Miele, L; Liguori, A; Marrone, G; Biolato, M; Araneo, C; Vaccaro, F G; Gasbarrini, A; Grieco, A

    2017-03-01

    Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.

  14. Effects of olive oil and its fractions on oxidative stress and the liver's fatty acid composition in 2,4-Dichlorophenoxyacetic acid-treated rats

    Directory of Open Access Journals (Sweden)

    Ellouz Meriem

    2010-10-01

    Full Text Available Abstract Background Olive oil's beneficial effects are not only related to its high content of oleic acid, but also to the antioxidant potential of its polyphenols. In this study, we assess the effects of virgin olive oil and its fractions on 2,4-D- induced oxidative damage in the liver of rats. Methods Male Wistar rats were randomly divided into eight groups of ten each: (C a control group, (D group that received 2,4-D (5 mg/kg b.w., (D/EVOO group treated with 2,4-D plus extra virgin olive oil, (D/OOHF group that received 2,4-D plus hydrophilic fraction, (D/OOLF group treated with 2,4-D plus lipophilic fraction, (EVOO group that received only extra virgin olive oil, (OOHF group given hydrophilic fraction and (OOLF group treated with lipophilic fraction. These components were daily administered by gavage for 4 weeks. Results A significant liver damage was observed in rats treated with 2,4-D via increased serum levels of transaminases and alkaline phosphatase, hepatic lipid peroxidation and decreased hepatic antioxidant enzyme activities, namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. The liver's fatty acid composition was also significantly modified with 2,4-D exposure. However, extra virgin olive oil and hydrophilic fraction intake during 2,4-D treatment induced a significant increase in the antioxidant enzyme activities and a decrease in the conjugated dienes (CD and thiobarbituric acid-reactive substances (TBARs levels in the liver. The lipophilic fraction supplemented to 2,4-D- treated rats did not show any improvement in the liver oxidative status while a marked improvement was detected in the hepatic fatty acid composition of rats supplemented with olive oil and the two fractions. Conclusion We concluded that the protective effect of olive oil against oxidative damage induced by 2,4-D is mainly related to the antioxidant potential of its hydrophilic fraction.

  15. Adrenic acid as an inflammation enhancer in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Horas H Nababan, Saut; Nishiumi, Shin; Kawano, Yuki; Kobayashi, Takashi; Yoshida, Masaru; Azuma, Takeshi

    2017-06-01

    This study was designed to identify novel links between lipid species and disease progression in non-alcoholic fatty liver disease (NAFLD). We analyzed lipid species in the liver and plasma of db/db mice fed a choline-deficient l-amino acid-defined, high-fat diet (CDAHFD) using liquid chromatography/mass spectrometry (LC/MS). An in vitro experiment was performed using HepG2 cells stimulated with recombinant human TNFα or IL1β. The expression of steatosis-, inflammation-, and fibrosis-related genes were analyzed. Plasma samples from NAFLD patients were also analyzed by LC/MS. The CDAHFD-fed db/db mice with hepatic steatosis, inflammation, mild fibrosis, obesity, and hypercholesterolemia displayed significantly higher hepatic and plasma levels of free adrenic acid (p < 0.05). The accumulated adrenic acid in the CDAHFD-fed db/db mice was associated with increased expression of ELOVL2 and 5, and the suppression of the acyl-CoA oxidase 1 gene during peroxisomal β-oxidation. The pretreatment of HepG2 cells with adrenic acid enhanced their cytokine-induced cytokines and chemokines mRNA expression. In NAFLD patients, the group with the highest ALT levels exhibited higher plasma adrenic acid concentrations than the other ALT groups (p-value for trend <0.001). Data obtained demonstrated that adrenic acid accumulation contributes to disease progression in NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. A diet high in α-linolenic acid and monounsaturated fatty acids attenuates hepatic steatosis and alters hepatic phospholipid fatty acid profile in diet-induced obese rats.

    Science.gov (United States)

    Hanke, Danielle; Zahradka, Peter; Mohankumar, Suresh K; Clark, Jaime L; Taylor, Carla G

    2013-01-01

    This study investigated the efficacy of the plant-based n-3 fatty acid, α-linolenic acid (ALA), a dietary precursor of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for modulating hepatic steatosis. Rats were fed high fat (55% energy) diets containing high oleic canola oil, canola oil, a canola/flax oil blend (C/F, 3:1), safflower oil, soybean oil, or lard. After 12 weeks, C/F and weight-matched (WM) groups had 20% less liver lipid. Body mass, liver weight, glucose and lipid metabolism, inflammation and molecular markers of fatty acid oxidation, synthesis, desaturation and elongation did not account for this effect. The C/F group had the highest total n-3 and EPA in hepatic phospholipids (PL), as well as one of the highest DHA and lowest arachidonic acid (n-6) concentrations. In conclusion, the C/F diet with the highest content of the plant-based n-3 ALA attenuated hepatic steatosis and altered the hepatic PL fatty acid profile. © 2013 Published by Elsevier Ltd.

  17. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-01-01

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  18. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  19. The fatty acid profile of rainbow trout liver cells modulates their tolerance to methylmercury and cadmium

    International Nuclear Information System (INIS)

    Ferain, Aline; Bonnineau, Chloé; Neefs, Ineke; Rees, Jean François; Larondelle, Yvan; Schamphelaere, Karel A.C.De; Debier, Cathy

    2016-01-01

    Highlights: • The phospholipid composition of rainbow trout liver cells was successfully changed. • Cell phospholipids influenced methylmercury (MeHg) and cadmium (Cd) toxicity. • Cells enriched in 18:3n-3, 20:5n-3 or 22:5n-6 were more resistant to MeHg and Cd. • Cell enrichment in 22:6n-3 increased resistance to Cd but not MeHg. - Abstract: The polyunsaturated fatty acid (PUFA) composition of fish tissues, which generally reflects that of the diet, affects various cellular properties such as membrane structure and fluidity, energy metabolism and susceptibility to oxidative stress. Since these cellular parameters can play an important role in the cellular response to organic and inorganic pollutants, a variation of the PUFA supply might modify the toxicity induced by such xenobiotics. In this work, we investigated whether the cellular fatty acid profile has an impact on the in vitro cell sensitivity to two environmental pollutants: methylmercury and cadmium. Firstly, the fatty acid composition of the rainbow trout liver cell line RTL-W1 was modified by enriching the growth medium with either alpha-linolenic acid (ALA, 18:3n-3), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) or docosapentaenoic acid (DPA, 22:5n-6). These modified cells and their control (no PUFA enrichment) were then challenged for 24 h with increasing concentrations of methylmercury or cadmium. We observed that (i) the phospholipid composition of the RTL-W1 cells was profoundly modulated by changing the PUFA content of the growth medium: major modifications were a high incorporation of the supplemented PUFA in the cellular phospholipids, the appearance of direct elongation and desaturation metabolites in the cellular phospholipids as well as a change in the gross phospholipid composition (PUFA and monounsaturated fatty acid (MUFA) levels and n-3/n-6 ratio); (ii) ALA, EPA and DPA enrichment significantly

  20. The fatty acid profile of rainbow trout liver cells modulates their tolerance to methylmercury and cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Ferain, Aline, E-mail: aline.ferain@uclouvain.be [Institute of Life Sciences, Université catholique de Louvain, Place Croix du Sud 2/L7.05.08, B-1348 Louvain-la-Neuve (Belgium); Bonnineau, Chloé [Institute of Life Sciences, Université catholique de Louvain, Place Croix du Sud 2/L7.05.08, B-1348 Louvain-la-Neuve (Belgium); Irstea, UR MALY, Centre de Lyon-Villeurbanne, rue de la Doua 5/32108, F-69616 Villeurbanne (France); Neefs, Ineke; Rees, Jean François; Larondelle, Yvan [Institute of Life Sciences, Université catholique de Louvain, Place Croix du Sud 2/L7.05.08, B-1348 Louvain-la-Neuve (Belgium); Schamphelaere, Karel A.C.De [Laboratory of Environmental Toxicology and Aquatic Ecology, Environmental Toxicology Unit, Ghent University, J. Plateaustraat 22, B-9000 Ghent (Belgium); Debier, Cathy [Institute of Life Sciences, Université catholique de Louvain, Place Croix du Sud 2/L7.05.08, B-1348 Louvain-la-Neuve (Belgium)

    2016-08-15

    Highlights: • The phospholipid composition of rainbow trout liver cells was successfully changed. • Cell phospholipids influenced methylmercury (MeHg) and cadmium (Cd) toxicity. • Cells enriched in 18:3n-3, 20:5n-3 or 22:5n-6 were more resistant to MeHg and Cd. • Cell enrichment in 22:6n-3 increased resistance to Cd but not MeHg. - Abstract: The polyunsaturated fatty acid (PUFA) composition of fish tissues, which generally reflects that of the diet, affects various cellular properties such as membrane structure and fluidity, energy metabolism and susceptibility to oxidative stress. Since these cellular parameters can play an important role in the cellular response to organic and inorganic pollutants, a variation of the PUFA supply might modify the toxicity induced by such xenobiotics. In this work, we investigated whether the cellular fatty acid profile has an impact on the in vitro cell sensitivity to two environmental pollutants: methylmercury and cadmium. Firstly, the fatty acid composition of the rainbow trout liver cell line RTL-W1 was modified by enriching the growth medium with either alpha-linolenic acid (ALA, 18:3n-3), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) or docosapentaenoic acid (DPA, 22:5n-6). These modified cells and their control (no PUFA enrichment) were then challenged for 24 h with increasing concentrations of methylmercury or cadmium. We observed that (i) the phospholipid composition of the RTL-W1 cells was profoundly modulated by changing the PUFA content of the growth medium: major modifications were a high incorporation of the supplemented PUFA in the cellular phospholipids, the appearance of direct elongation and desaturation metabolites in the cellular phospholipids as well as a change in the gross phospholipid composition (PUFA and monounsaturated fatty acid (MUFA) levels and n-3/n-6 ratio); (ii) ALA, EPA and DPA enrichment significantly

  1. Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase.

    Science.gov (United States)

    Lee, Ju-Hee; Baek, Su Youn; Jang, Eun Jeong; Ku, Sae Kwang; Kim, Kyu Min; Ki, Sung Hwan; Kim, Chang-Eop; Park, Kwang Il; Kim, Sang Chan; Kim, Young Woo

    2018-06-01

    Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver. Copyright © 2018. Published by Elsevier B.V.

  2. Effects of Natural Products on Fructose-Induced Nonalcoholic Fatty Liver Disease (NAFLD

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    Qian Chen

    2017-01-01

    Full Text Available As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD is related to several pathological processes, including: (1 augmenting lipogenesis; (2 leading to mitochondrial dysfunction; (3 stimulating the activation of inflammatory pathways; and (4 causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXRα, sterol regulatory element binding protein (SREBP-1/1c, acetyl-CoA carboxylase (ACC, fatty acid synthase (FAS, stearoyl-CoA desaturase (SCD, peroxisome proliferator–activated receptor α (PPARα, leptin nuclear factor-erythroid 2-related factor 2 (Nrf2, nuclear factor kappa B (NF-κB, tumor necrosis factor α (TNF-α, c-Jun amino terminal kinase (JNK, phosphatidylinositol 3-kinase (PI3K and adenosine 5′-monophosphate (AMP-activated protein kinase (AMPK. Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (−-epicatechin and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

  3. Hepatic unsaturated fatty acids in patients with non-alcoholic fatty liver disease assessed by 3.0 T MR spectroscopy

    International Nuclear Information System (INIS)

    Werven, J.R. van; Schreuder, T.C.M.A.; Nederveen, A.J.; Lavini, C.; Jansen, P.L.M.; Stoker, J.

    2010-01-01

    Rationale and objective: Non-alcoholic fatty liver disease (NAFLD) is related to the metabolic syndrome and obesity. Proton magnetic resonance spectroscopy ( 1 H MRS) is a non-invasive technique to assess hepatic triglyceride content (HTGC) and allows assessment of unsaturated fatty acids (UFA). There is increasing evidence that hepatic UFA are associated with the development of NAFLD. Therefore the objective of this study was to assess hepatic UFA in patients with NAFLD using 1 H MRS. Materials and methods: We included 26 consecutive patients with deranged liver enzymes, with and without type 2 diabetes mellitus (DM2), suspected for NAFLD. Liver function and metabolic parameters were assessed. 1 H MRS measurements were performed at 3.0 T. From the 1 H MR spectra two ratios were calculated: ratio 1 (UFA); unsaturated fatty acid peak vs. reference water peak and ratio 2 (HTGC); total fatty acid peak vs. reference water peak. Results: Twenty-six patients were included. In these patients hepatic UFA (ratio 1) correlated with AST/ALT ratio (r = -0.46, p = 0.02), glucose levels (r = 0.46, p = 0.018), HOMA-IR (r = 0.59, p = 0.004) and HTGC (r = 0.81, p 1 H MRS. 1 H MRS determined hepatic UFA correlate with clinical and metabolic parameters associated with NAFLD. Hepatic UFA are increased in patients with DM2. This study provides evidence for the use of non-invasive 1 H MRS to assess hepatic UFA in vivo.

  4. Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

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    Francesco Bellanti

    2018-05-01

    Full Text Available The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

  5. Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

    Science.gov (United States)

    Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

    2016-01-01

    Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

  6. Topical Formulation Comprising Fatty Acid Extract from Cod Liver Oil: Development, Evaluation and Stability Studies

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    Biljana Ilievska

    2016-06-01

    Full Text Available The purpose of this study was to develop a pharmaceutical formulation containing fatty acid extract rich in free omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid for topical use. Although the health benefits of cod liver oil and other fish oils taken orally as a dietary supplement have been acknowledged and exploited, it is clear that their use can be extended further to cover their antibacterial properties. In vitro evaluation showed that 20% (v/v fatty acid extract exhibits good activity against strains of the Gram-positive bacteria Staphylococcus aureus, Enterococcus faecalis, Streptoccoccus pyogenes and Streptoccoccus pneumonia. Therefore, free polyunsaturated fatty acids from cod liver oil or other fish oils can be used as safe and natural antibacterial agents. In this study, ointment compositions containing free fatty acids as active antibacterial agents were prepared by using various natural waxes and characterized. The effects of different waxes, such as carnauba wax, ozokerite wax, laurel wax, beeswax, rice bran wax, candelilla wax and microcrystalline wax, in the concentration range of 1% to 5% (w/w on the ointment texture, consistency and stability were evaluated. The results showed significant variations in texture, sensory and rheological profiles. This was attributed to the wax’s nature and chain composition. Microcrystalline wax gave the best results but laurel wax, beeswax and rice bran wax exhibited excellent texturing, similar sensory profiles and well-balanced rheological properties.

  7. The primary structure of fatty-acid-binding protein from nurse shark liver. Structural and evolutionary relationship to the mammalian fatty-acid-binding protein family.

    Science.gov (United States)

    Medzihradszky, K F; Gibson, B W; Kaur, S; Yu, Z H; Medzihradszky, D; Burlingame, A L; Bass, N M

    1992-02-01

    The primary structure of a fatty-acid-binding protein (FABP) isolated from the liver of the nurse shark (Ginglymostoma cirratum) was determined by high-performance tandem mass spectrometry (employing multichannel array detection) and Edman degradation. Shark liver FABP consists of 132 amino acids with an acetylated N-terminal valine. The chemical molecular mass of the intact protein determined by electrospray ionization mass spectrometry (Mr = 15124 +/- 2.5) was in good agreement with that calculated from the amino acid sequence (Mr = 15121.3). The amino acid sequence of shark liver FABP displays significantly greater similarity to the FABP expressed in mammalian heart, peripheral nerve myelin and adipose tissue (61-53% sequence similarity) than to the FABP expressed in mammalian liver (22% similarity). Phylogenetic trees derived from the comparison of the shark liver FABP amino acid sequence with the members of the mammalian fatty-acid/retinoid-binding protein gene family indicate the initial divergence of an ancestral gene into two major subfamilies: one comprising the genes for mammalian liver FABP and gastrotropin, the other comprising the genes for mammalian cellular retinol-binding proteins I and II, cellular retinoic-acid-binding protein myelin P2 protein, adipocyte FABP, heart FABP and shark liver FABP, the latter having diverged from the ancestral gene that ultimately gave rise to the present day mammalian heart-FABP, adipocyte FABP and myelin P2 protein sequences. The sequence for intestinal FABP from the rat could be assigned to either subfamily, depending on the approach used for phylogenetic tree construction, but clearly diverged at a relatively early evolutionary time point. Indeed, sequences proximately ancestral or closely related to mammalian intestinal FABP, liver FABP, gastrotropin and the retinoid-binding group of proteins appear to have arisen prior to the divergence of shark liver FABP and should therefore also be present in elasmobranchs

  8. Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease: Is the Liver Another Target?

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    Aibek eMirrakhimov

    2012-10-01

    Full Text Available Obstructive sleep apnea (OSA is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH. OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD. NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH, liver fibrosis and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure (CPAP treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1 IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA flux into the liver; (2 IH up-regulates lipid biosynthetic pathways in the liver; (3 IH induces oxidative stress in the liver; (4 IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

  9. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease

    Science.gov (United States)

    Gentile, Christopher L.; Nivala, Angela M.; Gonzales, Jon C.; Pfaffenbach, Kyle T.; Wang, Dong; Wei, Yuren; Jiang, Hua; Orlicky, David J.; Petersen, Dennis R.; Maclean, Kenneth N.

    2011-01-01

    The incidence of obesity is now at epidemic proportions and has resulted in the emergence of nonalcoholic fatty liver disease (NAFLD) as a common metabolic disorder that can lead to liver injury and cirrhosis. Excess sucrose and long-chain saturated fatty acids in the diet may play a role in the development and progression of NAFLD. One factor linking sucrose and saturated fatty acids to liver damage is dysfunction of the endoplasmic reticulum (ER). Although there is currently no proven, effective therapy for NAFLD, the amino sulfonic acid taurine is protective against various metabolic disturbances, including alcohol-induced liver damage. The present study was undertaken to evaluate the therapeutic potential of taurine to serve as a preventative treatment for diet-induced NAFLD. We report that taurine significantly mitigated palmitate-mediated caspase-3 activity, cell death, ER stress, and oxidative stress in H4IIE liver cells and primary hepatocytes. In rats fed a high-sucrose diet, dietary taurine supplementation significantly reduced hepatic lipid accumulation, liver injury, inflammation, plasma triglycerides, and insulin levels. The high-sucrose diet resulted in an induction of multiple components of the unfolded protein response in the liver consistent with ER stress, which was ameliorated by taurine supplementation. Treatment of mice with the ER stress-inducing agent tunicamycin resulted in liver injury, unfolded protein response induction, and hepatic lipid accumulation that was significantly ameliorated by dietary supplementation with taurine. Our results indicate that dietary supplementation with taurine offers significant potential as a preventative treatment for NAFLD. PMID:21957160

  10. PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver.

    Science.gov (United States)

    Demers, Annie; Samami, Samaneh; Lauzier, Benjamin; Des Rosiers, Christine; Ngo Sock, Emilienne Tudor; Ong, Huy; Mayer, Gaetan

    2015-12-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor thereby elevating plasma low-density lipoprotein cholesterol levels and the risk of coronary heart disease. Thus, the use of PCSK9 inhibitors holds great promise to prevent heart disease. Previous work found that PCSK9 is involved in triglyceride metabolism, independently of its action on low-density lipoprotein receptor, and that other yet unidentified receptors could mediate this effect. Therefore, we assessed whether PCSK9 enhances the degradation of CD36, a major receptor involved in transport of long-chain fatty acids and triglyceride storage. Overexpressed or recombinant PCSK9 induced CD36 degradation in cell lines and primary adipocytes and reduced the uptake of the palmitate analog Bodipy FL C16 and oxidized low-density lipoprotein in 3T3-L1 adipocytes and hepatic HepG2 cells, respectively. Surface plasmon resonance, coimmunoprecipitation, confocal immunofluorescence microscopy, and protein degradation pathway inhibitors revealed that PCSK9 directly interacts with CD36 and targets the receptor to lysosomes through a mechanism involving the proteasome. Importantly, the level of CD36 protein was increased by >3-fold upon small interfering RNA knockdown of endogenous PCSK9 in hepatic cells and similarly increased in the liver and visceral adipose tissue of Pcsk9(-/-) mice. In Pcsk9(-/-) mice, increased hepatic CD36 was correlated with an amplified uptake of fatty acid and accumulation of triglycerides and lipid droplets. Our results demonstrate an important role of PCSK9 in modulating the function of CD36 and triglyceride metabolism. PCSK9-mediated CD36 degradation may serve to limit fatty acid uptake and triglyceride accumulation in tissues, such as the liver. © 2015 American Heart Association, Inc.

  11. Effects of Eleutherococcus senticosus Cortex on Recovery from the Forced Swimming Test and Fatty Acid β-Oxidation in the Liver and Skeletal Muscle of mice.

    Science.gov (United States)

    Sumiyoshi, Maho; Kimura, Yoshiyuki

    2016-03-01

    The root and stem barks of Eleutherococcus senticosus have been used to treat emotional and physical fatigue in China, Russia, Korea, and Japan. The effects of E. senticosus on recovery from physical fatigue and the expenditure of energy currently remain unclear. We herein examined the effects of E. senticosus extract on recovery from physical fatigue after the forced swimming test as well as fatty acid β-oxidation in the liver and skeletal muscle of mice. 1) Physical fatigue; E. senticosus extract (500 and 1000 mg/kg, twice daily) was administered orally to ICR male mice for 7 consecutive days. After swimming had been performed for 15 min, each mouse was placed on the cover of a 100-mm culture plate, and the time for each mouse to move away from the cover was measured. 2) Fatty acid β-oxidation in the liver and skeletal muscle; E. senticosus extract (500 and 1000 mg/kg) was administered orally twice daily to C57BL/6J male mice for 21 consecutive days. The initial and final body and liver weight were measured, and then fatty acid β-oxidation activity in the liver and skeletal muscle was measured by methods using [1- 14 C] palmitic acid. Recovery times after forced swimming were shorter in E. senticosus extract (500 and 1000 mg/kg)-treated mice than in vehicle-treated mice. The body and liver weight had no effect by the oral administration of E. senticosus extract, vitamin mixture and L-carnitine. Fatty acid β-oxidation activity in skeletal muscle was increased by E. senticosus extract (500 and 1000 mg/kg). E. senticosus may enhance recovery from physical fatigue induced by forced swimming by accelerating energy changes through fatty acid β-oxidation in skeletal muscle.

  12. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy.

    Science.gov (United States)

    Cussons, Andrea J; Watts, Gerald F; Mori, Trevor A; Stuckey, Bronwyn G A

    2009-10-01

    There is an association between nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS). Marine-derived omega-3 fatty acids have favorable effects on cardiovascular risk and could reduce liver fat in NAFLD. The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors. We conducted a randomized, crossover study at a tertiary cardiovascular research center. Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m(2)) participated in the study. We compared 4g/d of omega-3 fatty acids with placebo over 8 wk. The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure. Omega-3 fatty acids significantly decreased liver fat content compared with placebo [10.2 (1.1) vs. 8.4 (0.9)%; P = 0.022]. There was also a reduction in triglycerides [1.19 (1.03-1.47) vs. 1.02 (0.93-1.18) mmol/liter; P = 0.002], systolic blood pressure [124.1 (12.1) vs. 122.3 (14.5) mm Hg; P = 0.018], and diastolic blood pressure [73.2 (8.4) vs. 69.7 (8.3) mm Hg; P = 0.005] with omega-3 fatty acids compared with placebo. Omega-3 fatty acids particularly decreased hepatic fat in women with hepatic steatosis, defined as liver fat percentage greater than 5% [18.2 (11.1) vs. 14.8 (9.3)%; P = 0.03]. Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. Whether this translates into a reduction in cardiometabolic events warrants further study.

  13. Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

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    Jieun Lee

    2016-06-01

    Full Text Available The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−, an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.

  14. Ginger Essential Oil Ameliorates Hepatic Injury and Lipid Accumulation in High Fat Diet-Induced Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Lai, Yi-Syuan; Lee, Wan-Ching; Lin, Yu-En; Ho, Chi-Tang; Lu, Kuan-Hung; Lin, Shih-Hang; Panyod, Suraphan; Chu, Yung-Lin; Sheen, Lee-Yan

    2016-03-16

    The objective of this study was to investigate the hepatoprotective efficacy and mechanism of action of ginger essential oil (GEO) against the development of nonalcoholic fatty liver disease (NAFLD). Mice were maintained on either a control diet or high-fat diet (HFD) supplemented with GEO (12.5, 62.5, and 125 mg/kg) or citral (2.5 and 25 mg/kg) for 12 weeks. We demonstrated that GEO and its major component (citral) lowered HFD-induced obesity in a dose-dependent manner, accompanied by anti-hyperlipidemic effects by reducing serum free fatty acid, triglyceride, and total cholesterol levels. Moreover, liver histological results showed that administration of 62.5 and 125 mg/kg GEO and 25 mg/kg citral significantly reduced hepatic lipid accumulation. Further assessment by Western blotting and investigation of the lipid metabolism revealed that hepatic protein expression of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and cytochrome P450 2E1 (CYP2E1) were down-regulated by GEO and citral, indicating that GEO and citral suppressed HFD-stimulated lipid biosynthesis and oxidative stress. Furthermore, GEO and citral effectively enhanced the antioxidant capacities and reduced inflammatory response in mouse liver, which exerted protective effects against steatohepatitis. Collectively, GEO and citral exhibited potent hepatoprotective effects against NAFLD induced by HFD in obese mice. Thus, GEO might be an effective dietary supplement to ameliorate NAFLD-related metabolic diseases, and citral could play a vital role in its management.

  15. Isolation and characterization of fatty acid binding protein in the liver of the nurse shark, Ginglymostoma cirratum.

    Science.gov (United States)

    Bass, N M; Manning, J A; Luer, C A

    1991-01-01

    1. A 14.5 kDa fatty acid binding protein was isolated from the liver of the nurse shark, Ginglymostoma cirratum. 2. Purified shark liver FABP (pI = 5.4) bound oleic acid at a single site with an affinity similar to that of mammalian FABP. 3. The apparent size, pI and amino acid composition of shark liver FABP indicate a close structural relationship between this protein and mammalian heart FABP.

  16. Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Dongxia Fu

    2018-03-01

    Full Text Available Background/Aims: Non-alcoholic fatty liver disease (NAFLD is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2 is involved in high fat diet (HFD-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT, aspartate transaminase (AST and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA, triglyceride (TG, total cholesterol (TC, ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS, HMG-CoA reductase (HMGCR and acetyl-Coenzyme A carboxylase (ACCα. In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing Cl

  17. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

    Czech Academy of Sciences Publication Activity Database

    Lake, A.D.; Novák, Petr; Shipkova, P.; Aranibar, N.; Robertson, D.G.; Reily, M.D.; Lehman-McKeeman, L.D.; Vaillancourt, R.R.; Cherrington, N.J.

    2015-01-01

    Roč. 47, č. 3 (2015), s. 603-615 ISSN 0939-4451 Institutional support: RVO:60077344 Keywords : Branched chain amino acid * nonalcoholic fatty liver disease * nonalcoholic steatohepatitis * metabolomics and transcriptomics Subject RIV: CE - Biochemistry Impact factor: 3.196, year: 2015

  18. Influence of maternal dietary n-3 fatty acids on breast milk and liver lipids of rat dams and offspring - a preliminary study

    DEFF Research Database (Denmark)

    Hartvigsen, M.S.; Mu, Huiling; Høy, Carl-Erik

    2003-01-01

    The impact of triacylglycerol (TAG) structure and level of n-3 fatty acids on the fatty acid profile of total breast milk lipids and total liver phospholipids (PL) of dams and offspring (1, 3 and 13 weeks of age), when administered during development, was examined. Pregnant rats were fed experime......The impact of triacylglycerol (TAG) structure and level of n-3 fatty acids on the fatty acid profile of total breast milk lipids and total liver phospholipids (PL) of dams and offspring (1, 3 and 13 weeks of age), when administered during development, was examined. Pregnant rats were fed...... experimental diets from the 8(th) day of pregnancy throughout lactation. After weaning and until 13 weeks of age, the offspring were fed the same diet as their dams. The experimental diets contained either a specific structured oil, linseed oil or fish oil. In the specific structured oil, a-linolenic acid (18...... fatty acids. Samples from three animals in each group were analyzed. The highest level of 22:6n-3 in the breast milk was obtained with diets containing this fatty acid itself. The fatty acid profile of rat dam liver PL was very different from the milk lipids indicating that the maternal dietary fats...

  19. Homozygous and heterozygous GH transgenesis alters fatty acid composition and content in the liver of Amago salmon (Oncorhynchus masou ishikawae

    Directory of Open Access Journals (Sweden)

    Manabu Sugiyama

    2012-08-01

    Growth hormone (GH transgenic Amago (Oncorhynchus masou ishikawae, containing the sockeye GH1 gene fused with metallothionein-B promoter from the same species, were generated and the physiological condition through lipid metabolism compared among homozygous (Tg/Tg and heterozygous GH transgenic (Tg/+ Amago and the wild type control (+/+. Previously, we have reported that the adipose tissue was generally smaller in GH transgenic fish compared to the control, and that the Δ-6 fatty acyl desaturase gene was down-regulated in the Tg/+ fish. However, fatty acid (FA compositions have not been measured previously in these fish. In this study we compared the FAs composition and content in the liver using gas chromatography. Eleven kinds of FA were detected. The composition of saturated and monounsaturated fatty acids (SFA and MUFA such as myristic acid (14:0, palmitoleic acid (16:1n-7, and cis-vaccenic acid (cis-18:1n-7 was significantly (P<0.05 decreased in GH transgenic Amago. On the other hand, the composition of polyunsaturated fatty acids (PUFAs such as linoleic acid (18:2n-6, arachidonic acid (20:4n-6, and docosapentaenoic acid (22:5n-3 was significantly (P<0.05 increased. Levels of serum glucose and triacylglycerol were significantly (P<0.05 decreased in the GH transgenics compared with +/+ fish. Furthermore, 3′-tag digital gene expression profiling was performed using liver tissues from Tg/Tg and +/+ fish, and showed that Mid1 interacting protein 1 (Mid1ip1, which is an important factor to activate Acetyl-CoA carboxylase (ACC, was down-regulated in Tg/Tg fish, while genes involved in FA catabolism were up-regulated, including long-chain-fatty-acid–CoA ligase 1 (ACSL1 and acyl-coenzyme A oxidase 3 (ACOX3. These data suggest that liver tissue from GH transgenic Amago showed starvation by alteration in glucose and lipid metabolism due to GH overexpression. The decrease of serum glucose suppressed Mid1ip1, and caused a decrease of de novo FA synthesis, resulting

  20. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.

    Science.gov (United States)

    Larter, Claire Z; Yeh, Matthew M; Haigh, W Geoffrey; Van Rooyen, Derrick M; Brooling, John; Heydet, Deborah; Nolan, Christopher J; Teoh, Narci C; Farrell, Geoffrey C

    2013-06-01

    Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. We sought to establish how dietary composition contributes to NASH pathogenesis. foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. Copyright © 2013 The Obesity Society.

  1. Modulation of intestinal and liver fatty acid-binding proteins in Caco-2 cells by lipids, hormones and cytokines.

    NARCIS (Netherlands)

    Dube, N.; Delvin, E.; Yotov, W.; Garofalo, C.; Bendayan, M.; Veerkamp, J.H.; Levy, E.

    2001-01-01

    Intestinal and liver fatty acid binding proteins (I- and L-FABP) are thought to play a role in enterocyte fatty acid (FA) trafficking. Their modulation by cell differentiation and various potential effectors was investigated in the human Caco-2 cell line. With the acquisition of enterocytic

  2. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet.

    Science.gov (United States)

    Raubenheimer, Peter J; Nyirenda, Moffat J; Walker, Brian R

    2006-07-01

    Liver fat accumulation is proposed to link obesity and insulin resistance. To dissect the role of liver fat in the insulin resistance of diet-induced obesity, we altered liver fat using a choline-deficient diet. C57Bl/6 mice were fed a low-fat (10% of calories) or high-fat (45% of calories) diet for 8 weeks; during the final 4 weeks, diets were either choline deficient or choline supplemented. In choline replete animals, high-fat feeding induced weight gain, elevated liver triglycerides (171%), hyperinsulinemia, and glucose intolerance. Choline deficiency did not affect body or adipose depot weights but amplified liver fat accumulation with high-fat diet (281%, P insulin (from 983 +/- 175 to 433 +/- 36 pmol/l, P phosphatidylcholine synthesis and of enzymes involved in free fatty acid esterification, without affecting those of de novo lipogenesis or fatty acid oxidation. We conclude that liver fat accumulation per se does not cause insulin resistance during high-fat feeding and that choline deficiency may shunt potentially toxic free fatty acids toward innocuous storage triglyceride in the liver.

  3. The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys.

    Directory of Open Access Journals (Sweden)

    Sheo B Singh

    Full Text Available Platensimycin (PTM is a natural antibiotic produced by Streptomyces platensis that selectively inhibits bacterial and mammalian fatty acid synthase (FAS without affecting synthesis of other lipids. Recently, we reported that oral administration of PTM in mouse models (db/db and db/+ with high de novo lipogenesis (DNL tone inhibited DNL and enhanced glucose oxidation, which in turn led to net reduction of liver triglycerides (TG, reduced ambient glucose, and improved insulin sensitivity. The present study was conducted to explore translatability and the therapeutic potential of FAS inhibition for the treatment of diabetes in humans.We tested PTM in animal models with different DNL tones, i.e. intrinsic synthesis rates, which vary among species and are regulated by nutritional and disease states, and confirmed glucose-lowering efficacy of PTM in lean NHPs with quantitation of liver lipid by MRS imaging. To understand the direct effect of PTM on liver metabolism, we performed ex vivo liver perfusion study to compare FAS inhibitor and carnitine palmitoyltransferase 1 (CPT1 inhibitor.The efficacy of PTM is generally reproduced in preclinical models with DNL tones comparable to humans, including lean and established diet-induced obese (eDIO mice as well as non-human primates (NHPs. Similar effects of PTM on DNL reduction were observed in lean and type 2 diabetic rhesus and lean cynomolgus monkeys after acute and chronic treatment of PTM. Mechanistically, PTM lowers plasma glucose in part by enhancing hepatic glucose uptake and glycolysis. Teglicar, a CPT1 inhibitor, has similar effects on glucose uptake and glycolysis. In sharp contrast, Teglicar but not PTM significantly increased hepatic TG production, thus caused liver steatosis in eDIO mice.These findings demonstrate unique properties of PTM and provide proof-of-concept of FAS inhibition having potential utility for the treatment of diabetes and related metabolic disorders.

  4. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Derdak, Zoltan; Villegas, Kristine A; Harb, Ragheb; Wu, Annie M; Sousa, Aryanna; Wands, Jack R

    2013-04-01

    p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  5. Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles.

    Directory of Open Access Journals (Sweden)

    Amany K Elshorbagy

    Full Text Available Although reduced glutathione (rGSH is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors, cysteine and glutamate. Plasma total cysteine (tCys is positively associated with stearoyl-coenzyme A desaturase (SCD activity and adiposity in humans and animal models.To explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice.Male C3H/HeH mice aged 11 weeks were fed a high-fat diet with or without BSO in drinking water (30 mmol/L for 8 weeks. Amino acid and fatty acid changes were assessed, as well as food consumption, energy expenditure, locomotor activity, body composition and liver vacuolation (steatosis.Despite higher food intake, BSO decreased particularly fat mass but also lean mass (both P<0.001, and prevented fatty liver vacuolation. Physical activity increased during the dark phase. BSO decreased plasma free fatty acids and enhanced insulin sensitivity. BSO did not alter liver rGSH, but decreased plasma total GSH (tGSH and rGSH (by ~70%, and liver tGSH (by 82%. Glutamate accumulated in plasma and liver. Urine excretion of cysteine and its precursors was increased by BSO. tCys, rCys and cystine decreased in plasma (by 23-45%, P<0.001 for all, but were maintained in liver, at the expense of decreased taurine. Free and total plasma concentrations of the SCD products, oleic and palmitoleic acids were decreased (by 27-38%, P <0.001 for all.Counterintuitively, block of GSH synthesis decreases circulating tCys, raising the question of whether the BSO-induced obesity-resistance is linked to cysteine depletion. Cysteine-supplementation of BSO-treated mice is warranted to dissect the effects of cysteine and GSH depletion on energy metabolism.

  6. A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Trasino, Steven E; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J

    2016-10-01

    Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies. • Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD.

  7. Recent insights into the biological functions of liver fatty acid binding protein 1

    Science.gov (United States)

    Wang, GuQi; Bonkovsky, Herbert L.; de Lemos, Andrew; Burczynski, Frank J.

    2015-01-01

    Over four decades have passed since liver fatty acid binding protein (FABP)1 was first isolated. There are few protein families for which most of the complete tertiary structures, binding properties, and tissue occurrences are described in such detail and yet new functions are being uncovered for this protein. FABP1 is known to be critical for fatty acid uptake and intracellular transport and also has an important role in regulating lipid metabolism and cellular signaling pathways. FABP1 is an important endogenous cytoprotectant, minimizing hepatocyte oxidative damage and interfering with ischemia-reperfusion and other hepatic injuries. The protein may be targeted for metabolic activation through the cross-talk among many transcriptional factors and their activating ligands. Deficiency or malfunction of FABP1 has been reported in several diseases. FABP1 also influences cell proliferation during liver regeneration and may be considered as a prognostic factor for hepatic surgery. FABP1 binds and modulates the action of many molecules such as fatty acids, heme, and other metalloporphyrins. The ability to bind heme is another cytoprotective property and one that deserves closer investigation. The role of FABP1 in substrate availability and in protection from oxidative stress suggests that FABP1 plays a pivotal role during intracellular bacterial/viral infections by reducing inflammation and the adverse effects of starvation (energy deficiency). PMID:26443794

  8. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Pengtao [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China); University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049 (China); Huang, Zhen [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021 (China); Wei, Taotao, E-mail: weitt@moon.ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101 (China)

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the number of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.

  9. Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Sonja M. Kessler

    2014-04-01

    Full Text Available Non-alcoholic steatohepatitis (NASH represents a risk factor for the development of hepatocellular carcinoma (HCC and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice. Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.

  10. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine

    DEFF Research Database (Denmark)

    Artmann, Andreas; Petersen, Gitte; Hellgren, Lars

    2008-01-01

    and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high...... (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic...... acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum...

  11. Fatty Acid–Regulated Transcription Factors in the Liver

    Science.gov (United States)

    Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

    2014-01-01

    Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

  12. Fatty Liver Disease

    Science.gov (United States)

    What is fatty liver disease? Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. Fatty liver disease is a condition in which fat builds ...

  13. The Peroxisomal Enzyme L-PBE Is Required to Prevent the Dietary Toxicity of Medium-Chain Fatty Acids

    Directory of Open Access Journals (Sweden)

    Jun Ding

    2013-10-01

    Full Text Available Specific metabolic pathways are activated by different nutrients to adapt the organism to available resources. Although essential, these mechanisms are incompletely defined. Here, we report that medium-chain fatty acids contained in coconut oil, a major source of dietary fat, induce the liver ω-oxidation genes Cyp4a10 and Cyp4a14 to increase the production of dicarboxylic fatty acids. Furthermore, these activate all ω- and β-oxidation pathways through peroxisome proliferator activated receptor (PPAR α and PPARγ, an activation loop normally kept under control by dicarboxylic fatty acid degradation by the peroxisomal enzyme L-PBE. Indeed, L-pbe−/− mice fed coconut oil overaccumulate dicarboxylic fatty acids, which activate all fatty acid oxidation pathways and lead to liver inflammation, fibrosis, and death. Thus, the correct homeostasis of dicarboxylic fatty acids is a means to regulate the efficient utilization of ingested medium-chain fatty acids, and its deregulation exemplifies the intricate relationship between impaired metabolism and inflammation.

  14. Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice.

    Science.gov (United States)

    Lohr, Kerstin; Pachl, Fiona; Moghaddas Gholami, Amin; Geillinger, Kerstin E; Daniel, Hannelore; Kuster, Bernhard; Klingenspor, Martin

    2016-10-01

    Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial-derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle-aged mice. Susceptibility to diet-induced obesity increased with age. Young adult and middle-aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age-related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat-fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid-derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet-induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  15. In vivo 19F-MRS observation of 5-FU metabolism in fatty liver induced by choline-deficient diet

    International Nuclear Information System (INIS)

    Otsuka, Hideki; Harada, Masafumi; Nishitani, Hiromu; Koga, Keiko.

    1996-01-01

    Using 19 F-MRS, 5-FU metabolism was investigated in rat fatty liver. Fatty liver was induced by choline-deficient diet (CD diet). This study showed differences in 5-FU metabolism between normal and fatty liver. After laparotomy, a surface coil was placed directly on the liver surface. Spectra were continuously obtained after injection of 5-FU 100 mg/kg body weight via a catheter inserted into femoral vein. We made MRI and 1 H-MRS study to examine the lipid accumulation. Histological study was also performed using HE (hematoxylin-eosin) and oil red stain. The livers of rats fed a CD diet showed very high intensity on T 1 -WI. 1 H-MRS was very useful in deteminating the fat content because the fat ratio demonstrated by 1 H-MRS is well correlated to histological findings. In 19 F-MRS, we recognized the following four peaks: 5-FU, FBAL, Fnct (fluoronucleotide) and FUPA. The decrease of 5-FU was not very apparent, but compared to the normal liver, the formation of Fnct increased and the formation of FBAL was suppressed in fatty liver. The rats fed a CD diet for four weeks showed a higher Fnct peak and lower FBAL peak compared with the results of rats fed a CD diet for two weeks. In a CD diet group, liver cell degeneration and necrotic changes were observed histologically. It is reported that cell degeneration is followed by cell proliferation in fatty liver induced by a choline deficient diet, and the high Fnct peak found in our study may reflect this phenomenon. The high Fnct peak on 19 F-MRS may correspond to recovering reaction from liver injury like fatty liver. (author)

  16. Diagnosis of fatty liver

    International Nuclear Information System (INIS)

    Saitoh, Shuichi; Nagamine, Takeaki; Takagi, Hitoshi

    1988-01-01

    Diagnostic values of various ultrasonographic findings were evaluated from fatty infiltration ratio calculated by liver specimens in 42 patients. The ratio of the CT number of liver to those of spleen were also compared with fatty infiltration ratio in 11 patients. Fatty bandless sign one plus (perirenal bright echo between the liver and the right kidney is masked partially) or more and the fatty score 3 (it is calculated by several ultrasonographic findings) and the less than 0.90 of the ratio of CT number of liver to those of spleen were useful for diagnosis of fatty liver, the sensitivity was 100%, 87.5%, 85.7% and the accuracy was 78.1%, 81.8%, 81.8% respectively. It was considered that these criteria were suitable in screening study of fatty liver. (author)

  17. Modulation of hepatic steatosis by dietary fatty acids

    Science.gov (United States)

    Ferramosca, Alessandra; Zara, Vincenzo

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and⁄or conflicting results in animal models. PMID:24587652

  18. Modulation of hepatic steatosis by dietary fatty acids.

    Science.gov (United States)

    Ferramosca, Alessandra; Zara, Vincenzo

    2014-02-21

    Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the "case" of olive oil, since several studies have often provided different and/or conflicting results in animal models.

  19. Lipopolysaccharide derived from the rumen down-regulates stearoyl-CoA desaturase 1 expression and alters fatty acid composition in the liver of dairy cows fed a high-concentrate diet.

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    Xu, Tianle; Tao, Hui; Chang, Guangjun; Zhang, Kai; Xu, Lei; Shen, Xiangzhen

    2015-03-07

    Dairy cows are often fed a high-concentrate diet to meet lactating demands, yet long-term concentrate feeding induces subacute ruminal acidosis (SARA) and leads to a decrease in milk fat. Stearoyl-CoA desaturase1 (SCD1) participates in fatty acid biosynthesis in the liver of lactating ruminants. Here, we conducted this study to investigate the impact of lipopolysaccharide derived from the rumen on SCD1 expression and on fatty acid composition in the liver of dairy cows fed a high-concentrate diet. Eight multiparous mid-lactating Holstein cows (455 ± 28 kg) were randomly assigned into two groups in the experiment and were fed a low-concentrate diet (LC) or high-concentrate diet (HC) for 18 weeks. The results showed that the total volatile fatty acids and lactic acid accumulated in the rumen, leading to a decreased rumen pH and elevated lipopolysaccharides (LPSs) in the HC group. The long chain fatty acid profile in the rumen and hepatic vein was remarkably altered in the animals fed the HC diet. The triglyceride (TG), non-esterified fatty acid (NEFA) and total cholesterol (TCH) content in the plasma was significantly decreased, whereas plasma glucose and insulin levels were increased. The expression of SCD1 in the liver was significantly down-regulated in the HC group. In regards to transcriptional regulators, the expression of sterol regulatory element binding transcription factors (SREBF1c, SREBF2) and SREBP cleavage activating protein (SCAP) was down-regulated, while peroxisome proliferator-activated receptor α (PPARα) was up-regulated. These data indicate that lipopolysaccharide derived from the rumen down-regulates stearoyl-CoA desaturase 1 expression and alters fatty acid composition in the liver of dairy cows fed a high-concentrate diet.

  20. Comparative Analysis of EPA/DHA-PL Forage and Liposomes in Orotic Acid-Induced Nonalcoholic Fatty Liver Rats and Their Related Mechanisms.

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    Chang, Mengru; Zhang, Tiantian; Han, Xiuqing; Tang, Qingjuan; Yanagita, Teruyoshi; Xu, Jie; Xue, Changhu; Wang, Yuming

    2018-02-14

    Nonalcoholic fatty liver disease (NAFLD) has become one predictive factor of death from various illnesses. The present study was to comparatively investigate the effects of eicosapentaenoic acid-enriched and docosahexaenoic acid-enriched phospholipids forage (EPA-PL and DHA-PL) and liposomes (lipo-EPA and lipo-DHA) on NAFLD and demonstrate the possible protective mechanisms involved. The additive doses of EPA-PL and DHA-PL in all treatment groups were 1% of total diets, respectively. The results showed that Lipo-EPA could significantly improve hepatic function by down-regulating orotic acid-induced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels by 55.6% and 34.2%, respectively (p DHA could also significantly suppress hepatic lipid accumulation mainly by enhancement of hepatic lipolysis and cholesterol efflux. Furthermore, DHA-PL played a certain role in inhibiting hepatic lipogenesis and accelerating cholesterol efflux. The results obtained in this work might contribute to the understanding of the biological activities of EPA/DHA-PL and liposomes and further investigation on its potential application values for food supplements.

  1. Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress.

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    Li, Bing-Hang; He, Fang-Ping; Yang, Xin; Chen, Yuan-Wen; Fan, Jian-Gao

    2017-02-01

    The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) has become one of the major public health threats in China and worldwide. However, during the development of NAFLD, the key mechanism underlying the progression of related fibrosis remains unclear, which greatly impedes the development of optimal NAFLD therapy. In the current study, we were endeavored to characterize a proinflammatory cytokine, CCL5, as a major contributor for fibrosis in NAFLD. The results showed that CCL5 was highly expressed in fatty liver and NASH patients. In NAFLD rats induced by 8-week-HFD, CCL5 and its receptor, CCR5, were significantly up-regulated and liver fibrosis exclusively occurred in this group. In addition, we showed that hepatocytes are the major source contributing to this CCL5 elevation. Interestingly, a CCL5 inhibitor Met-CCL5, significantly decreased liver fibrosis but not hepatic steatosis. Using a cell model of hepatic steatosis, we found that the conditioned medium of lipid-overloaded hepatocytes (Fa2N-4 cells) which produced excessive CCL5 stimulated the profibrotic activities of hepatic stellate cells (LX-2) as manifested by increased migration rate, proliferation and collagen production of LX-2 cells. CCL5 knockdown in Fa2N-4 cells, Met-CCL5 or CCR5 antibody treatment on LX-2 cells all significantly inhibited the conditioned medium of FFA-treated Fa2N-4 cells to exert stimulatory effects on LX-2 cells. Consistently, the conditioned medium of Fa2N-4 cells with CCL5 over-expression significantly enhanced migration rate, cell proliferation and collagen production of LX-2 cells. All these results support that CCL5 produced by steatotic hepatocytes plays an essential role in fibrotic signaling machinery of NAFLD. In addition, we were able to identify C/EBP-β as the up-stream regulator of CCL5 gene transcription in hepatocytes treated with free fatty acid (FFA). Our data strongly supported that CCL5 plays a pivotal regulatory role in

  2. Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

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    Ting Chen

    2016-01-01

    Full Text Available Recent experimental studies and clinical trials have shown that hepatic cholesterol metabolic disorders are closely related to the development of nonalcoholic fatty liver disease (NAFLD. The main goal of this study was to investigate the efficacy of the perilla oil rich in alpha-linolenic acid (ALA against NASH and gain a deep insight into its potential mechanisms. Rats were fed a high-fat/high-cholesterol diet (HFD supplement with perilla oil (POH for 16 weeks. Routine blood biochemical tests and histological staining illustrated that the perilla oil administration improved HFD-induced hyperlipidemia, reduced hepatic steatosis, and inhibited hepatic inflammatory infiltration and fibrosis. Perilla oil also increased fecal bile acid and cholesterol excretion. Hepatic RNA-Seq analysis found that the long time perilla oil supplement notably modified the gene expression involved in cholesterol metabolism. Our results implicate that, after long-term high level dietary cholesterol feeding, rat liver endogenous synthesis of cholesterol and cholesterol-rich low density lipoprotein uptake was significantly inhibited, and perilla oil did not modulate expression of genes responsible for cholesterol synthesis but did increase cholesterol removed from hepatocytes by conversion to bile acids and increased fecal cholesterol excretion.

  3. Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease.

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    Nobili, Valerio; Carpino, Guido; Alisi, Anna; De Vito, Rita; Franchitto, Antonio; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool. 20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters. GPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines. DHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

  4. Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease.

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    Valerio Nobili

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA, the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool.20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters.GPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii the reduction of the number of inflammatory macrophages; iv the increase of GPR120 expression in hepatocytes; v the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines.DHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

  5. Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells

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    Sawada Keisuke

    2012-03-01

    Full Text Available Abstract Background Fatty acid-induced insulin resistance and impaired glucose uptake activity in muscle cells are fundamental events in the development of type 2 diabetes and hyperglycemia. There is an increasing demand for compounds including drugs and functional foods that can prevent myocellular insulin resistance. Methods In this study, we established a high-throughput assay to screen for compounds that can improve myocellular insulin resistance, which was based on a previously reported non-radioisotope 2-deoxyglucose (2DG uptake assay. Insulin-resistant muscle cells were prepared by treating rat L6 skeletal muscle cells with 750 μM palmitic acid for 14 h. Using the established assay, the impacts of several fatty acids on myocellular insulin resistance were determined. Results In normal L6 cells, treatment with saturated palmitic or stearic acid alone decreased 2DG uptake, whereas unsaturated fatty acids did not. Moreover, co-treatment with oleic acid canceled the palmitic acid-induced decrease in 2DG uptake activity. Using the developed assay with palmitic acid-induced insulin-resistant L6 cells, we determined the effects of other unsaturated fatty acids. We found that arachidonic, eicosapentaenoic and docosahexaenoic acids improved palmitic acid-decreased 2DG uptake at lower concentrations than the other unsaturated fatty acids, including oleic acid, as 10 μM arachidonic acid showed similar effects to 750 μM oleic acid. Conclusions We have found that polyunsaturated fatty acids, in particular arachidonic and eicosapentaenoic acids prevent palmitic acid-induced myocellular insulin resistance.

  6. Lack of phosphatidylethanolamine N-methyltransferase in mice does not promote fatty acid oxidation in skeletal muscle.

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    Tasseva, Guergana; van der Veen, Jelske N; Lingrell, Susanne; Jacobs, René L; Vance, Dennis E; Vance, Jean E

    2016-02-01

    Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. Mice lacking PEMT are protected from high-fat diet-induced obesity and insulin resistance, and exhibit increased whole-body energy expenditure and oxygen consumption. Since skeletal muscle is a major site of fatty acid oxidation and energy utilization, we determined if rates of fatty acid oxidation/oxygen consumption in muscle are higher in Pemt(-/-) mice than in Pemt(+/+) mice. Although PEMT is abundant in the liver, PEMT protein and activity were undetectable in four types of skeletal muscle. Moreover, amounts of PC and PE in the skeletal muscle were not altered by PEMT deficiency. Thus, we concluded that any influence of PEMT deficiency on skeletal muscle would be an indirect consequence of lack of PEMT in liver. Neither the in vivo rate of fatty acid uptake by muscle nor the rate of fatty acid oxidation in muscle explants and cultured myocytes depended upon Pemt genotype. Nor did PEMT deficiency increase oxygen consumption or respiratory function in skeletal muscle mitochondria. Thus, the increased whole body oxygen consumption in Pemt(-/-) mice, and resistance of these mice to diet-induced weight gain, are not primarily due to increased capacity of skeletal muscle for utilization of fatty acids as an energy source. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  7. Dietary β-conglycinin prevents fatty liver induced by a high-fat diet by a decrease in peroxisome proliferator-activated receptor γ2 protein.

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    Yamazaki, Tomomi; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

    2012-02-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). Mice fed a high-fat diet, especially that of saturated-fat-rich oil, develop fatty liver with an increase in peroxisome proliferator-activated receptor (PPAR) γ2 protein in liver. The fatty liver induced by a high-fat diet is improved by knockdown of liver PPARγ2. In this study, we investigated whether β-conglycinin (a major protein of soy protein) could reduce PPARγ2 protein and prevent high-fat-diet-induced fatty liver in ddY mice. Mice were fed a high-starch diet (70 energy% [en%] starch) plus 20% (wt/wt) sucrose in their drinking water or a high-safflower-oil diet (60 en%) or a high-butter diet (60 en%) for 11 weeks, by which fatty liver is developed. As a control, mice were fed a high-starch diet with drinking water. Either β-conglycinin or casein (control) was given as dietary protein. β-Conglycinin supplementation completely prevented fatty liver induced by each type of diet, along with a reduction in adipose tissue weight. β-Conglycinin decreased sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) messenger RNAs (mRNAs) in sucrose-supplemented mice, whereas it decreased PPARγ2 mRNA (and its target genes CD36 and FSP27), but did not decrease SREBP-1c and ChREBP mRNAs, in mice fed a high-fat diet. β-Conglycinin decreased PPARγ2 protein and liver triglyceride (TG) concentration in a dose-dependent manner in mice fed a high-butter diet; a significant decrease in liver TG concentration was observed at a concentration of 15 en%. In conclusion, β-conglycinin effectively prevents fatty liver induced by a high-fat diet through a decrease in liver PPARγ2 protein. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Hepatic unsaturated fatty acids in patients with non-alcoholic fatty liver disease assessed by 3.0 T MR spectroscopy

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    Werven, J.R. van, E-mail: j.r.vanwerven@amc.uva.n [Department of Radiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands); Schreuder, T.C.M.A. [Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam (Netherlands); Nederveen, A.J.; Lavini, C. [Department of Radiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands); Jansen, P.L.M. [AMC Liver Center/Department of Hepatology, Academic Medical Center, Amsterdam (Netherlands); Stoker, J. [Department of Radiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands)

    2010-08-15

    Rationale and objective: Non-alcoholic fatty liver disease (NAFLD) is related to the metabolic syndrome and obesity. Proton magnetic resonance spectroscopy ({sup 1}H MRS) is a non-invasive technique to assess hepatic triglyceride content (HTGC) and allows assessment of unsaturated fatty acids (UFA). There is increasing evidence that hepatic UFA are associated with the development of NAFLD. Therefore the objective of this study was to assess hepatic UFA in patients with NAFLD using {sup 1}H MRS. Materials and methods: We included 26 consecutive patients with deranged liver enzymes, with and without type 2 diabetes mellitus (DM2), suspected for NAFLD. Liver function and metabolic parameters were assessed. {sup 1}H MRS measurements were performed at 3.0 T. From the {sup 1}H MR spectra two ratios were calculated: ratio 1 (UFA); unsaturated fatty acid peak vs. reference water peak and ratio 2 (HTGC); total fatty acid peak vs. reference water peak. Results: Twenty-six patients were included. In these patients hepatic UFA (ratio 1) correlated with AST/ALT ratio (r = -0.46, p = 0.02), glucose levels (r = 0.46, p = 0.018), HOMA-IR (r = 0.59, p = 0.004) and HTGC (r = 0.81, p < 0.001). In diabetic patients (n = 12) hepatic UFA correlated with alkaline phosphatase levels (r = 0.72, p = 0.01), HOMA-IR (r = 0.73, p = 0.01) and HTGC (r = 0.83, p = 0.002). Compared to non-diabetic patients with NAFLD, hepatic UFA levels were increased in patients with DM2 and NAFLD (0.032 vs. 0.014, p = 0.03). Conclusion: Hepatic UFA can be assessed with {sup 1}H MRS. {sup 1}H MRS determined hepatic UFA correlate with clinical and metabolic parameters associated with NAFLD. Hepatic UFA are increased in patients with DM2. This study provides evidence for the use of non-invasive {sup 1}H MRS to assess hepatic UFA in vivo.

  9. Foxa1 reduces lipid accumulation in human hepatocytes and is down-regulated in nonalcoholic fatty liver.

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    Marta Moya

    Full Text Available Triglyceride accumulation in nonalcoholic fatty liver (NAFL results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB. Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.

  10. Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease.

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    Sulin Cheng

    Full Text Available Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49 and women (n = 52 with and without NAFLD.Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS. Serum samples were analyzed using a nuclear magnetic resonance (NMR metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR. Muscle protein expression was analyzed by Western blot.Increased branched-chain amino acid (BCAA, aromatic amino acid (AAA and orosomucoid were associated with liver fat accumulation already in its early stage, independent of sex, obesity or insulin resistance (p<0.05 for all. Significant down-regulation of BCAA catabolism and fatty acid and energy metabolism was observed in the adipose tissue of the NAFLD group (p<0.001for all, whereas no aberrant gene expression in the skeletal muscle was found. Reduced BCAA catabolic activity was inversely associated with serum BCAA and liver fat content (p<0.05 for all.Liver fat accumulation, already in its early stage, is associated with increased serum branched-chain and aromatic amino acids. The observed associations of decreased BCAA catabolism activity, mitochondrial energy metabolism and serum BCAA concentration with liver fat content suggest that adipose tissue dysfunction may have a key role in the systemic nature of NAFLD pathogenesis.

  11. Omega-9 Oleic Acid Induces Fatty Acid Oxidation and Decreases Organ Dysfunction and Mortality in Experimental Sepsis.

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    Cassiano Felippe Gonçalves-de-Albuquerque

    Full Text Available Sepsis is characterized by inflammatory and metabolic alterations, which lead to massive cytokine production, oxidative stress and organ dysfunction. In severe systemic inflammatory response syndrome, plasma non-esterified fatty acids (NEFA are increased. Several NEFA are deleterious to cells, activate Toll-like receptors and inhibit Na+/K+-ATPase, causing lung injury. A Mediterranean diet rich in olive oil is beneficial. The main component of olive oil is omega-9 oleic acid (OA, a monounsaturated fatty acid (MUFA. We analyzed the effect of OA supplementation on sepsis. OA ameliorated clinical symptoms, increased the survival rate, prevented liver and kidney injury and decreased NEFA plasma levels in mice subjected to cecal ligation and puncture (CLP. OA did not alter food intake and weight gain but diminished reactive oxygen species (ROS production and NEFA plasma levels. Carnitine palmitoyltransferase IA (CPT1A mRNA levels were increased, while uncoupling protein 2 (UCP2 liver expression was enhanced in mice treated with OA. OA also inhibited the decrease in 5' AMP-activated protein kinase (AMPK expression and increased the enzyme expression in the liver of OA-treated mice compared to septic animals. We showed that OA pretreatment decreased NEFA concentration and increased CPT1A and UCP2 and AMPK levels, decreasing ROS production. We suggest that OA has a beneficial role in sepsis by decreasing metabolic dysfunction, supporting the benefits of diets high in monounsaturated fatty acids (MUFA.

  12. Analysis of mRNA expression of genes related to fatty acids synthesis in goose fatty liver

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    Shuxia Xiang

    2010-11-01

    Full Text Available The aim of our study was to evaluate the effect of overfeeding on mRNA expression levels of genes involved in lipogenesis, in order to understand the mechanism of hepatic stea - tosis in the goose. Using Landes geese (Anser anser and Sichuan White geese (Anser cygnoides as experimental animals, we quantified the mRNA expression of lipogenic genes, acetyl-CoA carboxylase-α (ACCα and fatty acid synthase (FAS, and of two transcription factors, sterol regulatory element-binding proteins- 1 (SREBP-1 and carbohydrate responsive element-binding protein (ChREBP by real-time polymerase chain reaction (RTPCR, and measured the lipid and triglyceride (TG content in the liver and the plasma level of glucose, insulin and TG. Our results indicated that compared to the control group, the overfeeding induced an increase of the lipid and TG content in the liver and also of the plasma insulin and TG concentration in both breeds. However, the plasma glucose level decreased after overfeeding in the Sichuan White goose, and there was no evident change in the Landes goose. Lastly, the mRNA expression of ACCα, FAS, SREBP-1 and ChREBP in the overfed group was lower than in the control group in both breeds. We concluded that the lipogenesis pathway plays a role in overfeeding- induced hepatic steatosis and that the decreased mRNA level of related genes may be the indicator of hepatic steatosis.

  13. Chlorophyll-derived fatty acids regulate expression of lipid metabolizing enzymes in liver - a nutritional opportunity

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    Wolfrum Christian

    2001-01-01

    Full Text Available Nutritional values of fatty acid classes are normally discussed on the basis of their saturated, monounsaturated and polyunsaturated structures with implicit understanding that they are straight-chain. Here we focus on chlorophyll-derived phytanic and pristanic acids that are minor isoprenoid branched-chain lipid constituents in food, but of unknown nutritional value. After describing the enzyme machinery that degrades these nutrient fatty acids in the peroxisome, we show by the criteria of a mouse model and of a human cell culture model that they induce with high potency expression of enzymes responsible for beta-oxidation of straight-chain fatty acids in the peroxisome. We summarize present mechanistic knowledge on fatty acid signaling to the nucleus, which involves protein/protein contacts between peroxisome proliferator activated receptor (PPAR and fatty acid binding protein (FABP. In this signaling event the branched-chain fatty acids are the most effective ones. Finally, on the basis of this nutrient-gene interaction we discuss nutritional opportunities and therapeutic aspects of the chlorophyll-derived fatty acids.

  14. A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation.

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    Bjørndal, Bodil; Berge, Christ; Ramsvik, Marie Sannes; Svardal, Asbjørn; Bohov, Pavol; Skorve, Jon; Berge, Rolf K

    2013-10-07

    There is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα). hTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma. The n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal β-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice. The FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.

  15. Effects of Stigmasterol and β-Sitosterol on Nonalcoholic Fatty Liver Disease in a Mouse Model: A Lipidomic Analysis.

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    Feng, Simin; Gan, Ling; Yang, Chung S; Liu, Anna B; Lu, Wenyun; Shao, Ping; Dai, Zhuqing; Sun, Peilong; Luo, Zisheng

    2018-04-04

    To study the effects of stigmasterol and β-sitosterol on high-fat Western diet (HFWD)-induced nonalcoholic fatty liver disease (NAFLD), lipidomic analyses were conducted in liver samples collected after 33 weeks of the treatment. Principal component analysis showed these phytosterols were effective in protecting against HFWD-induced NAFLD. Orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and S-plots showed that triacylglycerols (TGs), phosphatidylcholines, cholesteryl esters, diacylglycerols, and free fatty acids (FFAs) were the major lipid species contributing to these discriminations. The alleviation of NAFLD is mainly associated with decreases in hepatic cholesterol, TGs with polyunsaturated fatty acids, and alterations of free hepatic FFA. In conclusion, phytosterols, at a dose comparable to that suggested for humans by the FDA for the reduction of plasma cholesterol levels, are shown to protect against NAFLD in this long-term (33-week) study.

  16. Lipotoxic effect of p21 on free fatty acid-induced steatosis in L02 cells.

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    Jie-wei Wang

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is increasingly regarded as a hepatic manifestation of metabolic syndrome. Though with high prevalence, the mechanism is poorly understood. This study aimed to investigate the effects of p21 on free fatty acid (FFA-induced steatosis in L02 cells. We therefore analyzed the L02 cells with MG132 and siRNA treatment for different expression of p21 related to lipid accumulation and lipotoxicity. Cellular total lipid was stained by Oil Red O, while triglyceride content, cytotoxicity assays, lipid peroxidation markers and anti-oxidation levels were measured by enzymatic kits. Treatment with 1 mM FFA for 48 hr induced magnificent intracellular lipid accumulation and increased oxidative stress in p21 overload L02 cells compared to that in p21 knockdown L02 cells. By increasing oxidative stress and peroxidation, p21 accelerates FFA-induced lipotoxic effect in L02 cells and might provide information about potentially new targets for drug development and treatments of NAFLD.

  17. Gene polymorphisms of desaturase enzymes of polyunsaturated fatty acid metabolism and adiponutrin and the increased risk of nonalcoholic fatty liver disease

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    Manvi Vernekar; Deepak Amarapurkar; Kalpana Joshi; Rekha Singhal

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome (MetS). Adiponutrin gene polymorphisms have been associated with NAFLD worldwide. Polyunsaturated fatty acids (PUFAs) have been studied to have anti-inflammatory effects and plasma lipid lowering properties. PUFAs are endogenously synthesized with the help of delta-6-desaturase and delta-5-desaturase enzymes. They are encoded by FADS2 and FADS1 genes respectively. Polymorphisms in ...

  18. Sodium 4-phenylbutyrate prevents murine dietary steatohepatitis caused by trans-fatty acid plus fructose.

    Science.gov (United States)

    Morinaga, Maki; Kon, Kazuyoshi; Saito, Hiroaki; Arai, Kumiko; Kusama, Hiromi; Uchiyama, Akira; Yamashina, Shunhei; Ikejima, Kenichi; Watanabe, Sumio

    2015-11-01

    Excess consumption of trans-fatty acid could increase the risk of non-alcoholic steatohepatitis (NASH); however, treatment targeting trans-fatty acid-induced NASH has not been examined. Here we focused on the influence of trans-fatty acid intake on endoplasmic reticulum (ER) stress in hepatocytes, so we investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA), on trans-fatty acid-caused steatohepatitis using diabetic KK-A(y) mice. Elaidic acid (EA, trans-fatty acid) alone did not cause definitive liver injury. In contrast, EA plus low-dose fructose induced extensive apoptosis in hepatocytes with severe fat accumulation. EA plus fructose significantly increased ER stress markers such as glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2α (eIF2α) and phosphorylated c-jun N-terminal kinase (JNK), while PBA significantly reduced this response. In vitro, EA promoted expression of GRP78 and phosphorylation of eIF2α in primary-cultured hepatocytes. EA also increased hepatocellular susceptibility to low-dose tert-butyl hydroperoxide. Treatment with PBA significantly reduced these responses. In conclusion, EA potentiates susceptibly to non-hazardous dose of fructose, and increases ER and oxidative stress. PBA improved steatohepatitis induced by EA plus fructose through amelioration of ER stress. Therefore, ER stress-targeted therapy using a chemical chaperone is a promising novel strategy for trans-fatty acid-induced steatohepatitis.

  19. n-3 fatty acid-based parenteral nutrition improves postoperative recovery for cirrhotic patients with liver cancer: A randomized controlled clinical trial.

    Science.gov (United States)

    Zhang, Binhao; Wei, Gang; Li, Rui; Wang, Yanjun; Yu, Jie; Wang, Rui; Xiao, Hua; Wu, Chao; Leng, Chao; Zhang, Bixiang; Chen, Xiao-Ping

    2017-10-01

    A new lipid emulsion enriched in n-3 fatty acid has been reported to prevent hepatic inflammation in patients following major surgery. However, the role of n-3 fatty acid-based parenteral nutrition for postoperative patients with cirrhosis-related liver cancer is unclear. We investigated the safety and efficacy of n-3 fatty acid-based parenteral nutrition for cirrhotic patients with liver cancer followed hepatectomy. A prospective randomized controlled clinical trial (Registered under ClinicalTrials.gov Identifier no. NCT02321202) was conducted for cirrhotic patients with liver cancer that underwent hepatectomy between March 2010 and September 2013 in our institution. We compared isonitrogenous total parenteral nutrition with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for five days postoperatively, in the absence of enteral nutrition. We enrolled 320 patients, and 312 (97.5%) were included in analysis (155 in the control group and 157 in the treatment group). There was a significant reduction of morbidity and mortality in the treatment group, when compared with the control group (total complications 78 [50.32%] vs. 46 [29.30%]; P parenteral nutrition significantly improved postoperative recovery for cirrhotic patients with liver cancer following hepatectomy, with a significant reduction in overall mortality and length of hospital stay. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  20. Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway.

    Science.gov (United States)

    Chen, H L; Tsai, T C; Tsai, Y C; Liao, J W; Yen, C C; Chen, C M

    2016-12-12

    In recent years, people have changed their eating habits, and high-fructose-containing bubble tea has become very popular. High-fructose intake has been suggested to be a key factor that induces non-alcoholic fatty liver disease (NAFLD). Kefir, a fermented milk product composed of microbial symbionts, has demonstrated numerous biological activities, including antibacterial, antioxidant and immunostimulating effects. The present study aims to evaluate the effects of kefir peptides on high-fructose-induced hepatic steatosis and the possible molecular mechanism. An animal model of 30% high-fructose-induced NAFLD in C57BL/6J mice was established. The experiment is divided into the following six groups: (1) normal: H 2 O drinking water; (2) mock: H 2 O+30% fructose; (3) KL: low-dose kefir peptides (50 mg kg -1 )+30% fructose; (4) KM: medium-dose kefir peptides (100 mg kg -1 )+30% fructose; (5) KH: high-dose kefir peptides (150 mg kg -1 )+30% fructose; and (6) CFM: commercial fermented milk (100 mg kg -1 )+30% fructose. The results show that kefir peptides improve fatty liver syndrome by decreasing body weight, serum alanine aminotransferase, triglycerides, insulin and hepatic triglycerides, cholesterol, and free fatty acids as well as the inflammatory cytokines (TNF-α, IL-6 and IL-1β) that had been elevated in fructose-induced NAFLD mice. In addition, kefir peptides markedly increased phosphorylation of AMPK to downregulate its targeted enzymes, ACC (acetyl-CoA carboxylase) and SREBP-1c (sterol regulatory element-binding protein 1), and inhibited de novo lipogenesis. Furthermore, kefir peptides activated JAK2 to stimulate STAT3 phosphorylation, which can translocate to the nucleus, and upregulated several genes, including the CPT1 (carnitine palmitoyltransferase-1) involved in fatty acid oxidation. Our data have demonstrated that kefir peptides can improve the symptoms of NAFLD, including body weight, energy intake, inflammatory reaction and the

  1. Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway

    Science.gov (United States)

    Chen, H L; Tsai, T C; Tsai, Y C; Liao, J W; Yen, C C; Chen, C M

    2016-01-01

    Objective: In recent years, people have changed their eating habits, and high-fructose-containing bubble tea has become very popular. High-fructose intake has been suggested to be a key factor that induces non-alcoholic fatty liver disease (NAFLD). Kefir, a fermented milk product composed of microbial symbionts, has demonstrated numerous biological activities, including antibacterial, antioxidant and immunostimulating effects. The present study aims to evaluate the effects of kefir peptides on high-fructose-induced hepatic steatosis and the possible molecular mechanism. Results: An animal model of 30% high-fructose-induced NAFLD in C57BL/6J mice was established. The experiment is divided into the following six groups: (1) normal: H2O drinking water; (2) mock: H2O+30% fructose; (3) KL: low-dose kefir peptides (50 mg kg−1)+30% fructose; (4) KM: medium-dose kefir peptides (100 mg kg−1)+30% fructose; (5) KH: high-dose kefir peptides (150 mg kg−1)+30% fructose; and (6) CFM: commercial fermented milk (100 mg kg−1)+30% fructose. The results show that kefir peptides improve fatty liver syndrome by decreasing body weight, serum alanine aminotransferase, triglycerides, insulin and hepatic triglycerides, cholesterol, and free fatty acids as well as the inflammatory cytokines (TNF-α, IL-6 and IL-1β) that had been elevated in fructose-induced NAFLD mice. In addition, kefir peptides markedly increased phosphorylation of AMPK to downregulate its targeted enzymes, ACC (acetyl-CoA carboxylase) and SREBP-1c (sterol regulatory element-binding protein 1), and inhibited de novo lipogenesis. Furthermore, kefir peptides activated JAK2 to stimulate STAT3 phosphorylation, which can translocate to the nucleus, and upregulated several genes, including the CPT1 (carnitine palmitoyltransferase-1) involved in fatty acid oxidation. Conclusion: Our data have demonstrated that kefir peptides can improve the symptoms of NAFLD, including body weight, energy intake

  2. Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

    Science.gov (United States)

    Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

    1999-04-01

    Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

  3. Molecular pathways in non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Berlanga A

    2014-07-01

    Full Text Available Alba Berlanga,1,* Esther Guiu-Jurado,1,* José Antonio Porras,1,2 Teresa Auguet1,21Group GEMMAIR (AGAUR and Applied Medicine Research Group, Department of Medicine and Surgery, Universitat Rovira i Virgili (URV, IISPV, Hospital Universitari Joan XXIII, Tarragona, Spain; 2Department of Internal Medicine, Hospital Universitari Joan XXIII Tarragona, Tarragona, Spain *These authors contributed equally to this workAbstract: Non-alcoholic fatty liver disease (NAFLD is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the "double-hit" hypothesis. The primary insult or the "first hit" includes lipid accumulation in the liver, followed by a "second hit" in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA

  4. Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

    Science.gov (United States)

    Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

    2017-08-01

    The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.

  5. Relationship between nonalcoholic fatty liver disease and adipocyte fatty acid-binding protein

    Directory of Open Access Journals (Sweden)

    ZHOU Xiaoli

    2013-12-01

    Full Text Available ObjectiveTo investigate the relationship between nonalcoholic fatty liver disease (NAFLD and serum level of adipocyte fatty acid-binding protein (AFABP. MethodsA total of 160 patients who underwent physical examination in the Affiliated Hospital of Ningxia Medical University from July to November 2010 were included in our study. These subjects were divided into two groups according to the diagnostic criteria for NAFLD formulated by the Chinese Medical Association: control group (n=71 and NAFLD group (n=89. The two groups were compared with respect to general condition, body mass index (BMI, blood pressure, AFABP, serum insulin, and other serological indices. The relationship of serum AFABP with NAFLD and other metabolic parameters was analyzed using the Spearman linear correlation coefficient. Comparison of measurement data was made by t test and rank sum test; comparison of enumeration data was made by chi-square test. ResultsThere were more males than females in the NAFLD group. Compared with the control group, the NAFLD group had higher BMI and levels of blood glucose, triglyceride (TG, aspartate aminotransferase (AST, alanine aminotransferase (ALT, and uric acid and lower high-density lipoprotein (HDL level; in addition, the NAFLD group had significantly higher serum AFABP and insulin levels and homeostasis model assessment-estimated insulin resistance (HOMA-IR. The Spearman correlation analysis showed that serum AFABP was positively correlated with NAFLD, BMI, HOMA-IR, serum insulin, blood glucose, TG, ALT, AST, and uric acid but negatively correlated with HDL. After adjustment for sex, age, and BMI, serum AFABP was positively correlated with NAFLD, HOMA-IR, serum insulin, blood glucose, TG, ALT, and uric acid, but had no significant correlation with HDL and AST. ConclusionSerum AFABP is closely associated with NAFLD and may be an independent plasma marker of this disease. AFABP plays a causative role in the pathogenesis of NAFLD.

  6. Quantitative evaluation of fatty liver by computed tomography in rabbits

    International Nuclear Information System (INIS)

    Kawata, R.; Sakata, K.; Kunieda, T.; Saji, S.; Doi, H.; Nozawa, Y.

    1984-01-01

    Biochemical, histologic, and computed tomographic (CT) examinations of the liver were performed in 32 rabbits in which fatty liver was induced by prolonged intravenous fat infusion. In two groups of rabbits, in which 2 and 4 g/kg/day of fat emulsion was administered, respectively, posttreatment reduction in CT value of mild degree was observed. In the group that received 8 g/kg/day of fat emulsion, posttreatment change in CT value was sufficient for a diagnosis of fatty liver of moderate degree. Reduction in CT value in fatty liver might be due largely to accumulation of triglyceride and cholesterol in the liver cells. Significant correlation was found between changes in CT value of the liver and degrees of histological fat accumulation in the liver cells. Consecutive measurement of CT values of the liver during prolonged intravenous hyperalimentation is a nonagressive method of diagnosing fatty liver

  7. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

    Directory of Open Access Journals (Sweden)

    Wonbeak Yoo

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

  8. Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver

    Directory of Open Access Journals (Sweden)

    Tao Zeng

    2018-04-01

    Full Text Available Protein kinase B (PKB/Akt plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD. Previous studies suggest that cytochrome P4502E1 (CYP2E1 plays causal roles in the pathogenesis of alcoholic fatty liver (AFL. We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K and phosphatase and tensin homologue deleted on chromosome ten (PTEN, and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1 protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA and 4-hydroxynonenal (4-HNE-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ, an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2 cells compared with the negative control HepG2 (NC-HepG2 cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1 significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver. Keywords

  9. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    International Nuclear Information System (INIS)

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu; Yoo, Kyeong-Won; Song, Seung Ryel; Park, Do-Sim; So, Hong-Seob; Park, Raekil

    2013-01-01

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation

  10. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Yoo, Kyeong-Won [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Immune-network Pioneer Research Center, Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Song, Seung Ryel [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Do-Sim [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Department of Laboratory of Medicine, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); So, Hong-Seob [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Raekil [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)

    2013-12-06

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

  11. Effects of varying levels of n-6:n-3 fatty acid ratio on plasma fatty acid ...

    African Journals Online (AJOL)

    This study investigated the effects of varying dietary levels of n-6:n-3 fatty acid ratio on plasma fatty acid composition and prostanoid synthesis in pregnant rats. Four groups consisting of seven rats per group of non pregnant rats were fed diets with either a very low n-6:n-3 ratio of 50% soybean oil (SBO): 50% cod liver oil ...

  12. Protective role of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats.

    Science.gov (United States)

    Naresh Kumar, Rajendran; Sundaram, Ramalingam; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2013-01-05

    Hyperlipidemia is an associated complication of diabetes mellitus. The association of hyperglycemia with an alteration of lipid parameters presents a major risk for cardiovascular complications in diabetes. The present study was designed to examine the antihyperlipidemic effect of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats. The levels of blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, high density lipoprotein, lipoprotein lipase, lecithin cholesterol acyl transferase, 3-hydroxy 3-methylglutaryl coenzyme A reductase and fatty acid composition were estimated in plasma, liver and kidneys of control and experimental groups of rats. Oral administration of 20-OH ecdysone at a dose of 5mg/kg bodyweight per day to STZ-induced diabetic rats for a period of 30 days resulted in a significant reduction in fasting blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, 3-hydroxy 3-methylglutaryl coenzyme A reductase and elevation of high density lipoprotein, lipoprotein lipase and lecithin cholesterol acyl transferasein comparison with diabetic untreated rats. Moreover, administration of 20-OH ecdysone to diabetic rats also decreased the concentrations of fatty acids, viz., palmitic, stearic (16:1) and oleic acid (18:1), whereas linolenic (18:3) and arachidonic acid (20:4) were elevated. The antihyperlipidemic effect of 20-OH ecdysone was compared with glibenclamide a well-known antihyperglycemic drug. The result of the present study indicates that 20-OH ecdysone showed an antihyperlipidemic effect in addition to its antidiabetic effect in experimental diabetes. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Association of Blood Fatty Acid Composition and Dietary Pattern with the Risk of Non-Alcoholic Fatty Liver Disease in Patients Who Underwent Cholecystectomy.

    Science.gov (United States)

    Shim, Poyoung; Choi, Dongho; Park, Yongsoon

    2017-01-01

    The relationship between diet and non-alcoholic fatty liver disease (NAFLD) in patients with gallstone disease and in those who have a high risk for NAFLD has not been investigated. This study was conducted to investigate the association between the risk of NAFLD and dietary pattern in patients who underwent cholecystectomy. Additionally, we assessed the association between erythrocyte fatty acid composition, a marker for diet, and the risk of NAFLD. Patients (n = 139) underwent liver ultrasonography to determine the presence of NAFLD before laparoscopic cholecystectomy, reported dietary intake using food frequency questionnaire, and were assessed for blood fatty acid composition. Fifty-eight patients were diagnosed with NAFLD. The risk of NAFLD was negatively associated with 2 dietary patterns: consuming whole grain and legumes and consuming fish, vegetables, and fruit. NAFLD was positively associated with the consumption of refined grain, meat, processed meat, and fried foods. Additionally, the risk of NAFLD was positively associated with erythrocyte levels of 16:0 and 18:2t, while it was negatively associated with 20:5n3, 22:5n3, and Omega-3 Index. The risk of NAFLD was negatively associated with a healthy dietary pattern of consuming whole grains, legumes, vegetables, fish, and fruit and with an erythrocyte level of n-3 polyunsaturated fatty acids rich in fish. © 2017 S. Karger AG, Basel.

  14. Fish oil alleviated high-fat diet-induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: a transcriptomic study.

    Science.gov (United States)

    Yuan, Fahu; Wang, Hualin; Tian, Yu; Li, Qi; He, Lei; Li, Na; Liu, Zhiguo

    2016-02-01

    Intake of fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) is believed to be beneficial against development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. This study was to gain further understanding of the potential mechanisms of the protective effects of fish oil against NAFLD. Ten male Sprague-Dawley rats were fed a control diet (CON), a Western style high-fat and high-cholesterol diet (WD), or a WD diet containing fish oil (FOH) for 16 weeks respectively. The development of liver steatosis and fibrosis were verified by histological and biochemical examination. Hepatic transcriptome were extracted for RNA-seq analysis, and particular results were confirmed by real-time polymerase chain reaction (PCR). The consumption of fish oil significantly ameliorated WD-induced dyslipidemia, transaminase elevation, hepatic steatosis, inflammatory infiltration, and fibrosis. Hepatic RNA-Seq analysis showed that long-term intake of fish oil restored the expression of circadian clock-related genes per2 and per3, which were reduced in WD fed animals. Fish oil consumption also corrected the expression levels of genes involved in fatty acid and cholesterol metabolism, such as Srebf1, Fasn, Scd1, Insig2, Cd36, Cyp7a1, Abcg5, Abcg8 and Pcsk9. Moreover, the expression levels of pro-inflammation genes Mcp1, Socs2, Sema4a, and Cd44 in the FOH group were lower than that of WD group, implying that fish oil protects the liver against WD-induced hepatic inflammation. The present study demonstrates fish oil protects against WD-induced NALFD via improving lipid metabolism and ameliorating hepatic inflammation. Our findings add to the current understanding on the benefits of n-3 PUFAs against NAFLD.

  15. Nickel Inhibits Mitochondrial Fatty Acid Oxidation

    Science.gov (United States)

    Uppala, Radha; McKinney, Richard W.; Brant, Kelly A.; Fabisiak, James P.; Goetzman, Eric S.

    2015-01-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation—the pathway by which fatty acids are catabolized for energy—in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with L-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 hr), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  16. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

    Science.gov (United States)

    Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

    2017-12-01

    Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease

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    Jiyung Shin

    2013-11-01

    Full Text Available Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

  18. Omega-3 Fatty Acid Content in Various Tissues of Different Persian Gulf Fish

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    MJ Zibaee Nezhad

    2008-11-01

    Full Text Available Background: The fatty acids of omega-3 family have high nutritional value and can prevent coronary heart disease.These fatty acids are found in various fish and sea foods. To investigate the level of omega-3 fatty acids indifferent kind of fish head, muscle and liver from 30 species of fish collected from Persian Gulf.Material and Methods: In this experimental study, the fish were collected by hunting from Boushehr and Hormozgansea ports. Their head, muscle and liver fatty acids were determined on their methylated fatty acids dissolvedin N-hexin. Quantitative analysis of fatty acids was performed by gas chromatography (GC with methylmyristateused as the reference material in this analysis and the qualitative analysis of fatty acids was done bygas chromatography and mass spectrometer (GC- mass and cod liver oil which contained all of omega-3 fattyacids used as standard.Results: Our study showed that some fish were good sources of omega-3 fatty acids and Trout (Ghezel-ALA,Bartail flathead (Zaminkan-e-domnavari, Malabar blood snapper (Sorkhoo malabari had maximum levels ofomega-3 in all body tissues. Other types of fish were rich in omega 3 fatty acids in separate organs, such as liverin Bartail flathead (Zaminkan-e-domnavari, head in Sillago Sihama (Shoort and muscle in Trout (Ghezel-ALA. In contrast, lesser amount of omega 3 fatty acids is found in tissues of other species of fish such as Silverpomfret (Halva sefid, Longfin trevally (Gish-e-derazbale and Xiphophorus Hellerii (Dom-shamshiri.Conclusion: This research showed that the liver of fish had the highest level of omega-3 fatty acids and fish musclecontained more omega-3 fatty acids than the head. Thus for having maximum levels of omega-3 fatty acids inthe diet, all fish tissues can be served. As liver and head of fish are not usually consumed, it is recommended thatsuch organs be used for preparation of omega 3-containing cardio supportive supplements.

  19. Effect of L-ascorbic acid on nickel-induced alterations in serum lipid profiles and liver histopathology in rats.

    Science.gov (United States)

    Das, Kusal K; Gupta, Amrita Das; Dhundasi, Salim A; Patil, Ashok M; Das, Swastika N; Ambekar, Jeevan G

    2006-01-01

    Nickel exposure greatly depletes intracellular ascorbate and alters ascorbate-cholesterol metabolism. We studied the effect of the simultaneous oral treatment with L-ascorbic acid (50 mg/100 g body weight (BW) and nickel sulfate (2.0 mg/100 g BW, i.p) on nickelinduced changes in serum lipid profiles and liver histopathology. Nickel-treated rats showed a significant increase in serum low-density lipoprotein-cholesterol, total cholesterol, triglycerides, and a significant decrease in serum high-density lipoprotein-cholesterol. In the liver, nickel sulfate caused a loss of normal architecture, fatty changes, extensive vacuolization in hepatocytes, eccentric nuclei, and Kupffer cell hypertrophy. Simultaneous administration of L-ascorbic acid with nickel sulfate improved both the lipid profile and liver impairments when compared with rats receiving nickel sulfate only. The results indicate that L-ascorbic acid is beneficial in preventing nickel-induced lipid alterations and hepatocellular damage.

  20. Transcriptomic Changes in Liver of Young Bulls Caused by Diets Low in Mineral and Protein Contents and Supplemented with n-3 Fatty Acids and Conjugated Linoleic Acid.

    Directory of Open Access Journals (Sweden)

    Sara Pegolo

    Full Text Available The aim of the present study was to identify transcriptional modifications and regulatory networks accounting for physiological and metabolic responses to specific nutrients in the liver of young Belgian Blue × Holstein bulls using RNA-sequencing. A larger trial has been carried out in which animals were fed with different diets: 1] a conventional diet; 2] a low-protein/low-mineral diet (low-impact diet and 3] a diet enriched in n-3 fatty acids (FAs, conjugated linoleic acid (CLA and vitamin E (nutraceutical diet. The initial hypothesis was that the administration of low-impact and nutraceutical diets might influence the transcriptional profiles in bovine liver and the resultant nutrient fluxes, which are essential for optimal liver function and nutrient interconversion. Results showed that the nutraceutical diet significantly reduced subcutaneous fat covering in vivo and liver pH. Dietary treatments did not affect overall liver fat content, but significantly modified the liver profile of 33 FA traits (out of the total 89 identified by gas-chromatography. In bulls fed nutraceutical diet, the percentage of n-3 and CLA FAs increased around 2.5-fold compared with the other diets, whereas the ratio of n6/n3 decreased 2.5-fold. Liver transcriptomic analyses revealed a total of 198 differentially expressed genes (DEGs when comparing low-impact, nutraceutical and conventional diets, with the nutraceutical diet showing the greatest effects on liver transcriptome. Functional analyses using ClueGo and Ingenuity Pathway Analysis evidenced that DEGs in bovine liver were variously involved in energy reserve metabolic process, glutathione metabolism, and carbohydrate and lipid metabolism. Modifications in feeding strategies affected key transcription factors regulating the expression of several genes involved in fatty acid metabolism, e.g. insulin-induced gene 1, insulin receptor substrate 2, and RAR-related orphan receptor C. This study provides noteworthy

  1. Dietary Omega-3 Fatty Acid Deficiency and High Fructose Intake in the Development of Metabolic Syndrome, Brain Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Artemis P. Simopoulos

    2013-07-01

    Full Text Available Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS. Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD, promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.

  2. Effect of sulfonylureas on hepatic fatty acid oxidation

    International Nuclear Information System (INIS)

    Patel, T.B.

    1986-01-01

    In isolated rat livers perfused with oleic acid (0.1 mM), infusion of tolbutamide or glyburide decreased the rate of ketogenesis in a dose-dependent manner. The inhibition of fatty acid oxidation was maximal at 2.0 mM and 10 μM concentrations of tolbutamide and glyburide, respectively. Neither tolbutamide nor glyburide inhibited ketogenesis in livers perfused with octanoate. The inhibition of hepatic ketogenesis by sulfonylureas was independent of perfusate oleic acid concentration. Additionally, in rat livers perfused with oleic acid in the presence of L-(-)-carnitine (10 mM), submaximal concentrations of tolbutamide and glyburide did not inhibit hepatic ketogenesis. Finally, glyburide infusion into livers perfused with [U- 1 $C]oleic acid (0.1 mM) increased the rate of 14 C label incorporation into hepatic triglycerides by 2.5-fold. These data suggest that both tolbutamide and glyburide inhibit long-chain fatty acid oxidation by inhibition the key regulatory enzyme, carnitine palmitoyltransferase I, most probably by competing with L-(-)-carnitine

  3. Clinical investigation of fatty liver by CT

    International Nuclear Information System (INIS)

    Kato, Katsumoto; Takayama, Tetsuo; Sano, Hiroshi; Katada, Naoyuki; Takeichi, Masayuki

    1984-01-01

    CT findings of 56 cases of diffuse fatty infiltration comfirmed by liver biopsy were investigated and compared with those of chronic hepatitis and liver cirrhosis. We found that the diagnosis of severe fatty infiltration (fatty liver) can be specifically possible when the ratios of CT values of liver to those of spleen are less than 0.85 and it is reasonable criterion for diagnosis of fatty liver by CT. This criterion was satisfied by 197 studies (2.9%), 169 cases with fatty liver (diffuse: 141 cases, focal: 28 cases) of 6800 CT studies of liver. Obesity, diabetes and alcohol abuse were main causative factors in both diffuse and focal fatty liver. The percentage of cases showing no abnormal results in blood chemistry tests was great compared with the previous report based on liver biopsy. The changes of CT values of liver faithfully reflected the improvement of each causal factor and reciprocal changes were observed between diffuse and focal fatty liver in repeated CT examination. So, CT is useful in estimating the effect of treatment as well as in diagnosis of fatty liver. Focal fatty liver is temporary manifestation during the proscess of development or improvement of fatty liver. (author)

  4. Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

    Science.gov (United States)

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

    2012-03-01

    The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. Copyright © 2010 Elsevier GmbH. All rights reserved.

  5. CT values of fatty liver due to L-asparaginase administration

    Energy Technology Data Exchange (ETDEWEB)

    Muraki, Kotaro; Kubo, Kazuaki; Hamamoto, Kazuko; Ueda, Kazuhiro; Kashiwado, Kozo; Ito, Katsuhide (Hiroshima Red Cross Hospital (Japan))

    1984-02-01

    Chemotherapy involving L-asparaginase was performed on a 9-year-old female child with malignant lymphoma, and a 3-year-old male child and a 14-year-old female child with acute lymphatic leukemia, and the course of L-asparaginase-induced fatty liver was followed up primarily by CT findings. In all 3 cases, L-asparaginase administration caused a marked fatty liver characterized by a diffuse cold area of the liver and a decrease in the value of the liver (liver/spleen<1) on CT. Hypoproteinemia, hypofibrinogenemia and elevations of GOT and GPT were simultaneously observed, but marked anemia, pancreatitis, decreased glucose tolerance and central nervous disorder did not occur. Recovery of fatty liver was slower in CT findings than in blood biochemistry, taking about 4 weeks.

  6. Biological study of some labeled C16 fatty acids

    Energy Technology Data Exchange (ETDEWEB)

    Riche, F.; Mathieu, J.P.; Busquet, G.; Vidal, M.; Comet, M.; Pernin, C. (C.H.R.U. de Grenoble, 38 - La Tronche (France)); Godart, J.; Benabed, A. (Institut des Sciences Nucleaires, 38 - Grenoble (France)); Bardy, A. (C.E.A.-ORIS, 91 - Gif-sur-Yvette (France))

    1983-01-01

    The evolution of myocardial, blood, liver and kidney activity is studied in mice after I.V. injection of some labelled C16 fatty acids. With ..omega.. iodo fatty acids, the presence or absence of a double bond and the character Z or E have no influence on the tissue activity. The presence of a triple bond decreases the fixation, modifies the intramyocardial metabolism of the fatty acid and accelerates the rate of decrease of myocardial activity. ..omega.. bromo fatty acid have the same maximal fixation as ..omega.. iodo fatty acid but a more rapid decrease of myocardial activity. ..cap alpha.. iodo fatty acid has a very low myocardial fixation.

  7. Biological study of some labeled C16 fatty acids

    International Nuclear Information System (INIS)

    Riche, F.; Mathieu, J.P.; Busquet, G.; Vidal, M.; Comet, M.; Pernin, C.; Godart, J.; Benabed, A.; Bardy, A.

    1983-01-01

    The evolution of myocardial, blood, liver and kidney activity is studied in mice after I.V. injection of some labelled C16 fatty acids. With ω iodo fatty acids, the presence or absence of a double bond and the character Z or E have no influence on the tissue activity. The presence of a triple bond decreases the fixation, modifies the intramyocardial metabolism of the fatty acid and accelerates the rate of decrease of myocardial activity. ω bromo fatty acid have the same maximal fixation as ω iodo fatty acid but a more rapid decrease of myocardial activity. α iodo fatty acid has a very low myocardial fixation [fr

  8. Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice.

    Science.gov (United States)

    Kim, Ja Kyung; Lee, Kwan Sik; Lee, Dong Ki; Lee, Su Yeon; Chang, Hye Young; Choi, Junjeong; Lee, Jung Il

    2014-12-19

    Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

  9. Metabolic profiling of fatty liver in young and middle‐aged adults: Cross‐sectional and prospective analyses of the Young Finns Study

    Science.gov (United States)

    Würtz, Peter; Suomela, Emmi; Lehtovirta, Miia; Kangas, Antti J.; Jula, Antti; Mikkilä, Vera; Viikari, Jorma S.A.; Juonala, Markus; Rönnemaa, Tapani; Hutri‐Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Soininen, Pasi; Ala‐Korpela, Mika; Raitakari, Olli T.

    2016-01-01

    Nonalcoholic fatty liver is associated with obesity‐related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis‐related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty‐eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population‐based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34‐49 years (19% prevalence). Cross‐sectional associations as well as 4‐year and 10‐year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P fatty acids including omega‐6 (OR = 0.37, 0.32‐0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491‐500). PMID:27775848

  10. Incorporation and fatty acid composition in liver of Nile tilapia fed with flaxseed oil - doi: 10.4025/actascitechnol.v33i2.7970

    Directory of Open Access Journals (Sweden)

    Polyana Batoqui França

    2011-04-01

    Full Text Available One of the most consumed freshwater fish in South America is Nile tilapia. The present study examined the effects of flaxseed oil (FO, source of alfa-linolenic acid (LNA, on the total lipid composition and polyunsaturated fatty acid, n-6 and n-3 PUFA, contents on Nile tilapia (Oreochromis niloticus liver. Tilapias were given diets with increasing levels 0.00, 1.2, 2.50, 3.75 and 5.00% (w w-1 of FO as a replacement of sunflower oil for five months. Fatty acids analysis of methyl esters revealed 45 fatty acids common to all treatments. The increase of flaxseed oil resulted in a decrease in total n-6 PUFA (35.1 to 21.1% and an increase in n-3 PUFA (3.3 to 18.5%. The diet with LNA underwent sequential desaturation and elongation in liver, leading to an increase in all n-3 PUFA and a decrease in n-6/n-3 ratios (10.7 to 1.1. The manipulation of fatty acids with FO may be used to increase n-3 PUFA and to help balance n-6/n-3 PUFA in dietary supplements, thus, the liver tilapia becomes one product with major nutritional value.

  11. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

    Science.gov (United States)

    Chow, Monica D; Lee, Yi-Horng; Guo, Grace L

    2017-08-01

    Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Analysis of the ligand binding properties of recombinant bovine liver-type fatty acid binding protein

    DEFF Research Database (Denmark)

    Rolf, B; Oudenampsen-Krüger, E; Börchers, T

    1995-01-01

    The coding part of the cDNA for bovine liver-type fatty acid binding protein (L-FABP) has been amplified by RT-PCR, cloned and used for the construction of an Escherichia coli (E. coli) expression system. The recombinant protein made up to 25% of the soluble E. coli proteins and could be isolated...

  13. Changes in cholesterol content and fatty acid composition of serum lipid in irradiated rat

    International Nuclear Information System (INIS)

    Ohashi, Shigeru

    1979-01-01

    The effect of a single dose of whole body irradiation on the serum cholesterol content and fatty acid composition of serum lipids in rats was investigated. A change in the fatty acid composition of liver lipids was also observed. After 600 rad of irradiation, the cholesterol content increased, reached a maximum 3 days after irradiation, and then decreased. After irradiation, an increase in cholesterol content and a marked decrease in triglyceride content were observed, bringing about a change in the amount of total serum lipids. The fatty acid compositions of normal and irradiated rat sera were compared. The relative percentages of palmitic and oleic acids in total lipids decreased while those of stearic and arachidonic acids increased. Serum triglyceride had trace amounts of arachidonic acid and the unsaturated fatty acid component decreased after irradiation. On the other hand, unsaturated fatty acid in cholesterol ester increased after irradiation, while linoleic and arachidonic acids made up 29% and 22% in the controls and 17% and 61% after irradiation, respectively. The fatty acid composition of total liver lipids after irradiation showed a decrease in palmitic and oleic acids and an increase in stearic and arachidonic acids, the same trend as observed in serum lipid fatty acid. Liver cholesterol ester showed trace amounts of linoleic and arachidonic acids and an increase in short-chain fatty acid after irradiation. The major component of serum phospholipids was phosphatidylcholine while palmitostearyl lecithine and unsaturated fatty acid were minor components. Moreover, phosphatidylcholine and phosphatidylethanolamine were the major components of liver phospholipids, having highly unsaturated fatty acids. The changes in fatty acid composition were similar to the changes in total phospholipids. (J.P.N.)

  14. Urine liver fatty acid binding protein and chronic kidney disease progression

    DEFF Research Database (Denmark)

    Khatir, Dinah S; Bendtsen, Mette D; Birn, Henrik

    2017-01-01

    , regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, 51Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L......Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR...

  15. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity.

    Science.gov (United States)

    Thupari, J N; Pinn, M L; Kuhajda, F P

    2001-07-13

    Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy. Copyright 2001 Academic Press.

  16. CT values of fatty liver due to L-asparaginase administration

    International Nuclear Information System (INIS)

    Muraki, Kotaro; Kubo, Kazuaki; Hamamoto, Kazuko; Ueda, Kazuhiro; Kashiwado, Kozo; Ito, Katsuhide

    1984-01-01

    Chemotherapy involving L-asparaginase was performed on a 9-year-old female child with malignant lymphoma, and a 3-year-old male child and a 14-year-old female child with acute lymphatic leukemia, and the course of L-asparaginase-induced fatty liver was followed up primarily by CT findings. In all 3 cases, L-asparaginase administration caused a marked fatty liver characterized by a diffuse cold area of the liver and a decrease in the value of the liver (liver/spleen<1) on CT. Hypoproteinemia, hypofibrinogenemia and elevations of GOT and GPT were simultaneously observed, but marked anemia, pancreatitis, decreased glucose tolerance and central nervous disorder did not occur. Recovery of fatty liver was slower in CT findings than in blood biochemistry, taking about 4 weeks. (Chiba, N.)

  17. Nonalcoholic Fatty Liver Disease Treatment

    Directory of Open Access Journals (Sweden)

    M Sadeghian

    2014-04-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is increasing in pediatric age group parallel to the growing prevalence of obesity and overweight all around the world. So changing in life style and   interventions on obesogenic environment is cornerstone of NAFLD therapy in obese children. Some experts recommend that children and adolescents be encouraged to follow a low-fat, low-glycemic-index diet that includes eating a minimum of 5 servings of vegetables and fruits daily, engaging in physical activity for at least 1 hour daily, and minimizing television/computer time to 2 hours daily.  In spite of effectiveness of weight loss and exercise in improvement NAFLD, this goal is very difficult to be achieved and pharmacological approaches have become necessary. Pharmacologic therapies against one or more specific factors and/or molecules involved in the development of NAFLD (i.e., insulin resistance, free fatty acid lipid toxicity, and oxidative stress also might slow the progression of NAFLD to NASH or cirrhosis.  On this basis, insulin sensitizers, antioxidants, cytoprotective agents, and dietary supplementations have been evaluated in pediatric clinical trials but there is no approved pharmacologic therapy for NAFLD or NASH. Not all obese children affected by NAFLD. Diet modification and regular exercise beside to serial medical follow up highly suggested for this group of children. Normal weight and thin children with NAFLD or NASH should be investigated appropriately in a logical manner based on causes of primary liver steatosis in children and treatment of underlying disease can cause improvement fatty liver in these patients.   Keywords: Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Children; Steatosis; Treatment

  18. Histopathologic Evaluation of Nonalcoholic Fatty Liver Disease in Hypothyroidism-Induced Rats

    Directory of Open Access Journals (Sweden)

    Şule Demir

    2016-01-01

    Full Text Available It is speculated that thyroid hormones may be involved in nonalcoholic fatty liver disease (NAFLD pathogenesis. A literature scan, however, demonstrated conflicting results from studies investigating the relationship between hypothyroidism and NAFLD. Therefore, our study aims to evaluate NAFLD, from the histopathologic perspective, in hypothyroidism-induced rats. Wistar rats were divided into 2 groups: the experimental group consumed water containing methimazole 0.025% (MMI, Sigma, USA for 12 weeks and the control group consumed tap water. At the end of week 12, serum glucose, ALT, AST, triglyceride, HDL, LDL, TSH, fT4, fT3, visfatin, and insulin assays were performed. Sections were stained with hematoxylin-eosin and “Oil Red-O” for histopathologic examination of the livers. In our study, we detected mild hepatosteatosis in all hypothyroidism-induced rats. There was statistically significant difference with respect to obesity between the two groups (p0.05. In conclusion, we found that hypothyroidism-induced rats had mild hepatosteatosis as opposed to the control group histopathologically. Our study indicates that hypothyroidism can cause NAFLD.

  19. Euterpe edulis Extract but Not Oil Enhances Antioxidant Defenses and Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Rats

    Directory of Open Access Journals (Sweden)

    Rodrigo Barros Freitas

    2016-01-01

    Full Text Available We investigated the effects of E. edulis bioproducts (lyophilized pulp [LEE], defatted lyophilized pulp [LDEE], and oil [EO] on nonalcoholic fatty liver disease (NAFLD induced by a high-fat diet (HFD in rats. All products were chemically analyzed. In vivo, 42 rats were equally randomized into seven groups receiving standard diet, HFD alone or combined with EO, LEE, or LDEE. After NAFLD induction, LEE, LDEE, or EO was added to the animals’ diet for 4 weeks. LEE was rich in polyunsaturated fatty acids. From LEE degreasing, LDEE presented higher levels of anthocyanins and antioxidant capacity in vitro. Dietary intake of LEE and especially LDEE, but not EO, attenuated diet-induced NAFLD, reducing inflammatory infiltrate, steatosis, and lipid peroxidation in liver tissue. Although both E. edulis bioproducts were not hepatotoxic, only LDEE presented sufficient benefits to treat NAFLD in rats, possibly by its low lipid content and high amount of phenols and anthocyanins.

  20. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Nielsen, Stine Elkjaer; Sugaya, Takeshi; Hovind, Peter

    2010-01-01

    Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor...

  1. Fatty Liver

    International Nuclear Information System (INIS)

    Filippone, A.; Digiovandomenico, V.; Digiovandomenico, E.; Genovesi, N.; Bonomo, L.

    1991-01-01

    The authors report their experience with the combined use of US and CT in the study of diffuse and subtotal fatty infiltration of the liver. An apparent disagreement was initially found between the two examinations in the study of fatty infiltration. Fifty-five patients were studied with US and CT of the upper abdomen, as suggested by clinics. US showed normal liver echogenicity in 30 patients and diffuse increased echogenicity (bright liver) in 25 cases. In 5 patients with bright liver, US demonstrated a solitary hypoechoic area, appearing as a 'skip area', in the quadrate lobe. In 2 patients with bright liver, the hypoechoic area was seen in the right lobe and exhibited no typical US features of 'Skip area'. Bright liver was quantified by measuring CT density of both liver and spleen. The relative attenuation values of spleen and liver were compared on plain and enhanced CT scans. In 5 cases with a hypoechoic area in the right lobe, CT findings were suggestive of hemangioma. A good correlation was found between broght liver and CT attenuation values, which decrease with increasing fat content of the liver. Moreover, CT attenuation values confirmed US findings in the study of typical 'skip area', by demonstrating normal density - which suggests that CT can characterize normal tissue in atypical 'skip area'

  2. Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

    Energy Technology Data Exchange (ETDEWEB)

    Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 China (China); Chonan, Ritsu [Koei Kogyo Co., Ltd., Tokyo, 101-0063 Japan (Japan); Yamahara, Johji [Pharmafood Institute, Kyoto, 602-8136 Japan (Japan); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 China (China); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000 Australia (Australia)

    2014-10-15

    Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

  3. Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

    International Nuclear Information System (INIS)

    Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

    2014-01-01

    Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

  4. Dietary (n-6 : n-3 Fatty Acids Alter Plasma and Tissue Fatty Acid Composition in Pregnant Sprague Dawley Rats

    Directory of Open Access Journals (Sweden)

    Amira Abdulbari Kassem

    2012-01-01

    Full Text Available The objective of this paper is to study the effects of varying dietary levels of n-6 : n-3 fatty acid ratio on plasma and tissue fatty acid composition in rat. The treatment groups included control rats fed chow diet only, rats fed 50% soybean oil (SBO: 50% cod liver oil (CLO (1 : 1, 84% SBO: 16% CLO (6 : 1, 96% SBO: 4% CLO (30 : 1. Blood samples were taken at day 15 of pregnancy, and the plasma and tissue were analyzed for fatty acid profile. The n-3 PUFA in plasma of Diet 1 : 1 group was significantly higher than the other diet groups, while the total n-6 PUFA in plasma was significantly higher in Diet 30 : 1 group as compared to the control and Diet 1 : 1 groups. The Diet 1 : 1 group showed significantly greater percentages of total n-3 PUFA and docosahexaenoic acid in adipose and liver tissue, and this clearly reflected the contribution of n-3 fatty acids from CLO. The total n-6 PUFA, linoleic acid, and arachidonic acid were significantly difference in Diet 30 : 1 as compared to Diet 1 : 1 and control group. These results demonstrated that the dietary ratio of n-6 : n-3 fatty acid ratio significantly affected plasma and tissue fatty acids profile in pregnant rat.

  5. Dietary (n-6 : n-3) fatty acids alter plasma and tissue fatty acid composition in pregnant Sprague Dawley rats.

    Science.gov (United States)

    Kassem, Amira Abdulbari; Abu Bakar, Md Zuki; Yong Meng, Goh; Mustapha, Noordin Mohamed

    2012-01-01

    The objective of this paper is to study the effects of varying dietary levels of n-6 : n-3 fatty acid ratio on plasma and tissue fatty acid composition in rat. The treatment groups included control rats fed chow diet only, rats fed 50% soybean oil (SBO): 50% cod liver oil (CLO) (1 : 1), 84% SBO: 16% CLO (6 : 1), 96% SBO: 4% CLO (30 : 1). Blood samples were taken at day 15 of pregnancy, and the plasma and tissue were analyzed for fatty acid profile. The n-3 PUFA in plasma of Diet 1 : 1 group was significantly higher than the other diet groups, while the total n-6 PUFA in plasma was significantly higher in Diet 30 : 1 group as compared to the control and Diet 1 : 1 groups. The Diet 1 : 1 group showed significantly greater percentages of total n-3 PUFA and docosahexaenoic acid in adipose and liver tissue, and this clearly reflected the contribution of n-3 fatty acids from CLO. The total n-6 PUFA, linoleic acid, and arachidonic acid were significantly difference in Diet 30 : 1 as compared to Diet 1 : 1 and control group. These results demonstrated that the dietary ratio of n-6 : n-3 fatty acid ratio significantly affected plasma and tissue fatty acids profile in pregnant rat.

  6. Dietary (n-6 : n-3) Fatty Acids Alter Plasma and Tissue Fatty Acid Composition in Pregnant Sprague Dawley Rats

    Science.gov (United States)

    Kassem, Amira Abdulbari; Abu Bakar, Md Zuki; Yong Meng, Goh; Mustapha, Noordin Mohamed

    2012-01-01

    The objective of this paper is to study the effects of varying dietary levels of n-6 : n-3 fatty acid ratio on plasma and tissue fatty acid composition in rat. The treatment groups included control rats fed chow diet only, rats fed 50% soybean oil (SBO): 50% cod liver oil (CLO) (1 : 1), 84% SBO: 16% CLO (6 : 1), 96% SBO: 4% CLO (30 : 1). Blood samples were taken at day 15 of pregnancy, and the plasma and tissue were analyzed for fatty acid profile. The n-3 PUFA in plasma of Diet 1 : 1 group was significantly higher than the other diet groups, while the total n-6 PUFA in plasma was significantly higher in Diet 30 : 1 group as compared to the control and Diet 1 : 1 groups. The Diet 1 : 1 group showed significantly greater percentages of total n-3 PUFA and docosahexaenoic acid in adipose and liver tissue, and this clearly reflected the contribution of n-3 fatty acids from CLO. The total n-6 PUFA, linoleic acid, and arachidonic acid were significantly difference in Diet 30 : 1 as compared to Diet 1 : 1 and control group. These results demonstrated that the dietary ratio of n-6 : n-3 fatty acid ratio significantly affected plasma and tissue fatty acids profile in pregnant rat. PMID:22489205

  7. Evaluation of usefulness of 99mTc-GSA liver scintigraphy on fatty liver in the rat

    International Nuclear Information System (INIS)

    Kimoto, Mitsunori; Akaki, Shiro; Kohno, Yoshihiro; Gohbara, Hideo; Sakae, Katsuyoshi; Nagaya, Isao; Takeda, Yoshihiro; Hiraki, Yoshio

    1994-01-01

    99m Tc-GSA is a new liver-imaging radiopharmaceutical which binds to the asialoglycoprotein receptors on the hepatocytes. We evaluated liver injury induced by fatty infiltration in the rats. Studies were performed in the Wistar rats under control conditions (6 cases), and with choline deficiency diet for 2, 4, 6, 10 and 12 weeks (6 cases respectively). 99m Tc-GSA was administered via the inferior vena cava. Immediately after injection, a dynamic imaging study was performed for 30 min. t 90 (the time at which the liver time-activity curve reached 90% of its peak), K u and K d (calculated by 2 compartment model) were used as parameters which reflect on asialoglycoprotein receptors on the hepatocytes. t 90 prolonged, and K u and K d decreased according to the severity of fatty infiltration. These results suggest that 99m Tc-GSA is useful for evaluating liver injury induced by fatty infiltration. (author)

  8. Cholesterol and fatty acids profile of Brazilian commercial chicken giblets.

    Science.gov (United States)

    Pereira, Nádia Rosa; Muniz, Edvani Curti; Matsushita, Makoto; Evelázio de Souza, Nilson

    2002-06-01

    This study was carried out to determine the chemical composition, cholesterol contents and fatty acids profile of Brazilian commercial chicken giblets. The analysis were performed in gizzard, liver and heart in natura and also in cooked gizzard, fried liver and roasted heart. Fat and cholesterol contents ranged from 0.88% and 72.68 mg/100 g, in cooked gizzard, to 22.19% and 213.18 mg/100 g, in roasted heart. As the fat content gets higher, so does the cholesterol content. Palmitic (C16:0) and stearic acids (C18:0) were the predominant saturated fatty acids (SFA). The C16:0 ranged from 6.39% in cooked gizzard to 18.51% in fried liver. The C18:0 level ranged from 6.62% in roasted heart to 19.19% in cooked gizzard. Linoleic acid (C18:2 omega 6) was the predominant polyunsaturated fatty acid (PUFA). The data revealed that the three different analysed giblets presented a good PUFA/SFA ratio, with values of 1.11, 1.14 and 1.40 for cooked gizzard, fried liver and roasted heart, respectively.

  9. Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jing-Na Deng

    2015-01-01

    Full Text Available This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2, which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c, fatty acid synthesis (FAS, and acetyl-CoA carboxylase (ACC proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC.

  10. Inhibition of Fatty Acid Synthesis Induces Apoptosis of Human Pancreatic Cancer Cells.

    Science.gov (United States)

    Nishi, Koji; Suzuki, Kenta; Sawamoto, Junpei; Tokizawa, Yuma; Iwase, Yumiko; Yumita, Nagahiko; Ikeda, Toshihiko

    2016-09-01

    Cancer cells tend to have a high requirement for lipids, including fatty acids, cholesterol and triglyceride, because of their rapid proliferative rate compared to normal cells. In this study, we investigated the effects of inhibition of lipid synthesis on the proliferation and viability of human pancreatic cancer cells. Of the inhibitors of lipid synthesis that were tested, 5-(tetradecyloxy)-2-furoic acid (TOFA), which is an inhibitor of acetyl-CoA carboxylase, and the fatty acid synthase (FAS) inhibitors cerulenin and irgasan, significantly suppressed the proliferation of MiaPaCa-2 and AsPC-1 cells. Treatment of MiaPaCa-2 cells with these inhibitors significantly increased the number of apoptotic cells. In addition, TOFA increased caspase-3 activity and induced cleavage of poly (ADP-ribose) polymerase in MiaPaCa-2 cells. Moreover, addition of palmitate to MiaPaCa-2 cells treated with TOFA rescued cells from apoptotic cell death. These results suggest that TOFA induces apoptosis via depletion of fatty acids and that, among the various aspects of lipid metabolism, inhibition of fatty acid synthesis may be a notable target for the treatment of human pancreatic cancer cells. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Protective Effects of Korean Red Ginseng against Alcohol-Induced Fatty Liver in Rats

    Directory of Open Access Journals (Sweden)

    Hyo Jin Lee

    2015-06-01

    Full Text Available The present study tested the hypothesis that Korean red ginseng (KRG provides a protective effect against alcoholic fatty liver. Male Sprague-Dawley rats were divided into four groups and fed a modified Lieber-DeCarli diet containing 5% (w/v alcohol or an isocaloric amount of dextrin-maltose for the controls for 6 weeks: normal control (CON, alcohol control (ET, and ET treated with 125 or 250 mg/kg body weight/day of KRG (RGL or RGH, respectively. Compared with the CON group, the ET group exhibited a significant increase in triglycerides, total cholesterol and the presence of lipid droplets in the liver, and a decrease in fat mass, which were all attenuated by KRG supplementation in adose-dependent manner. The mitigation was accompanied by AMP-activated protein kinase (AMPK signaling pathways in the liver and adipose tissue. In addition, suppression in the alcohol-induced changes of adipose adipokine mRNA expression was also observed in KRG supplementation group. These findings suggest that KRG may have the potential to ameliorate alcoholic fatty liver by suppressing inappropriate lysis of adipose tissue and preventing unnecessary de novo lipogenesis in the liver, which are mediated by AMPK signaling pathways. A mechanism for an interplay between the two organs is still needed to be examined with further assays.

  12. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

    International Nuclear Information System (INIS)

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J.; Marin, Jose J.G.

    2009-01-01

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion ( TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

  13. Design and rationale of the WELCOME trial: A randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected].

    Science.gov (United States)

    Scorletti, E; Bhatia, L; McCormick, K G; Clough, G F; Nash, K; Calder, P C; Byrne, C D

    2014-03-01

    Non-alcoholic fatty liver disease (NAFLD) represents a range of liver conditions from simple fatty liver to progressive end stage liver disease requiring liver transplantation. NAFLD is common in the population and in certain sub groups (e.g. type 2 diabetes) up to 70% of patients may be affected. NAFLD is not only a cause of end stage liver disease and hepatocellular carcinoma, but is also an independent risk factor for type 2 diabetes and cardiovascular disease. Consequently, effective treatments for NAFLD are urgently needed. The WELCOME study is testing the hypothesis that treatment with high dose purified long chain omega-3 fatty acids will have a beneficial effect on a) liver fat percentage and b) two histologically validated algorithmically-derived biomarker scores for liver fibrosis. In a randomised double blind placebo controlled trial, 103 participants with NAFLD were randomised to 15-18months treatment with either 4g/day purified long chain omega-3 fatty acids (Omacor) or 4g/day olive oil as placebo. Erythrocyte percentage DHA and EPA enrichment (a validated proxy for hepatic enrichment) was determined by gas chromatography. Liver fat percentage was measured in three discrete liver zones by magnetic resonance spectroscopy (MRS). We also measured body fat distribution, physical activity and a range of cardiometabolic risk factors. Recruitment started in January 2010 and ended in June 2011. We identified 178 potential participants, and randomised 103 participants who met the inclusion criteria. The WELCOME study was approved by the local ethics committee (REC: 08/H0502/165; www.clinicalTrials.gov registration number NCT00760513). Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

    Science.gov (United States)

    Cravatt, B F; Giang, D K; Mayfield, S P; Boger, D L; Lerner, R A; Gilula, N B

    1996-11-07

    Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.

  15. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration.

    Science.gov (United States)

    Alvarez-Sola, Gloria; Uriarte, Iker; Latasa, M Ujue; Fernandez-Barrena, Maite G; Urtasun, Raquel; Elizalde, Maria; Barcena-Varela, Marina; Jiménez, Maddalen; Chang, Haisul C; Barbero, Roberto; Catalán, Victoria; Rodríguez, Amaia; Frühbeck, Gema; Gallego-Escuredo, José M; Gavaldà-Navarro, Aleix; Villarroya, Francesc; Rodriguez-Ortigosa, Carlos M; Corrales, Fernando J; Prieto, Jesus; Berraondo, Pedro; Berasain, Carmen; Avila, Matias A

    2017-10-01

    Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration. Fgf15 -/- mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH. Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15 -/- mice. Hepatic expression of Pparγ2 was elevated in Fgf15 -/- mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH. FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression . Perioperative administration of Fibapo improves fatty liver regeneration. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  16. Docosahexaenoic acid and other fatty acids induce a decrease in pHi in Jurkat T-cells

    OpenAIRE

    Aires, Virginie; Hichami, Aziz; Moutairou, Kabirou; Khan, Naim Akhtar

    2003-01-01

    Docosahexaenoic acid (DHA) induced rapid (t1/2=33 s) and dose-dependent decreases in pHi in BCECF-loaded human (Jurkat) T-cells. Addition of 5-(N,N-dimethyl)-amiloride, an inhibitor of Na+/H+ exchanger, prolonged DHA-induced acidification as a function of time, indicating that the exchanger is implicated in pHi recovery.Other fatty acids like oleic acid, arachidonic acid, eicosapentaenoic acid, but not palmitic acid, also induced a fall in pHi in these cells.To assess the role of calcium in t...

  17. N-3 fatty acids reduced trans fatty acids retention and increased docosahexaenoic acid levels in the brain.

    Science.gov (United States)

    Lavandera, Jimena Verónica; Saín, Juliana; Fariña, Ana Clara; Bernal, Claudio Adrián; González, Marcela Aída

    2017-09-01

    The levels of docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) are critical for the normal structure and function of the brain. Trans fatty acids (TFA) and the source of the dietary fatty acids (FA) interfere with long-chain polyunsaturated fatty acids (LC-PUFA) biosynthesis. The aim of this study was to investigate the effect of TFA supplementation in diets containing different proportions of n-9, n-6, and n-3 FA on the brain FA profile, including the retention of TFA, LC-PUFA levels, and n-6/n-3 PUFA ratios. These parameters were also investigated in the liver, considering that LC-PUFA are mainly bioconverted from their dietary precursors in this tissue and transported by serum to the brain. Also, stearoyl-CoA desaturase-1 (SCD1) and sterol regulatory element-binding protein-1c (SREBP-1c) gene expressions were evaluated. Male CF1 mice were fed (16 weeks) diets containing different oils (olive, corn, and rapeseed) with distinct proportions of n-9, n-6, and n-3 FA (55.2/17.2/0.7, 32.0/51.3/0.9, and 61.1/18.4/8.6), respectively, substituted or not with 0.75% of TFA. FA composition of the brain, liver, and serum was assessed by gas chromatography. TFA were incorporated into, and therefore retained in the brain, liver, and serum. However, the magnitude of retention was dependent on the tissue and type of isomer. In the brain, total TFA retention was lower than 1% in all diets. Dietary n-3 PUFA decreased TFA retention and increased DHA accretion in the brain. The results underscore the importance of the type of dietary FA on the retention of TFA in the brain and also on the changes of the FA profile.

  18. Dietary capsaicin and antibiotics act synergistically to reduce non-alcoholic fatty liver disease induced by high fat diet in mice.

    Science.gov (United States)

    Hu, Jingjuan; Luo, Haihua; Jiang, Yong; Chen, Peng

    2017-06-13

    The prevalence of non-alcoholic fatty liver disease is increasing rapidly worldwide. However, effective strategies for combating high-fat diet (HFD) induced obesity, fatty liver and metabolic disorder are still limited, and outcomes remain poor. In the present study, we evaluated the combined actions of dietary capsaicin and antibiotics on HFD-induced physiological abnormalities in mice. C57BL/6 male mice were fed with HFD (60% calories from fat) for 17 weeks, and the resultant pathophysiological effects were examined. Antibiotic treatment markedly attenuated gut inflammation and leakiness induced by HFD, whereas capsaicin showed limited effects on the gut. However, dietary capsaicin significantly increased PPAR-α expression in adipose tissue, while antibiotics had no such effect. Animals treated with a combination of capsaicin and antibiotics had the smallest body weight gain and fat pad index, as well as the lowest hepatic fat accumulation. Combination treatment also maximally improved insulin responsiveness, as indicated by insulin tolerance tests. These results suggest the co-treatment of capsaicin and antibiotics, a novel combination strategy, would play synergistically to attenuate the HFD-induced obesity, fatty liver and metabolic disorder.

  19. Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice

    Directory of Open Access Journals (Sweden)

    Han-Sol Park

    2016-04-01

    Full Text Available BackgroundNon-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH, but underlying mechanisms of this prevention are largely unknown.MethodsSeven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day, for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver.ResultsStatin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels.ConclusionStatins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.

  20. AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development.

    Science.gov (United States)

    Boudaba, Nadia; Marion, Allison; Huet, Camille; Pierre, Rémi; Viollet, Benoit; Foretz, Marc

    2018-02-01

    Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Role of hepatic de novo lipogenesis in the development of fasting-induced fatty liver in the American mink (Neovison vison).

    Science.gov (United States)

    Rouvinen-Watt, Kirsti; Harris, Lora; Dick, Morag; Pal, Catherine; Lei, Sha; Mustonen, Anne-Mari; Nieminen, Petteri

    2012-10-28

    American mink (Neovison vison) develop fatty liver quickly in response to food deprivation, which results in preferential mobilisation of n-3 PUFA. The altered n-3:n-6 PUFA ratio in the liver may activate the endocannabinoid system resulting in increased lipid synthesis. The objective of the present study was to investigate the effects of feeding intensity (80 or 120% RDA), dietary fat source (n-3, n-6 or n-9 fatty acids (FA)) and short-term fasting (1-7 d) on hepatic de novo lipogenesis (DNL) and the development of fatty liver in mink. Significantly elevated expression of mRNA encoding for acetyl-CoA carboxylase-1 (ACC-1) and FA synthase (FAS) was observed in the liver of mink fasted for 5-7 d, while upon re-feeding for 28 d after a 7 d food deprivation, DNL returned to pre-fasting levels. The females had a higher expression of ACC-1 and FAS mRNA than the males. In the non-fasted animals, dietary fat source and feeding intensity had significant effects on ACC-1 mRNA. The highest levels were observed in the mink fed the rapeseed oil (n-9) diet at 80% RDA, while the lowest levels were seen when the same diet was fed at 120% RDA. For FAS, the highest gene expression was seen in the fasted mink fed at 80% RDA and the lowest in the non-fasted mink fed at 80%. It is concluded that short-term food deprivation induces hepatic lipidosis in mink and that during this process, hepatic DNL further exacerbates liver fat accumulation.

  2. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids.

    Science.gov (United States)

    Choi, Sun Ju; Kim, Francis; Schwartz, Michael W; Wisse, Brent E

    2010-06-01

    Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFalpha, as judged by induction of IkappaBalpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IkappaBalpha protein, and TNFalpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P fatty acid (100, 250, or 500 microM for neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.

  3. Iodine 123-17-iodoheptadecanoic acid for metabolic liver studies in humans

    International Nuclear Information System (INIS)

    Hoeck, A.S.; Spohr, G.; Schmitz, M.; Notohamiprodjo, G.; Porschen, R.; Vyska, K.; Freundlieb, C.; Shreeve, W.W.; Feinendegen, L.E.

    1986-01-01

    (17- 123 I)-Iodoheptadecanoic acid ([ 123 I]HA) was used for dynamic planar scintigraphy of the liver in normal individuals (control I), in patients without liver disease but with elevated serum cholesterol and/or triglycerides (control II), and in patient groups with alcohol-induced fatty liver (PG I), fatty liver not due to alcohol (PG II), alcohol-induced liver cirrhosis (PG III), or liver cirrhosis of the posthepatitic type (PG IV). Tracer uptake and elimination time were assayed in different liver regions; mean elimination time was expressed for total liver. In control I, tracer uptake was homogeneous, and mean elimination time was 20.7 +/- 5.3 min without significant local variations. In control II, tracer uptake was reduced but homogeneous and mean elimination time was 59.4 +/- 35.8 min with some local variations. In PG I, uptake was reduced and inhomogeneous and elimination time was the same as in control I, irrespective of cholesterol and triglyceride values. In PG II, uptake was the same as in PG I but mean elimination time was 48 +/- 8.1 min with some local variations. In PG III, uptake was extremely reduced and spotty and elimination time correlated with the severity of disease from 19 to 881 min in different liver regions

  4. Effect of cottonseed and canola seed on unsaturated fatty acid ...

    African Journals Online (AJOL)

    student

    biohydrogenation in the rumen and showed that the type of dietary fat has a marked impact on lipid ... Keywords: Extruded oil seed, fatty acid, lamb plasma, liver, Mehraban lambs ..... Effects of diets low in fat or essential fatty acids on the fatty ... Review: Erythrocyte membrane: structure, function, and pathophysiology. Vet.

  5. Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Ganji, Shobha H; Kukes, Gary D; Lambrecht, Nils; Kashyap, Moti L; Kamanna, Vaijinath S

    2014-02-15

    Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

  6. Bitter melon extract ameliorates palmitate-induced apoptosis via inhibition of endoplasmic reticulum stress in HepG2 cells and high-fat/high-fructose-diet-induced fatty liver

    Directory of Open Access Journals (Sweden)

    Hwa Joung Lee

    2018-03-01

    Full Text Available Background: Bitter melon (BM improves glucose level, lipid homeostasis, and insulin resistance in vivo. However, the preventive mechanism of BM in nonalcoholic fatty liver disease (NAFLD has not been elucidated yet. Aim & Design: To determine the protective mechanism of bitter melon extract (BME, we performed experiments in vitro and in vivo. BME were treated palmitate (PA-administrated HepG2 cells. C57BL/6J mice were divided into two groups: high-fat/high-fructose (HF/HFr without or with BME supplementation (100 mg/kg body weight. Endoplasmic reticulum (ER stress, apoptosis, and biochemical markers were then examined by western blot and real-time PCR analyses. Results: BME significantly decreased expression levels of ER-stress markers (including phospho-eIF2α, CHOP, and phospho-JNK [Jun N-terminal kinases] in PA-treated HepG2 cells. BME also significantly decreased the activity of cleaved caspase-3 (a well known apoptotic-induced molecule and DNA fragmentation. The effect of BME on ER stress–mediated apoptosis in vitro was similarly observed in HF/HFr-fed mice in vivo. BME significantly reduced HF/HFr-induced hepatic triglyceride (TG and serum alanine aminotransferase (ALT as markers of hepatic damage in mice. In addition, BME ameliorated HF/HFr-induced serum TG and serum-free fatty acids. Conclusion: These data indicate that BME has protective effects against ER stress mediated apoptosis in HepG2 cells as well as in HF/HFr-induced fatty liver of mouse. Therefore, BME might be useful for preventing and treating NAFLD.

  7. Small-angle X-ray-scattering investigation and structural-model study of the fatty-acid synthetase from pig liver

    International Nuclear Information System (INIS)

    Folkhard, W.; Felser, B.; Pilz, I.; Kratky, O.; Dutler, H.; Vogel, H.

    1977-01-01

    The structure of the fatty acid synthetase from pig liver was studied on models based upon structural and functional properties selected from pertinent results available from numerous investigations carried out with fatty acid synthetase from this and other sources. When comparing small-angle X-ray-scattering curves calculated with these models and curves obtained from small-angle X-ray-scattering experiments carried out with the pig-liver enzyme, we tried to select a model which would lead to an acceptable correlation between the calculated and the experimental curves and at the same time fulfil the known structural and the functional requirements. The comparison of the curves was started with a model of low complexity. The observed discrepancy, together with arguments from the structural and the functional properties, helped decide which is the next most reasonable model to be considered. This procedure was repeated for five models of increasing complexity. In the model which led to the best fit the multienzyme complex is composed of two halves in an asymmetric conformation including hollow spaces. This highly anisotropic model would imply that the two halves change their conformation each time a synthetic cycle is completed and that the growing fatty acid is handed over from one half to the other. (orig.) [de

  8. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

    Science.gov (United States)

    Xia, Bo; Cai, Guo He; Yang, Hao; Wang, Shu Pei; Mitchell, Grant A; Wu, Jiang Wei

    2017-12-01

    Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

  9. Non-Alcoholic Fatty Liver Disease in Children: Focus on Nutritional Interventions

    Directory of Open Access Journals (Sweden)

    Min Yang

    2014-10-01

    Full Text Available With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD.

  10. Nonalcoholic Fatty Liver Disease & NASH

    Science.gov (United States)

    ... Eating, Diet, & Nutrition Clinical Trials Wilson Disease Nonalcoholic Fatty Liver Disease & NASH View or Print All Sections Definition & Facts Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat ...

  11. Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues.

    Science.gov (United States)

    Chai, Chofit; Rivkin, Mila; Berkovits, Liav; Simerzin, Alina; Zorde-Khvalevsky, Elina; Rosenberg, Nofar; Klein, Shiri; Yaish, Dayana; Durst, Ronen; Shpitzen, Shoshana; Udi, Shiran; Tam, Joseph; Heeren, Joerg; Worthmann, Anna; Schramm, Christoph; Kluwe, Johannes; Ravid, Revital; Hornstein, Eran; Giladi, Hilla; Galun, Eithan

    2017-11-01

    Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of β-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce

  12. The association of vitamin D deficiency with non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Metin Küçükazman

    2014-08-01

    Full Text Available OBJECTIVE: Vitamin D deficiency has been related to diabetes, hypertension, hyperlipidemia and peripheral vascular disease. In this study, we aimed to investigate the role of vitamin D status in non-alcoholic fatty liver disease. METHODS: We included 211 consecutive subjects to examine the presence of non-alcoholic fatty liver disease. Of these subjects, 57 did not have non-alcoholic fatty liver disease and 154 had non-alcoholic fatty liver disease. RESULTS: The non-alcoholic fatty liver disease group had significantly higher fasting blood glucose (p = 0.005, uric acid (p = 0.001, aspartate aminotransferase (p<0.001, alanine aminotransferase (p<0.001, γ-glutamyltransferase (p<0.0001, alkaline phosphatase (p = 0.028, HbA1c (p<0.001, ferritin (p<0.001, insulin (p = 0.016, C-peptide (p = 0.001, HOMA-IR (p = 0.003, total cholesterol (p = 0.001, triglyceride (p = 0.001 and white blood cell (p = 0.04 levels. In contrast, the non-alcoholic fatty liver disease group had significantly lower 25(OHD levels (12.3±8.9 ng/dl, p<0.001 compared with those of the control group (20±13.6 ng/dl. CONCLUSIONS: In this study, we found lower serum 25(OHD levels in patients with non-alcoholic fatty liver disease than in subjects without non-alcoholic fatty liver disease. To establish causality between vitamin D and non-alcoholic fatty liver disease, further interventional studies with a long-term follow-up are needed.

  13. Dietary Flaxseed Oil Prevents Western-Type Diet-Induced Nonalcoholic Fatty Liver Disease in Apolipoprotein-E Knockout Mice

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    Hao Han

    2017-01-01

    Full Text Available The prevalence of nonalcoholic fatty liver disease (NAFLD has dramatically increased globally during recent decades. Intake of n-3 polyunsaturated fatty acids (PUFAs, mainly eicosapentaenoic acid (EPA, C20:5n-3 and docosahexaenoic acid (DHA, C22:6n-3, is believed to be beneficial to the development of NAFLD. However, little information is available with regard to the effect of flaxseed oil rich in α-linolenic acid (ALA, C18:3n-3, a plant-derived n-3 PUFA, in improving NAFLD. This study was to gain the effect of flaxseed oil on NAFLD and further investigate the underlying mechanisms. Apolipoprotein-E knockout (apoE-KO mice were given a normal chow diet, a western-type high-fat and high-cholesterol diet (WTD, or a WTD diet containing 10% flaxseed oil (WTD + FO for 12 weeks. Our data showed that consumption of flaxseed oil significantly improved WTD-induced NAFLD, as well as ameliorated impaired lipid homeostasis, attenuated oxidative stress, and inhibited inflammation. These data were associated with the modification effects on expression levels of genes involved in de novo fat synthesis (SREBP-1c, ACC, triacylglycerol catabolism (PPARα, CPT1A, and ACOX1, inflammation (NF-κB, IL-6, TNF-α, and MCP-1, and oxidative stress (ROS, MDA, GSH, and SOD.

  14. External Validation of Fatty Liver Index for Identifying Ultrasonographic Fatty Liver in a Large-Scale Cross-Sectional Study in Taiwan

    Science.gov (United States)

    Fang, Kuan-Chieh; Wang, Yuan-Chen; Huo, Teh-Ia; Huang, Yi-Hsiang; Yang, Hwai-I; Su, Chien-Wei; Lin, Han-Chieh; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

    2015-01-01

    Background and Aims The fatty liver index (FLI) is an algorithm involving the waist circumference, body mass index, and serum levels of triglyceride and gamma-glutamyl transferase to identify fatty liver. Although some studies have attempted to validate the FLI, few studies have been conducted for external validation among Asians. We attempted to validate FLI to predict ultrasonographic fatty liver in Taiwanese subjects. Methods We enrolled consecutive subjects who received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was applied to diagnose fatty liver. The ability of the FLI to detect ultrasonographic fatty liver was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results Among the 29,797 subjects enrolled in this study, fatty liver was diagnosed in 44.5% of the population. Subjects with ultrasonographic fatty liver had a significantly higher FLI than those without fatty liver by multivariate analysis (odds ratio 1.045; 95% confidence interval, CI 1.044–1.047, pfatty liver (AUROC: 0.827, 95% confidence interval, 0.822–0.831). An FLI fatty liver. Moreover, an FLI ≥ 35 (positive likelihood ratio (LR+) 3.12) for males and ≥ 20 (LR+ 4.43) for females rule in ultrasonographic fatty liver. Conclusions FLI could accurately identify ultrasonographic fatty liver in a large-scale population in Taiwan but with lower cut-off value than the Western population. Meanwhile the cut-off value was lower in females than in males. PMID:25781622

  15. 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.

  16. Diagnostic methods of fatty liver disease

    International Nuclear Information System (INIS)

    Kukuk, Guido Matthias; Sprinkart, Alois Martin; Traeber, Frank

    2017-01-01

    Fatty liver disease is defined as an abnormal accumulation of lipids into the cytoplasm of hepatocytes. Different kinds of fatty liver diseases are becoming the most important etiologies of end-stage liver disease in the western world. Because fatty liver is a theoretically reversible process, timely and accurate diagnosis is a prerequisite for potential therapeutic options. This work describes major diagnostic methods and discusses particular advantages and disadvantages of various techniques.

  17. Role of fatty-acid synthesis in dendritic cell generation and function.

    Science.gov (United States)

    Rehman, Adeel; Hemmert, Keith C; Ochi, Atsuo; Jamal, Mohsin; Henning, Justin R; Barilla, Rocky; Quesada, Juan P; Zambirinis, Constantinos P; Tang, Kerry; Ego-Osuala, Melvin; Rao, Raghavendra S; Greco, Stephanie; Deutsch, Michael; Narayan, Suchithra; Pachter, H Leon; Graffeo, Christopher S; Acehan, Devrim; Miller, George

    2013-05-01

    Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

  18. Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

    Science.gov (United States)

    Sookoian, Silvia; Castaño, Gustavo O; Scian, Romina; Fernández Gianotti, Tomas; Dopazo, Hernán; Rohr, Cristian; Gaj, Graciela; San Martino, Julio; Sevic, Ina; Flichman, Diego; Pirola, Carlos J

    2016-02-01

    Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown. We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS. Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included. Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations. In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and

  19. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Hiroshi Sakugawa; Fukunori Kinjo; Atsushi Saito; Tomofumi Nakayoshi; Kasen Kobashigawa; Tsuyoshi Yamashiro; Tatsuji Maeshiro; Satoru Miyagi; Joji Shiroma; Akiyo Toyama; Tomokuni Nakayoshi

    2005-01-01

    AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease.However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type Ⅵ collagen 7S domain and hyaluronic acid.METHODS: One hundred and twelve patients with histologically proven NAFLD were studied.RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type Ⅵ collagen 7S domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type Ⅵ collagen 7S domain, 86% and hyaluronic acid,92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type Ⅵ collagen 7S domain (≥5.0 ng/mL),84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis.CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

  20. Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing.

    Science.gov (United States)

    Bourre, J M

    2004-01-01

    Among various organs, in the brain, the fatty acids most extensively studied are omega-3 fatty acids. Alpha-linolenic acid (18:3omega3) deficiency alters the structure and function of membranes and induces minor cerebral dysfunctions, as demonstrated in animal models and subsequently in human infants. Even though the brain is materially an organ like any other, that is to say elaborated from substances present in the diet (sometimes exclusively), for long it was not accepted that food can have an influence on brain structure, and thus on its function. Lipids, and especially omega-3 fatty acids, provided the first coherent experimental demonstration of the effect of diet (nutrients) on the structure and function of the brain. In fact the brain, after adipose tissue, is the organ richest in lipids, whose only role is to participate in membrane structure. First it was shown that the differentiation and functioning of cultured brain cells requires not only alpha-linolenic acid (the major component of the omega-3, omega3 family), but also the very long omega-3 and omega-6 carbon chains (1). It was then demonstrated that alpha-linolenic acid deficiency alters the course of brain development, perturbs the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (2). This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioural upset (3). Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Recent

  1. Effects of elastase on fatty liver

    International Nuclear Information System (INIS)

    Ogura, Kazuo; Shimizu, Yoshikazu; Hihara, Masafumi; Ando, Hideki; Nishiyama, Masateru; Tano, Hironobu

    1984-01-01

    Elastase (Elaszym 6T) was administered, in addition to the dietary instruction, to three patients with fatty liver. CT scanning revealed marked improvement in fatty liver. Transaminase levels returned to normal, total cholesterol levels tended to decrease, and HDL-cholesterol levels tended to increase. These results suggest that elastase is effective in the treatment of fatty liver. (Namekawa, K.)

  2. External validation of fatty liver index for identifying ultrasonographic fatty liver in a large-scale cross-sectional study in Taiwan.

    Directory of Open Access Journals (Sweden)

    Bi-Ling Yang

    Full Text Available The fatty liver index (FLI is an algorithm involving the waist circumference, body mass index, and serum levels of triglyceride and gamma-glutamyl transferase to identify fatty liver. Although some studies have attempted to validate the FLI, few studies have been conducted for external validation among Asians. We attempted to validate FLI to predict ultrasonographic fatty liver in Taiwanese subjects.We enrolled consecutive subjects who received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was applied to diagnose fatty liver. The ability of the FLI to detect ultrasonographic fatty liver was assessed by analyzing the area under the receiver operating characteristic (AUROC curve.Among the 29,797 subjects enrolled in this study, fatty liver was diagnosed in 44.5% of the population. Subjects with ultrasonographic fatty liver had a significantly higher FLI than those without fatty liver by multivariate analysis (odds ratio 1.045; 95% confidence interval, CI 1.044-1.047, p< 0.001. Moreover, FLI had the best discriminative ability to identify patients with ultrasonographic fatty liver (AUROC: 0.827, 95% confidence interval, 0.822-0.831. An FLI < 25 (negative likelihood ratio (LR- 0.32 for males and <10 (LR- 0.26 for females rule out ultrasonographic fatty liver. Moreover, an FLI ≥ 35 (positive likelihood ratio (LR+ 3.12 for males and ≥ 20 (LR+ 4.43 for females rule in ultrasonographic fatty liver.FLI could accurately identify ultrasonographic fatty liver in a large-scale population in Taiwan but with lower cut-off value than the Western population. Meanwhile the cut-off value was lower in females than in males.

  3. Identification of fatty acids and fatty acid amides in human meibomian gland secretions.

    Science.gov (United States)

    Nichols, Kelly K; Ham, Bryan M; Nichols, Jason J; Ziegler, Corrie; Green-Church, Kari B

    2007-01-01

    The complex superficial lipid layer of the tear film functions to prevent evaporation and maintain tear stability. Although classes of lipids found in the tear film have been reported, individual lipid species are currently being studied with more sophisticated. The purpose of this work was to show the identification of fatty acids and the fatty acid amides in human meibomian gland secretions by using electrospray mass spectrometry. methods. Human meibomian gland secretions (meibum) were analyzed by electrospray quadrupole time-of-flight mass spectrometry (positive- and negative-ion mode). Accurate mass determination and collision-induced dissociation of meibum, and lipid standards were used to identify lipid species. Mass analysis of meibum in an acidic chloroform-methanol solution in positive-ion mode revealed a mass peak of m/z 282.3, which was identified as the protonated molecule of oleamide [C(18)H(35)NO+H](+). The high-resolution mass analysis of the m/z 282.2788 peak (oleamide) demonstrated a mass accuracy of 3.2 parts per million (ppm). Collision-induced dissociation of this species from meibum, compared with an oleamide standard, confirmed its identification. Myristic, palmitic, stearic, and oleic free fatty acids were identified in a similar manner, as were the other fatty acid amides (myristamide, palmitamide, stearamide, and erucamide). The findings indicate that oleamide (cis-9-octadecenamide), an endogenous fatty acid primary amide, is a predominant component of meibum when examined by electrospray mass spectrometry. The novel finding of oleamide and other members of the fatty acid amide family in the tear film could lead to additional insights into the role of fatty acid amide activity in human biological systems and may indicate a new function for this lipid class of molecules in ocular surface signaling and/or in the maintenance of the complex tear film.

  4. Influence of Temperature, Environmental Salinity and Fasting on the Patterns of Fatty Acid Synthesized by Gills and Liver of the European Eel (Anguilla Anguilla)

    DEFF Research Database (Denmark)

    Hansen, Heinz Johs. Max; Abraham, S.

    1983-01-01

    A rise in temperature on the average from 8 to 28 degrees C resulted in an enhanced relative incorporation of 1-14Cacetate into saturated fatty acids in liver tissue. The same effect was seen in gill tissue, but only after incubation in vitro and when the precursor was injected into the eel. When 1...... in the gills, due to the labelled precursor itself taking part in biological ion transport when it is added to the water. It would appear that palmitoleic acid plays a special role in the function of the salt transport cell. When 1-14Cacetate was added to the water in the incubation tank...... there was a significantly enhanced percentage incorporation into saturated gill fatty acids in fresh water relative to sea water. Fasting led to less relative incorporation of 1-14Cacetate into saturated liver fatty acids in vitro....

  5. Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

    Science.gov (United States)

    Chen, Shuai; Kang, Yujia; Sun, Yan; Zhong, Yanhong; Li, Yanli; Deng, Lijuan; Tao, Jin; Li, Yang; Tian, Yingpu; Zhao, Yinan; Cheng, Jianghong; Liu, Wenjie; Feng, Gen-Sheng; Lu, Zhongxian

    2016-12-01

    Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

  6. Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions

    Directory of Open Access Journals (Sweden)

    Yong-Jik Lee

    2017-01-01

    Full Text Available To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ, phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK, phosphorylated acetyl-CoA carboxylase (p-ACC, malonyl-CoA decarboxylase (MCD, medium chain acyl-CoA dehydrogenase (MCAD, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1, fatty acid synthase (FAS, and tumor necrosis factor-alpha (TNF-α. Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660. Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway.

  7. Hepatoprotective Effect and Synergism of Bisdemethoycurcumin against MCD Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

    Science.gov (United States)

    Kim, Sung-Bae; Kang, Ok-Hwa; Lee, Young-Seob; Han, Sin-Hee; Ahn, Young-Sup; Cha, Seon-Woo; Seo, Yun-Soo; Kong, Ryong; Kwon, Dong-Yeul

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC) is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD)-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment), MCD diet (MCD diet only), MCD + silymarin (SIL) 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent against NAFLD.

  8. Hepatoprotective Effect and Synergism of Bisdemethoycurcumin against MCD Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

    Directory of Open Access Journals (Sweden)

    Sung-Bae Kim

    Full Text Available Nonalcoholic fatty liver disease (NAFLD, the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver disease over the last decade in developed countries. NAFLD includes a spectrum of pathological hepatic changes, such as steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Bisdemethoxycurcumin (BDMC is polyphenolic compounds with a diarylheptanoid skeleton, curcumin close analogues, which is derived from the Curcumae Longae Rhizoma. While the rich bioavailability research of curcumin, BDMC is the poor studies. We investigated whether BDMC has the hepatoprotective effect and combinatory preventive effect with silymarin on methionine choline deficient (MCD-diet-induced NAFLD in C57BL/6J mice. C57BL/6J mice were divided into five groups of normal (normal diet without any treatment, MCD diet (MCD diet only, MCD + silymarin (SIL 100 mg/kg group, MCD + BDMC 100 mg/kg group, MCD + SIL 50 mg/kg + BDMC 50 mg/kg group. Body weight, liver weight, liver function tests, histological changes were assessed and quantitative real-time polymerase chain reaction and Western blot analyses were conducted after 4 weeks. Mice lost body weight on the MCD-diet, but BDMC did not lose less than the MCD-diet group. Liver weights decreased from BDMC, but they increased significantly in the MCD-diet groups. All liver function test values decreased from the MCD-diet, whereas those from the BDMC increased significantly. The MCD- diet induced severe hepatic fatty accumulation, but the fatty change was reduced in the BDMC. The BDMC showed an inhibitory effect on liver lipogenesis by reducing associated gene expression caused by the MCD-diet. In all experiments, the combinations of BDMC with SIL had a synergistic effect against MCD-diet models. In conclusion, our findings indicate that BDMC has a potential suppressive effect on NAFLD. Therefore, our data suggest that BDMC may act as a novel and potent therapeutic agent

  9. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Tang, Y; Bian, Z; Zhao, L; Liu, Y; Liang, S; Wang, Q; Han, X; Peng, Y; Chen, X; Shen, L; Qiu, D; Li, Z; Ma, X

    2011-11-01

    Mechanisms associated with the progression of simple steatosis to non-alcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (T(regs)) play a critical role in regulating inflammatory processes in non-alcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose T(reg)-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (HF) diet for 8 weeks. Mice in the HF group had a significantly higher frequency of liver Th17 cells compared to ND-fed mice. Neutralization of interleukin (IL)-17 in HF mice ameliorated lipopolysaccharide (LPS)-induced liver injury reflected by decreased serum alanine aminotransferase (ALT) levels and reduced inflammatory cell infiltrates in the liver. In vitro, HepG2 cells cultured in the presence of free fatty acids (FFA; oleic acid and palmitic acid) for 24 h and IL-17 developed steatosis via insulin-signalling pathway interference. IL-17 and FFAs synergized to induce IL-6 production by HepG2 cells and murine primary hepatocytes which, in combination with transforming growth factor (TGF-β), expanded Th17 cells. It is likely that a similar process occurs in NASH patients, as there were significant levels of IL-17(+) cell infiltrates in NASH patient livers. The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls. Th17 cells and IL-17 were associated with hepatic steatosis and proinflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis. Strategies designed to alter the balance between Th17 cells and T(regs) should be explored as a means of preventing progression to NASH and advanced liver diseases in NAFLD patients. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for

  10. Profiling Abscisic Acid-Induced Changes in Fatty Acid Composition in Mosses.

    Science.gov (United States)

    Shinde, Suhas; Devaiah, Shivakumar; Kilaru, Aruna

    2017-01-01

    In plants, change in lipid composition is a common response to various abiotic stresses. Lipid constituents of bryophytes are of particular interest as they differ from that of flowering plants. Unlike higher plants, mosses have high content of very long-chain polyunsaturated fatty acids. Such lipids are considered to be important for survival of nonvascular plants. Here, using abscisic acid (ABA )-induced changes in lipid composition in Physcomitrella patens as an example, a protocol for total lipid extraction and quantification by gas chromatography (GC) coupled with flame ionization detector (FID) is described.

  11. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Nielsen, Stine Elkjaer; Sugaya, Takeshi; Hovind, Peter

    2010-01-01

    Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor...... of progression to micro- and macroalbuminuria in type 1 diabetes....

  12. Forms of n-3 (ALA, C18:3n-3 or DHA, C22:6n-3) Fatty Acids Affect Carcass Yield, Blood Lipids, Muscle n-3 Fatty Acids and Liver Gene Expression in Lambs.

    Science.gov (United States)

    Ponnampalam, Eric N; Lewandowski, Paul A; Fahri, Fahri T; Burnett, Viv F; Dunshea, Frank R; Plozza, Tim; Jacobs, Joe L

    2015-11-01

    The effects of supplementing diets with n-3 alpha-linolenic acid (ALA) and docosahexaenoic acid (DHA) on plasma metabolites, carcass yield, muscle n-3 fatty acids and liver messenger RNA (mRNA) in lambs were investigated. Lambs (n = 120) were stratified to 12 groups based on body weight (35 ± 3.1 kg), and within groups randomly allocated to four dietary treatments: basal diet (BAS), BAS with 10.7 % flaxseed supplement (Flax), BAS with 1.8 % algae supplement (DHA), BAS with Flax and DHA (FlaxDHA). Lambs were fed for 56 days. Blood samples were collected on day 0 and day 56, and plasma analysed for insulin and lipids. Lambs were slaughtered, and carcass traits measured. At 30 min and 24 h, liver and muscle samples, respectively, were collected for determination of mRNA (FADS1, FADS2, CPT1A, ACOX1) and fatty acid composition. Lambs fed Flax had higher plasma triacylglycerol, body weight, body fat and carcass yield compared with the BAS group (P DHA supplementation increased carcass yield and muscle DHA while lowering plasma insulin compared with the BAS diet (P DHA treatment increased (P DHA concentration. Liver mRNA FADS2 was higher and CPT1A lower in the DHA group (P DHA diet. In summary, supplementation with ALA or DHA modulated plasma metabolites, muscle DHA, body fat and liver gene expression differently.

  13. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

    2015-07-01

    Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015 American Society for Nutrition.

  14. Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease

    OpenAIRE

    Sunny, Nishanth E.; Kalavalapalli, Srilaxmi; Bril, Fernando; Garrett, Timothy J.; Nautiyal, Manisha; Mathew, Justin T.; Williams, Caroline M.; Cusi, Kenneth

    2015-01-01

    Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperin...

  15. CT number of the fatty liver

    International Nuclear Information System (INIS)

    Maeda, Hiroko; Kawai, Takeshi; Kanasaki, Yoshiki; Akagi, Hiroaki

    1981-01-01

    This report is studied on CT number and CT images of the eight cases with fatty liver. Five of these cases showed the reversal of densities of the liver and vessels. In these cases, the diagnoses of the fatty liver were easible. In other cases, the diagnoses were possible only by comparison of the CT number of the liver and spleen because the CT number of normal liver were higher than those of the spleen. In the results which we examined the correlation of the CT number and specific gravities of the blood, normal saline, distilled water, mayonnaise, eatable iol, ethyl alcohol and lard, we observed the linear relationship between CT number and specific gravities. And so, we think that the diagnosis of the fatty liver and the degree of fatty infiltration can be guessed by the CT number of the liver and spleen. (author)

  16. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

    Science.gov (United States)

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

    2015-01-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

  17. Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice

    Science.gov (United States)

    Hou, Po-Hsun; Chang, Geng-Ruei; Chen, Chin-Pin; Lin, Yen-Ling; Chao, I-Shuan; Shen, Ting-Ting; Mao, Frank Chiahung

    2018-01-01

    Objective(s): Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet. Materials and Methods: Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured. Results: Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly. Conclusion: Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver. PMID:29922430

  18. Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review.

    Science.gov (United States)

    Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R; Partovi, Nilufar; Yoshida, Eric M

    2016-09-28

    Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited

  19. Electron autoradiographic study of intracellular conversion of fatty acids into glycogen in rats with alloxan diabetes

    International Nuclear Information System (INIS)

    Lebkova, N.P.; Bobkov, Y.I.; Gorbonova, V.D.; Kolesova, O.E.

    1985-01-01

    An electron-autoradiographic study was undertaken of the intracellular distribution of hydrogen of fatty acids in alloxan diabetes. Alloxan diabetes was induced in rats; between 2 weeks and 2 months after development of the disease 0.1 ml of tritium-oleic or tritium-arachidonic acid was injected into the caudel vein of the rats. After decapitation, myocardial tissue from the subendocardial zone of the left ventricle, liver tissue, and glycogen isolated from the liver by a biochemical method, were taken for electron-autoradiographic investigation. Analysis of the data showed that a radioactive isotope, injected into the blood stream of the animals in the form of oleic or arachidonic acids, is incorporated into various structures of hepatocytes and cardiomyocytes. Direct proof is obtained to show that glycogen in hepatocytes and cardiomyoctyes of diabetic rats may be formed from fatty acids

  20. Early Effect of High Dose of Ionizing Radiation Exposure on Plasma Lipids Profile and Liver Fatty Acids Composition in Rats

    International Nuclear Information System (INIS)

    Noaman, E.; Mansour, S.Z.; Ibrahim, N.K.

    2005-01-01

    The present study was conducted to analyze the effect of acute gamma-irradiation on rats at supralethal doses of 20 Gy to determine the synthesis and amounts of free fatty acids, neutral lipids and phospholipids of plasma and liver after 24 and 48 h of gamma-irradiation. Male Wistar rats weighing 120+- 20 g were exposed to 20 Gy of gamma radiation (dose rate of 0.59 Gy/min). Exposure of rats to ionizing radiation resulted in significant alterations in the assayed parameters indicating lipid metabolism disturbance. Plasma cholesterol and phospholipid levels increased up to 71.3 and 71.5 %, respectively, after 24 h from radiation exposure and then returned to 28 and 27 % change in-compare with control values after 48 h post-irradiation. Plasma triacylglycerol concentrations increased concomitantly with irradiation, but their values are less high than cholesterol and phospholipid levels recording significant changes at 19 and 9 % comparing with control rats. Lipid peroxidation measured as MDA recorded significant elevation after 24 and 48 h post irradiation. It was shown that the synthesis of free fatty acids, cholesterol, cholesterol ethers and phospholipids was activated 48 h after irradiation at 20 Gy. The amount of free fatty acids of the rat liver decreased at 20 Gy exposures. This is assumed to be a result of the radioresistance to some degree in the system of free fatty acid synthesis of the rat to the gamma-irradiation in the lethal doses

  1. Pomegranate seed oil influences the fatty acids profile and reduces the activity of desaturases in livers of Sprague-Dawley rats.

    Science.gov (United States)

    Białek, Agnieszka; Stawarska, Agnieszka; Bodecka, Joanna; Białek, Małgorzata; Tokarz, Andrzej

    2017-07-01

    The aim of our study was to compare the influence of diet supplementation with pomegranate seed oil - as conjugated linolenic acids (CLnA) source, or conjugated linoleic acids (CLA) and to examine the mechanism of their activity. The content of fatty acids, levels of biomarkers of lipids' oxidation and the activity of key enzymes catalyzing lipids metabolism were measured. Obtained results revealed that conjugated fatty acids significantly decrease the activity of Δ5-desaturase (p=0.0001) and Δ6-desaturase (p=0.0008) and pomegranate seed oil reduces their activity in the most potent way. We confirmed that diet supplementation with pomegranate seed oil - a rich source of punicic acid leads to the increase of cis-9, trans-11 CLA content in livers (p=0.0003). Lack of side effects and beneficial influence on desaturases activity and fatty acids profile claim pomegranate seed oil to become interesting alternative for CLA as functional food. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Hannele Yki-Järvinen

    2015-11-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL to non-alcoholic steatohepatitis (NASH and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD. Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA as compared to monounsaturated (MUFA or polyunsaturated (PUFA fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

  3. New Insights from Rodent Models of Fatty Liver Disease

    Science.gov (United States)

    2011-01-01

    Abstract Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned. Antioxid. Redox Signal. 15, 535–550. PMID:21126212

  4. Maternal intake of trans-unsaturated or interesterified fatty acids during pregnancy and lactation modifies mitochondrial bioenergetics in the liver of adult offspring in mice.

    Science.gov (United States)

    de Velasco, Patricia C; Chicaybam, Gustavo; Ramos-Filho, Dionizio M; Dos Santos, Raísa M A R; Mairink, Caroline; Sardinha, Fátima L C; El-Bacha, Tatiana; Galina, Antonio; Tavares-do-Carmo, Maria das Graças

    2017-07-01

    The quality of dietary lipids in the maternal diet can programme the offspring to diseases in later life. We investigated whether the maternal intake of palm oil or interesterified fat, substitutes for trans-unsaturated fatty acids (FA), induces metabolic changes in the adult offspring. During pregnancy and lactation, C57BL/6 female mice received normolipidic diets containing partially hydrogenated vegetable fat rich in trans-unsaturated fatty acids (TG), palm oil (PG), interesterified fat (IG) or soyabean oil (CG). After weaning, male offspring from all groups received the control diet until day 110. Plasma glucose and TAG and liver FA profiles were ascertained. Liver mitochondrial function was accessed with high-resolution respirometry by measuring VO2, fluorimetry for detection of hydrogen peroxide (H2O2) production and mitochondrial Ca2+ uptake. The results showed that the IG offspring presented a 20 % increase in plasma glucose and both the IG and TG offspring presented a 2- and 1·9-fold increase in TAG, respectively, when compared with CG offspring. Liver MUFA and PUFA contents decreased in the TG and IG offspring when compared with CG offspring. Liver MUFA content also decreased in the PG offspring. These modifications in FA composition possibly affected liver mitochondrial function, as respiration was impaired in the TG offspring and H2O2 production was higher in the IG offspring. In addition, mitochondrial Ca2+ retention capacity was reduced by approximately 40 and 55 % in the TG and IG offspring, respectively. In conclusion, maternal consumption of trans-unsaturated and interesterified fat affected offspring health by compromising mitochondrial bioenergetics and lipid metabolism in the liver.

  5. Gestational age dependent changes of the fetal brain, liver and adipose tissue fatty acid compositions in a population with high fish intakes

    NARCIS (Netherlands)

    Kuipers, Remko S.; Luxwolda, Martine F.; Offringa, Pieter J.; Boersma, E. Rudy; Dijck-Brouwer, D. A. Janneke; Muskiet, Frits A. J.

    2012-01-01

    Introduction: There are no data on the intrauterine fatty acid (FA) compositions of brain, liver and adipose tissue of infants born to women with high fish intakes. Subjects and methods: We analyzed the brain (n = 18), liver (n = 14) and adipose tissue (n = 11) FA compositions of 20 stillborn

  6. Genetics Home Reference: non-alcoholic fatty liver disease

    Science.gov (United States)

    ... individual is considered to have a fatty liver (hepatic steatosis) if the liver contains more than 5 to ... Resources Genetic Testing (2 links) Genetic Testing Registry: Fatty liver disease, nonalcoholic 1 Genetic Testing Registry: Fatty liver ...

  7. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers.

    Science.gov (United States)

    Anavi, Sarit; Madar, Zecharia; Tirosh, Oren

    2017-10-01

    Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Fatty liver incidence and predictive variables

    International Nuclear Information System (INIS)

    Tsuneto, Akira; Seto, Shinji; Maemura, Koji; Hida, Ayumi; Sera, Nobuko; Imaizumi, Misa; Ichimaru, Shinichiro; Nakashima, Eiji; Akahoshi, Masazumi

    2010-01-01

    Although fatty liver predicts ischemic heart disease, the incidence and predictors of fatty liver need examination. The objective of this study was to determine fatty liver incidence and predictive variables. Using abdominal ultrasonography, we followed biennially through 2007 (mean follow-up, 11.6±4.6 years) 1635 Nagasaki atomic bomb survivors (606 men) without fatty liver at baseline (November 1990 through October 1992). We examined potential predictive variables with the Cox proportional hazard model and longitudinal trends with the Wilcoxon rank-sum test. In all, 323 (124 men) new fatty liver cases were diagnosed. The incidence was 19.9/1000 person-years (22.3 for men, 18.6 for women) and peaked in the sixth decade of life. After controlling for age, sex, and smoking and drinking habits, obesity (relative risk (RR), 2.93; 95% confidence interval (CI), 2.33-3.69, P<0.001), low high-density lipoprotein-cholesterol (RR, 1.87; 95% CI, 1.42-2.47; P<0.001), hypertriglyceridemia (RR, 2.49; 95% CI, 1.96-3.15; P<0.001), glucose intolerance (RR, 1.51; 95% CI, 1.09-2.10; P=0.013) and hypertension (RR, 1.63; 95% CI, 1.30-2.04; P<0.001) were predictive of fatty liver. In multivariate analysis including all variables, obesity (RR, 2.55; 95% CI, 1.93-3.38; P<0.001), hypertriglyceridemia (RR, 1.92; 95% CI, 1.41-2.62; P<0.001) and hypertension (RR, 1.31; 95% CI, 1.01-1.71; P=0.046) remained predictive. In fatty liver cases, body mass index and serum triglycerides, but not systolic or diastolic blood pressure, increased significantly and steadily up to the time of the diagnosis. Obesity, hypertriglyceridemia and, to a lesser extent, hypertension might serve as predictive variables for fatty liver. (author)

  9. Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.

    Science.gov (United States)

    Tsai, Meng-Tsz; Chen, Yu-Jen; Chen, Ching-Yi; Tsai, Mong-Hsun; Han, Chia-Li; Chen, Yu-Ju; Mersmann, Harry J; Ding, Shih-Torng

    2017-03-01

    Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model. Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis. Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 μM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined. Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S -transferase (GST) concentrations are well-established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition ( P steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro ( P < 0.05). Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic indicators for NAFLD in the future. © 2017 American Society for Nutrition.

  10. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

    Science.gov (United States)

    Firneisz, Gábor

    2014-07-21

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

  11. Effect of Non-Esterified Fatty Acids on Fatty Acid Metabolism-Related Genes in Calf Hepatocytes Cultured in Vitro

    Directory of Open Access Journals (Sweden)

    Peng Li

    2013-11-01

    Full Text Available Background: NEFA plays numerous roles in the metabolism of glucose, lipids, and proteins. A number of experimental studies have shown that NEFA may have an important role in fatty acid metabolism in the liver, especially in dairy cows that experience negative energy balance (NEB during early lactation. Methods: In this study, using fluorescent quantitative RT-PCR, ELISA, and primary hepatocytes cultured in vitro, we examined the effect of NEFA (0, 0.2, 0.4, 0.8, 1.6, and 3.2 mmol/L on fatty acid metabolism by monitoring the mRNA and protein expression of the following key enzymes: long chain acyl-CoA synthetase (ACSL, carnitine palmitoyltransferase IA (CPT IA, long chain acyl-CoA dehydrogenase (ACADL, and acetyl-CoA carboxylase (ACC. Results: The mRNA and protein expression levels of ACSL and ACADL markedly increased as the concentration of NEFA in the media was increased. The mRNA and protein expression levels of CPT IA were enhanced significantly when the NEFA concentrations increased from 0 to 1.6 mmol/L and decreased significantly when the NEFA concentrations increased from 1.6 to 3.2 mmol/L. The mRNA and protein expression of ACC decreased gradually with increasing concentrations of NEFA. Conclusion: These findings indicate that increased NEFA significantly promote the activation and β-oxidation of fatty acids, but very high NEFA concentrations may inhibit the translocation of fatty acids into mitochondria of hepatocytes. This may explain the development of ketosis or liver lipidosis in dairy cows. CPT IA might be the key control enzyme of the fatty acid oxidation process in hepatocytes.

  12. Aspirin increases mitochondrial fatty acid oxidation

    International Nuclear Information System (INIS)

    Uppala, Radha; Dudiak, Brianne; Beck, Megan E.; Bharathi, Sivakama S.; Zhang, Yuxun; Stolz, Donna B.; Goetzman, Eric S.

    2017-01-01

    The metabolic effects of salicylates are poorly understood. This study investigated the effects of aspirin on fatty acid oxidation. Aspirin increased mitochondrial long-chain fatty acid oxidation, but inhibited peroxisomal fatty acid oxidation, in two different cell lines. Aspirin increased mitochondrial protein acetylation and was found to be a stronger acetylating agent in vitro than acetyl-CoA. However, aspirin-induced acetylation did not alter the activity of fatty acid oxidation proteins, and knocking out the mitochondrial deacetylase SIRT3 did not affect the induction of long-chain fatty acid oxidation by aspirin. Aspirin did not change oxidation of medium-chain fatty acids, which can freely traverse the mitochondrial membrane. Together, these data indicate that aspirin does not directly alter mitochondrial matrix fatty acid oxidation enzymes, but most likely exerts its effects at the level of long-chain fatty acid transport into mitochondria. The drive on mitochondrial fatty acid oxidation may be a compensatory response to altered mitochondrial morphology and inhibited electron transport chain function, both of which were observed after 24 h incubation of cells with aspirin. These studies provide insight into the pathophysiology of Reye Syndrome, which is known to be triggered by aspirin ingestion in patients with fatty acid oxidation disorders. - Highlights: • Aspirin increases mitochondrial—but inhibits peroxisomal—fatty acid oxidation. • Aspirin acetylates mitochondrial proteins including fatty acid oxidation enzymes. • SIRT3 does not influence the effect of aspirin on fatty acid oxidation. • Increased fatty acid oxidation is likely due to altered mitochondrial morphology and respiration.

  13. Growth Performance, Meat Quality and Fatty Acid Metabolism Response of Growing Meat Rabbits to Dietary Linoleic Acid

    Directory of Open Access Journals (Sweden)

    R. G. Li

    2012-08-01

    Full Text Available An experiment was conducted to determine the effects of different amounts of dietary linoleic acid (LA on growth performance, serum biochemical traits, meat quality, fatty acids composition of muscle and liver, acetyl-CoA carboxylase (ACC and carnitine palmitoyl transferase 1 (CPT 1 mRNA expression in the liver of 9 wks old to 13 wks old growing meat rabbits. One hundred and fifty 9 wks old meat rabbits were allocated to individual cages and randomly divided into five groups. Animals in each group were fed with a diet with the following LA addition concentrations: 0, 3, 6, 9 and 12 g/kg diet (as-fed basis and LA concentrations were 0.84, 1.21, 1.34, 1.61 and 1.80% in the diet, respectively. The results showed as follows: the dietary LA levels significantly affected muscle color of LL included a* and b* of experimental rabbits (p<0.05. The linear effect of LA on serum high density lipoprotein cholesterol was obtained (p = 0.0119. The saturated fatty acids (SFAs and monounsaturated fatty acids (MUFAs contents of LL decreased and the polyunsaturated fatty acids (PUFAs content of LL increased with dietary LA increase (p<0.0001. The PUFA n-6 content and PUFA n-3 content in the LL was significantly affected by the dietary LA levels (p<0.01, p<0.05. The MUFAs content in the liver decreased and the PUFAs contents in the liver increased with dietary LA increase (p<0.0001. The PUFA n-6 content and the PUFA n-6/n-3 ratio in the liver increased and PUFA n-3 content in the liver decreased with dietary LA increase (p<0.01. The linear effect of LA on CPT 1 mRNA expression in the liver was obtained (p = 0.0081. In summary, dietary LA addition had significant effects on liver and muscle fatty acid composition (increased PUFAs of 9 wks old to 13 wks old growing meat rabbits, but had little effects on growth performance, meat physical traits and mRNA expression of liver relative enzyme of experimental rabbits.

  14. Deleterious effect of n-3 polyunsaturated fatty acids in non-alcoholic steatohepatitis in the fat-1 mouse model

    Directory of Open Access Journals (Sweden)

    Diana Shefer-Weinberg

    2017-04-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD represents a spectrum of pathologies, ranging from hepatocellular steatosis to non-alcoholic steatohepatitis (NASH, fibrosis and cirrhosis. It has been suggested that fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFA induce beneficial effects in NAFLD. However, n-3 PUFA are sensitive to peroxidation that generate free radicals and reactive aldehydes. We aimed at determining whether changing the tissue ratio of n-3 to n-6 PUFA may be beneficial or alternatively harmful to the etiology of NAFLD. The transgenic Fat-1 mouse model was used to determine whether n-3 PUFA positively or negatively affect the development of NAFLD. fat-1mice express the fat-1 gene of Caenorhabditis elegans, which encodes an n-3 fatty-acid desaturase that converts n-6 to n-3 fatty acids. Wild-type C57BL/6 mice served as the control group. Both groups of mice were fed methionine and choline deficient (MCD diet, which induces NASH within 4 weeks. The study shows that NASH developed faster and was more severe in mice from the fat-1 group when compared to control C57BL/6 mice. This was due to enhanced lipid peroxidation of PUFA in the liver of the fat-1 mice as compared to the control group. Results of our mice study suggest that supplementing the diet of individuals who develop or have fatty livers with n-3 PUFA should be carefully considered and if recommended adequate antioxidants should be added to the diet in order to reduce such risk.

  15. Fatty Liver Index and Lipid Accumulation Product Can Predict Metabolic Syndrome in Subjects without Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Yuan-Lung Cheng

    2017-01-01

    Full Text Available Background. Fatty liver index (FLI and lipid accumulation product (LAP are indexes originally designed to assess the risk of fatty liver and cardiovascular disease, respectively. Both indexes have been proven to be reliable markers of subsequent metabolic syndrome; however, their ability to predict metabolic syndrome in subjects without fatty liver disease has not been clarified. Methods. We enrolled consecutive subjects who received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Fatty liver disease was diagnosed by abdominal ultrasonography. The ability of the FLI and LAP to predict metabolic syndrome was assessed by analyzing the area under the receiver operating characteristic (AUROC curve. Results. Male sex was strongly associated with metabolic syndrome, and the LAP and FLI were better than other variables to predict metabolic syndrome among the 29,797 subjects. Both indexes were also better than other variables to detect metabolic syndrome in subjects without fatty liver disease (AUROC: 0.871 and 0.879, resp., and the predictive power was greater among women. Conclusion. Metabolic syndrome increases the cardiovascular disease risk. The FLI and LAP could be used to recognize the syndrome in both subjects with and without fatty liver disease who require lifestyle modifications and counseling.

  16. Molecular classification of fatty liver by high-throughput profiling of protein post-translational modifications.

    Science.gov (United States)

    Urasaki, Yasuyo; Fiscus, Ronald R; Le, Thuc T

    2016-04-01

    We describe an alternative approach to classifying fatty liver by profiling protein post-translational modifications (PTMs) with high-throughput capillary isoelectric focusing (cIEF) immunoassays. Four strains of mice were studied, with fatty livers induced by different causes, such as ageing, genetic mutation, acute drug usage, and high-fat diet. Nutrient-sensitive PTMs of a panel of 12 liver metabolic and signalling proteins were simultaneously evaluated with cIEF immunoassays, using nanograms of total cellular protein per assay. Changes to liver protein acetylation, phosphorylation, and O-N-acetylglucosamine glycosylation were quantified and compared between normal and diseased states. Fatty liver tissues could be distinguished from one another by distinctive protein PTM profiles. Fatty liver is currently classified by morphological assessment of lipid droplets, without identifying the underlying molecular causes. In contrast, high-throughput profiling of protein PTMs has the potential to provide molecular classification of fatty liver. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  17. Homocysteine regulates fatty acid and lipid metabolism in yeast.

    Science.gov (United States)

    Visram, Myriam; Radulovic, Maja; Steiner, Sabine; Malanovic, Nermina; Eichmann, Thomas O; Wolinski, Heimo; Rechberger, Gerald N; Tehlivets, Oksana

    2018-04-13

    S -Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S -adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Deregulation of fatty acid metabolism and cannabinoid receptors in liver of morbidly obese women with non-alcoholic fatty liver disease

    OpenAIRE

    Berlanga Bustos, Alba

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH), with the latter being more frequently progressive. Due to lipid accumulation in the human liver seems to be a crucial mechanism in the NAFLD pathogenesis, an improved understanding of the underlying mechanisms leading to the initial hepatic lipid accumulation could be of great interest for controlling the progression of NAFLD. It has also been repor...

  19. MR and magnetisation transfer imaging in cirrhotic and fatty livers

    International Nuclear Information System (INIS)

    Alanen, A.; Komu, M.; Leino, R.; Toikkanen, S.

    1998-01-01

    Purpose: To determine whether low-field MR fat/water separation and magnetisation transfer (MT) techniques are useful in studying the livers of patients with parenchymal liver diseases in vivo. Material and Methods: MR and MT imaging of the liver in 33 patients (14 with primary biliary cirrhosis, 15 with alcohol-induced liver disease, and 4 with fatty liver) was performed by means of the fat/water separation technique at 0.1 T. The relaxation time T1 and the MT contrast (MTC) parameter of liver and spleen tissue were measured, and the relative proton density fat content N(%) and MTC of the liver were calculated from the separate fat and water images. The value of N(%) was also compared with the percentage of fatty hepatocytes at histology. Results: The relaxation rate R1 of liver measured from the magnitude image, and the difference in the value of MTC measured form the water image compared with the one measured from the fat and water magnitude image, both depended linearly on the value of N(%). The value of N(%) correlated significantly with the percentage of the fatty hepatocytes. In in vivo fatty tissue, fat infiltration increased both the observed relaxation rate R1 and the measured magnetisation ratio (the steady state magnetisation M s divided by the equilibrium magnetisation M o , M s /M o ) and consequently decreased the MT efficiency measured in a magnitude MR image. The amount of liver fibrosis did not correlate with the value of MTC measured after fat separation. Conclusion: Our results in studying fatty livers with MR imaging and the MT method show that the fat/water separation gives more reliable parametric results. Characterisation of liver cirrhosis by means of the MTC parameter is not reliable, even after fat separation. (orig.)

  20. SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

    Science.gov (United States)

    Li, Xinwei; Huang, Weikun; Gu, Jingmin; Du, Xiliang; Lei, Lin; Yuan, Xue; Sun, Guoquan; Wang, Zhe; Li, Xiaobing; Liu, Guowen

    2015-10-01

    Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver. Copyright © 2015. Published by Elsevier Inc.

  1. The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role In the Development of Liver Stage Malarial Parasites

    Science.gov (United States)

    Yu, Min; Santha Kumar, T. R.; Nkrumah, Louis J.; Coppi, Alida; Retzlaff, Silke; Li, Celeste D.; Kelly, Brendan J.; Moura, Pedro A.; Lakshmanan, Viswanathan; Freundlich, Joel S.; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H.-C.; Falkard, Brie; Sidhu, Amar bir Singh; Purcell, Lisa A.; Gratraud, Paul; Kremer, Laurent; Waters, Andy P.; Schiehser, Guy; Jacobus, David P.; Janse, Chris J.; Ager, Arba; Jacobs, William R.; Sacchettini, James C.; Heussler, Volker; Sinnis, Photini; Fidock, David A.

    2008-01-01

    SUMMARY Fatty acid biosynthesis has been viewed as an important biological function of and therapeutic target for Plasmodium falciparum asexual blood stage infection. This apicoplast-resident type II pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of the bacterial FabI inhibitor triclosan. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood stage growth. In contrast, mosquito-derived fabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver stage development in vitro. This is characterized by an inability to form intra-hepatic merosomes that normally initiate blood stage infections. These data illuminate key differences between liver and blood stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions. PMID:19064257

  2. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.

    Science.gov (United States)

    Yu, Min; Kumar, T R Santha; Nkrumah, Louis J; Coppi, Alida; Retzlaff, Silke; Li, Celeste D; Kelly, Brendan J; Moura, Pedro A; Lakshmanan, Viswanathan; Freundlich, Joel S; Valderramos, Juan-Carlos; Vilcheze, Catherine; Siedner, Mark; Tsai, Jennifer H-C; Falkard, Brie; Sidhu, Amar Bir Singh; Purcell, Lisa A; Gratraud, Paul; Kremer, Laurent; Waters, Andrew P; Schiehser, Guy; Jacobus, David P; Janse, Chris J; Ager, Arba; Jacobs, William R; Sacchettini, James C; Heussler, Volker; Sinnis, Photini; Fidock, David A

    2008-12-11

    The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.

  3. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    International Nuclear Information System (INIS)

    Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  4. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  5. Preparation of polyunsaturated fatty acid concentrates from the liver oil of dogfish (Squalus acanthias from the Black Sea.

    Directory of Open Access Journals (Sweden)

    Stefanova, K.

    1997-06-01

    Full Text Available The fatty acid composition of the liver oil from the Black Sea dogfish Squalus acanthias, as well as its seasonal variations were determined. A scheme for concentration of polyunsaturated fatty acids from the dogfish liver oil by urea complexation was proposed. From 360g of free fatty acids a 48g concentrate was obtained, containing 7,8% C20:4, 16,4% C20:5. 9,2% C22:5 and 49,7% C22:6.

    Se ha determinado la composición en ácidos grasos del aceite de hígado de cazón (Squalus acanthias del Mar Negro, así como sus variaciones estacionales. Se propone un esquema para la concentración de ácidos grasos poliinsaturados de aceite de hígado de cazón mediante complexión de urea. A partir de 360g de ácidos grasos libres se obtuvo un concentrado de 48g, que contenía 7,8% C20:4, 16,4% C20:5, 9,2% C22:5 y 49,7% C22:6.

  6. Consequences of the Combined α-tocopherol, Ascorbic Acid and α-lipoic Acid on the Glutathione, Cholesterol and Fatty Acid Composition in Muscle and Liver of Diabetic Rats

    OpenAIRE

    Okkes YILMAZ; Yasemin ERSAN; Ayse Dilek OZSAHIN; Ali Ihsan OZTURK; Yusuf OZKAN

    2013-01-01

    Objective(s): Our objective was to evaluate the effects of a triple antioxidant combination [?-tocopherol (AT), ascorbic acid (AA) and ?-lipoic acid (LA); AT+AA+LA] on the cholesterol and glutathione levels, and the fatty acid composition of liver and muscle tissues in diabetic rats. Materials and Methods: Forty-three Wistar rats were randomly divided into five groups. The first group was used as a control. The second, third and fourth groups received STZ (45 mg/kg) in citrate buffer. The fou...

  7. Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress

    Science.gov (United States)

    Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states. PMID:23035112

  8. Association between Serum Uric Acid and Non-Alcoholic Fatty Liver Disease: A Meta-Analysis.

    Science.gov (United States)

    Darmawan, Guntur; Hamijoyo, Laniyati; Hasan, Irsan

    2017-04-01

    non-alcoholic fatty liver disease (NAFLD) is known to be associated with some metabolic disorders. Recent studies suggested the role of uric acid in NAFLD through oxidative stress and inflammatory process. This study is aimed to evaluate the association between serum uric acid and NAFLD. a systematic literature review was conducted using Pubmed and Cochrane library. The quality of all studies was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). All data were analyzed using REVIEW MANAGER 5.3. eleven studies from America and Asia involving 100,275 subjects were included. The pooled adjusted OR for NAFLD was 1.92 (95% CI: 1.66-2.23; puric acid levels and severity of NAFLD. No publication bias was observed. our study demonstrated association between serum uric acid level and NAFLD. This finding brings a new insight of uric acid in clinical practice. Increased in serum uric acid levels might serve as a trigger for physician to screen for NAFLD.

  9. Elevation of urinary liver-type fatty acid binding protein after cardiac catheterization related to cardiovascular events

    Directory of Open Access Journals (Sweden)

    Kamijo-Ikemori A

    2015-08-01

    Full Text Available Atsuko Kamijo-Ikemori,1,3 Nobuyuki Hashimoto,2 Takeshi Sugaya,1 Katsuomi Matsui,1 Mikako Hisamichi,1 Yugo Shibagaki,1 Fumihiko Miyake,2 Kenjiro Kimura1 1Department of Nephrology and Hypertension, 2Department of Cardiology, 3Department of Anatomy, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Purpose: Contrast medium (CM induces tubular hypoxia via endothelial damage due to direct cytotoxicity or viscosity. Urinary liver-type fatty acid binding protein (L-FABP increases along with tubular hypoxia and may be a detector of systemic circulation injury. The aim of this study was to evaluate the clinical usefulness of detecting increases in urinary L-FABP levels due to administration of CM, as a prognostic biomarker for cardiovascular disease in patients without occurrence of CM-induced nephropathy undergoing cardiac catheterization procedure (CCP. Methods: Retrospective longitudinal analyses of the relationship between urinary L-FABP levels and occurrence of cardiovascular events were performed (n=29. Urinary L-FABP was measured by ELISA before CCP, and at 6, 12, 24, and 48 hours after CCP. Results: Urinary L-FABP levels were significantly higher at 12 hours (P<0.05 and 24 hours (P<0.005 after CCP compared with before CCP, only in the patients with occurrence of cardiovascular events (n=17, but not in those without cardiovascular events (n=12. The parameter with the largest area under the curve (0.816 for predicting the occurrence of cardiovascular events was the change in urinary L-FABP at 24 hours after CCP. The difference in urinary L-FABP levels (ΔL-FABP ≥11.0 µg/g creatinine between before CCP and at 24 hours after CCP was a risk factor for the occurrence of cardiovascular events (hazard ratio, 4.93; 95% confidence interval, 1.27–19.13; P=0.021. Conclusion: Measurement of urinary L-FABP before CCP and at 24 hours after CCP in patients with mild to moderate renal dysfunction may be an important indicator for risk

  10. Reciprocal effects of 5-(tetradecyloxy)-2-furoic acid on fatty acid oxidation.

    Science.gov (United States)

    Otto, D A; Chatzidakis, C; Kasziba, E; Cook, G A

    1985-10-01

    Under certain incubation conditions 5-(tetradecyloxy)-2-furoic acid (TOFA) stimulated the oxidation of palmitate by hepatocytes, as observed by others. A decrease in malonyl-CoA concentration accompanied the stimulation of oxidation. Under other conditions, however, TOFA inhibited fatty acid oxidation. The observed effects of TOFA depended on the TOFA and fatty acid concentrations, the cell concentration, the time of TOFA addition relative to the addition of fatty acid, and the nutritional state of the animal (fed or starved). The data indicate that only under limited incubation conditions may TOFA be used as an inhibitor of fatty acid synthesis without inhibition of fatty acid oxidation. When rat liver mitochondria were preincubated with TOFA, ketogenesis from palmitate was slightly inhibited (up to 20%) at TOFA concentrations that were less than that of CoA, but the inhibition became almost complete (up to 90%) when TOFA was greater than or equal to the CoA concentration. TOFA had only slight or no inhibitory effects on the oxidation of palmitoyl-CoA, palmitoyl(-)carnitine, or butyrate. Since TOFA can be converted to TOFyl-CoA, the data suggest that the inhibition of fatty acid oxidation from palmitate results from the decreased availability of CoA for extramitochondrial activation of fatty acids. These data, along with previous data of others, indicate that inhibition of fatty acid oxidation by CoA sequestration is a common mechanism of a group of carboxylic acid inhibitors. A general caution is appropriate with regard to the interpretation of results when using TOFA in studies of fatty acid oxidation.

  11. Bifidobacterium breve with α-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome.

    Science.gov (United States)

    Barrett, Eoin; Fitzgerald, Patrick; Dinan, Timothy G; Cryan, John F; Ross, R Paul; Quigley, Eamonn M; Shanahan, Fergus; Kiely, Barry; Fitzgerald, Gerald F; O'Toole, Paul W; Stanton, Catherine

    2012-01-01

    The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (10(9) microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (pbreve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (pbreve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (pbreve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (pbreve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (pbreve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats significantly modified the palmitoleic acid, arachidonic acid and docosahexaenoic acid contents in tissues. The effect was not observed in non-separated animals.

  12. Fatty acid synthase regulates the chemosensitivity of breast cancer cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Al-Bahlani, Shadia; Al-Lawati, Hanaa; Al-Adawi, Moza; Al-Abri, Nadia; Al-Dhahli, Buthaina; Al-Adawi, Kawther

    2017-06-01

    Fatty acid synthase (FASN) is a key enzyme in fat biosynthesis that is over-expressed in advanced breast cancer stages. Cisplatin (CDDP) is a platinum-based drug used in the treatment of certain types of this disease. Although it was shown that FASN inhibition induced apoptosis by enhancing the cytotoxicity of certain drugs in breast cancer, its role in regulating the chemosensitivity of different types of breast cancer cells to CDDP-induced apoptosis is not established yet. Therefore, two different breast cancer cell lines; triple negative breast cancer (TNBC; MDA-MB-231) and triple positive breast cancer (TPBC; BT-474) cells were used to examine such role. We show that TNBC cells had naturally less fat content than TPBC cells. Subsequently, the fat content increased in both cells when treated with Palmitate rather than Oleate, whereas both fatty acids produced apoptotic ultra-structural effects and attenuated FASN expression. However, Oleate increased FASN expression in TPBC cells. CDDP decreased FASN expression and increased apoptosis in TNBC cells. These effects were further enhanced by combining CDDP with fatty acids. We also illustrate that the inhibition of FASN by either siRNA or exogenous inhibitor decreased CDDP-induced apoptosis in TPBC cells suggesting its role as an apoptotic factor, while an opposite finding was observed in TNBC cells when siRNA and fatty acids were used, suggesting its role as a survival factor. To our knowledge, we are the first to demonstrate a dual role of FASN in CDDP-induced apoptosis in breast cancer cells and how it can modulate their chemosensitivity.

  13. Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation

    NARCIS (Netherlands)

    Benthem, L; Keizer, Klaas-Jan; Wiegman, CH; De Boer, SF; Strubbe, JH; Steffens, AB; Kuipers, F; Scheurink, AJW

    2000-01-01

    We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the

  14. CONTENT AND FATTY ACID COMPOSITION OF ESTERIFIED CHOLESTEROL OF LIVER AND REPRODUCTION ABILITY OF BROOD CARP (CYPRINUS CARPIO CARPIO WITH DIFFERENT LEVELS OF VITAMIN A IN FORMULATED FEED

    Directory of Open Access Journals (Sweden)

    I. Hrytsyniak

    2015-09-01

    Full Text Available Purpose. To investigate the effect of increased amounts of vitamin A in the diet on the fatty acid composition of esterified cholesterol of liver and reproduction ability of brood carp females and males. Methodology. The experiment was conducted in pre-spawning period using three groups of brood carp. The control group of carp received standard granulated feed. Experimental groups of brood carps additionally received retynilatsetat in the composition of the above-mentioned fodder. Findings. It was found that the liver of females and males of brood carp of experimental groups, which received vitamin A at a quantity of 2500 and 5000 IU/kg of feed in the composition of standard granulated formulated feed during pre-spawning period had shown a dose-dependent reduction in the content of esterified cholesterol. At the same time, the level of monounsaturated fatty acids of n-9 family decreases significantly and dose-dependently in its fatty acid composition, however, there is an increase in the level of saturated fatty acids with paired and unpaired quantities of carbon atoms in the chain as well as polyunsaturated fatty acids of n-6 family and especially n-3 family. Females of brood carp in the experimental groups, which were fed with additional vitamin A at a quantity of 2500 and 5000 IU/kg of standard granulated formulated feed during pre-spawning period, had an increase in working and relative fecundity, while males had an increase in sperm volume. At the same time, the output of larvae from eggs increases significantly and dose-dependently. Originality. For the first time it was found that the liver of brood carp females and males, which received increased quantities of vitamin A in the composition of standard granulated formulated feed during pre-spawning period, had the reduction in the content of esterified cholesterol. the level of monounsaturated fatty acids of n-9 family decreases significantly and dose-dependently in its fatty acid

  15. [Advances in the pathogenesis of non alcoholic fatty liver disease].

    Science.gov (United States)

    Pár, Alajos; Pár, Gabriella

    2017-06-01

    Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen-associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894.

  16. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

    International Nuclear Information System (INIS)

    Zhang, Yu-Kun Jennifer; Yeager, Ronnie L.; Tanaka, Yuji; Klaassen, Curtis D.

    2010-01-01

    Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstα1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.

  17. A Polysaccharide from Ganoderma atrum Improves Liver Function in Type 2 Diabetic Rats via Antioxidant Action and Short-Chain Fatty Acids Excretion.

    Science.gov (United States)

    Zhu, Ke-Xue; Nie, Shao-Ping; Tan, Le-He; Li, Chuan; Gong, De-Ming; Xie, Ming-Yong

    2016-03-09

    The present study was to evaluate the beneficial effect of polysaccharide isolated from Ganoderma atrum (PSG-1) on liver function in type 2 diabetic rats. Results showed that PSG-1 decreased the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), while increasing hepatic glycogen levels. PSG-1 also exerted strong antioxidant activities, together with upregulated mRNA expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), glucose transporter-4 (GLUT4), phosphoinositide 3-kinase (PI3K), and phosphorylated-Akt (p-Akt) in the liver of diabetic rats. Moreover, the concentrations of short-chain fatty acids (SCFA) were significantly higher in the liver, serum, and faeces of diabetic rats after treating with PSG-1 for 4 weeks. These results suggest that the improvement of PSG-1 on liver function in type 2 diabetic rats may be due to its antioxidant effects, SCFA excretion in the colon from PSG-1, and regulation of hepatic glucose uptake by inducing GLUT4 translocation through PI3K/Akt signaling pathways.

  18. A Case of Montelukast-Induced Churg-Strauss Syndrome Associated with Liver Dysfunction

    Directory of Open Access Journals (Sweden)

    Keiji Matsui

    2011-01-01

    Full Text Available A 64-year-old woman was admitted to hospital due to protracted diarrhea and liver dysfunction. The patient was diagnosed as Churg-Strauss syndrome (CSS due to asthma, paranasal sinusitis, hypereosinophilia, and polyneuropathy. There was a history of taking montelukast, a leukotriene receptor antagonist (LTRA, which is thought to have some relationship with CSS. The liver biopsy specimen showed eosinophilic infiltration and centrolobular fatty change. In this paper, we review the relationship between LTRA and CSS. Several lines of evidence suggest that leukotriene plays an important role in maintaining neural tissues. We also review the potential relationship between centrolobular fatty change and pivoxil-containing antibiotics, which was prescribed for sinusitis before admission. Carnitine deficiency induced by pivoxil-containing agents may cause impaired fatty acid oxidation in mitochondria.

  19. Experimental Protoporphyria: Effect of Bile Acids on Liver Damage Induced by Griseofulvin

    Directory of Open Access Journals (Sweden)

    María del Carmen Martinez

    2015-01-01

    Full Text Available The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA, dehydrocholic (DHA, chenodeoxycholic, or ursodeoxycholic (URSO. The administration of Gris alone increased the activities of glutathione reductase (GRed, superoxide dismutase (SOD, alkaline phosphatase (AP, gamma glutamyl transpeptidase (GGT, and glutathione-S-transferase (GST, as well as total porphyrins, glutathione (GSH, and cytochrome P450 (CYP levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

  20. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

    Science.gov (United States)

    Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

    2017-04-01

    For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (PBCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

    DEFF Research Database (Denmark)

    Madsen, Lise; Petersen, Rasmus K; Steffensen, Knut R

    2008-01-01

    The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced...

  2. Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization

    Science.gov (United States)

    The incidence of nonalcoholic fatty liver disease (NAFLD) is escalating paralleled with obesity rates in both adults and children. Mammalian sirtuin 1 (SIRT1), a highly conserved NAD+-dependent protein deacetylase, has been identified as a metabolic regulator of lipid homeostasis and a potential tar...

  3. Clofibric acid increases the formation of oleic acid in endoplasmic reticulum of the liver of rats.

    Science.gov (United States)

    Hirose, Akihiko; Yamazaki, Tohru; Sakamoto, Takeshi; Sunaga, Katsuyoshi; Tsuda, Tadashi; Mitsumoto, Atsushi; Kudo, Naomi; Kawashima, Yoichi

    2011-01-01

    The effects of 2-(4-chlorophenoxy)-2-methylpropionic acid (clofibric acid) on the formation of oleic acid (18:1) from stearic acid (18:0) and utilization of the 18:1 formed for phosphatidylcholine (PC) formation in endoplasmic reticulum in the liver of rats were studied in vivo. [¹⁴C]18:0 was intravenously injected into control Wistar male rats and rats that had been fed on a diet containing 0.5% (w/w) clofibric acid for 7 days; and the distribution of radiolabeled fatty acids among subcellular organelles, microsomes, peroxisomes, and mitochondria, was estimated on the basis of correction utilizing the yields from homogenates of marker enzymes for these organelles. The radioactivity was mostly localized in microsomes and the radiolabeled fatty acids present in microsomes were significantly increased by the treatment of rats with clofibric acid. The formation of radiolabeled 18:1 in microsomes markedly increased and incorporations of the formed [¹⁴C]18:1 into PC and phosphatidylethanolamine in microsomes were augmented in response to clofibric acid. The [¹⁴C]18:1 incorporated into PC was mostly located at the C-2 position, but not the C-1 position, of PC, and the radioactivity in 18:1 at the C-2 position of PC was strikingly increased by clofibric acid. These results obtained from the in vivo experiments directly link the findings that clofibric acid treatment induces microsomal stearoyl-CoA desaturase and 1-acylglycerophosphocholine acyltransferase in the liver and the findings that the treatment with the drug elevated absolute mass and mass proportion of 18:1 at the C-2 position, but not the C-1 position, of PC in the liver together.

  4. [Progress in research of the mechanisms related with the hepatic steatosis in the nonalcoholic fatty liver disease].

    Science.gov (United States)

    Shi, Li-Juan; Song, Guang-Yao

    2013-12-01

    With the increased morbidity of Nonalcoholic fatty liver disease, the pathogenesis of which has become one of the focuses for researchers. Many details need to be clarified. The hepatic steatosis has been taken as the clinical pathological characters and the "golden standard of diagnosis" for the nonalcoholic fatty liver disease. More and more studies have shown that the hepatic steatosis (mainly as triglycerides) is the consequence of hepatic lipid metabolism disequilibrium. Generally, the related metabolism pathways including lipid input, lipid uptake, de novo lipogenesis, fatty acid oxidation, fatty acid reesterification, and lipid secretion etc. In this review, we focused on the progress of some key enzymes involved in these pathways in order to clarify the possible molecular mechanisms and the effective targets so that to broad our vision about the prevention and treatment of non-alcoholic fatty liver disease.

  5. Interaction of LY171883 and other peroxisome proliferators with fatty-acid-binding protein isolated from rat liver.

    Science.gov (United States)

    Cannon, J R; Eacho, P I

    1991-01-01

    Fatty-acid-binding protein (FABP) is a 14 kDa protein found in hepatic cytosol which binds and transports fatty acids and other hydrophobic ligands throughout the cell. The purpose of this investigation was to determine whether LY171883, a leukotriene D4 antagonist, and other peroxisome proliferators bind to FABP and displace an endogenous fatty acid. [3H]Oleic acid was used to monitor the elution of FABP during chromatographic purification. [14C]LY171883 had a similar elution profile when substituted in the purification, indicating a common interaction with FABP. LY171883 and its structural analogue, LY189585, as well as the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate, bezafibrate and WY14,643, displaced [3H]oleic acid binding to FABP. Analogues of LY171883 that do not induce peroxisome proliferation only weakly displaced oleate binding. [3H]Ly171883 bound directly to FABP with a Kd of 10.8 microM, compared with a Kd of 0.96 microM for [3H]oleate. LY171883 binding was inhibited by LY189585, clofibric acid, ciprofibrate and bezafibrate. These findings demonstrate that peroxisome proliferators, presumably due to their structural similarity to fatty acids, are able to bind to FABP and displace an endogenous ligand from its binding site. Interaction of peroxisome proliferators with FABP may be involved in perturbations of fatty acid metabolism caused by these agents as well as in the development of the pleiotropic response of peroxisome proliferation. Images Fig. 2. PMID:1747111

  6. Non-Alcoholic Fatty Liver Disease in HIV Infection.

    Science.gov (United States)

    Macías, Juan; Pineda, Juan A; Real, Luis M

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.

  7. Amphiphile-induced heart muscle-cell (myocyte) injury: effects of intracellular fatty acid overload.

    Science.gov (United States)

    Janero, D R; Burghardt, C; Feldman, D

    1988-10-01

    Lipid amphiphile toxicity may be an important contributor to myocardial injury, especially during ischemia/reperfusion. In order to investigate directly the potential biochemical and metabolic effects of amphiphile overload on the functioning heart muscle cell (myocyte), a novel model of nonesterified fatty acid (NEFA)-induced myocyte damage has been defined. The model uses intact, beating neonatal rat myocytes in primary monolayer culture as a study object and 5-(tetradecyloxy)-2-furoic acid (TOFA) as a nonmetabolizable fatty acid. Myocytes incubated with TOFA accumulated it as NEFA, and the consequent NEFA amphiphile overload elicited a variety of cellular defects (including decreased beating rate, depletion of high-energy stores and glycogen pools, and breakdown of myocyte membrane phospholipid) and culminated in cell death. The amphiphile-induced cellular pathology could be reversed by removing TOFA from the culture medium, which resulted in intracellular TOFA "wash-out." Although the development and severity of amphiphile-induced myocyte injury could be correlated with both the intracellular TOFA/NEFA content (i.e., the level of TOFA to which the cells were exposed) and the duration of this exposure, removal of amphiphile overload did not inevitably lead to myocyte recovery. TOFA had adverse effects on myocyte mitochondrial function in situ (decoupling of oxidative phosphorylation, impairing respiratory control) and on myocyte oxidative catabolism (transiently increasing fatty acid beta oxidation, citric acid cycle flux, and glucose oxidation). The amphiphile-induced bioenergetic abnormalities appeared to constitute a state of "metabolic anoxia" underlying the progression of myocyte injury to cell death. This anoxic state could be ameliorated to some extent, but not prevented, by carbohydrate catabolism.

  8. Water Extract of Dolichos lablab Attenuates Hepatic Lipid Accumulation in a Cellular Nonalcoholic Fatty Liver Disease Model.

    Science.gov (United States)

    Im, A-Rang; Kim, Yun Hee; Lee, Hye Won; Song, Kwang Hoon

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is rising in prevalence worldwide. Therapeutic strategies for patients with NAFLD are limited by a lack of effective drugs. In this report, we show that Dolichos lablab water extract (DLL-Ex) protects against free fatty acid (FFA)-induced lipid accumulation and attenuates expression of genes involved in lipid droplet accumulation in cellular NAFLD models. The hepatoprotective effects and underlying mechanism of DLL-Ex were assessed using an in vitro cellular model in which NAFLD was simulated by inducing excessive FFA influx into hepatocytes. HepG2 cells were treated with DLL-Ex and FFAs for 24 h, after which intracellular lipid content was observed by using Nile Red and Oil Red O staining. Quantitative real-time polymerase chain reaction was used to measure expression levels of genes related to FFA-mediated cellular energy depletion. Western blotting was used to measure protein levels of phosphorylated c-Jun N-terminal kinase, AMP-activated protein kinase alpha (AMPKα), and peroxisome proliferator-activated receptor γ coactivator 1 alpha. In HepG2 cells, DLL-Ex inhibited expression of CD36, which regulates fatty acid uptake, as well as BODIPY-labeled fatty acid uptake. Additionally, DLL-Ex significantly attenuated FFA-mediated cellular energy depletion and mitochondrial membrane depolarization. Furthermore, DLL-Ex enhanced phosphorylation of AMPK, indicating that AMPK is a critical regulator of DLL-Ex-mediated inhibition of hepatic lipid accumulation, possibly through its antioxidative effect. These results demonstrate that DLL-Ex exerts potent anti-NAFLD activity, suggesting that it could be a potential adjuvant treatment for patients with NAFLD.

  9. HEPATIC FATTY ACID PROFILE OF RATS FED A TRIHEPTANOIN-BASED KETOGENIC DIET.

    Science.gov (United States)

    Vieira de Melo, Ingrid Sofia; Da Rocha Ataide, Terezinha; Lima de Oliveira, Suzana; Bezerra Bueno, Nassib; Duarte de Freitas, Johnnatan; Goulart Sant'Ana, Antônio Euzébio

    2015-07-01

    the aim of this study was to evaluate the influence of consumption of a ketogenic diet supplemented with triheptanoin, a medium-chain anaplerotic triacylglycerol, on the liver fatty acid profile of Wistar rats. three groups of male Wistar rats (n = 10) were submitted to an AIN-93 control diet, a triheptanoin- based ketogenic diet, or a soybean oil-based ketogenic diet for 60 days. Excised livers were subjected to lipid extraction and methylation to obtain fatty acids methyl esters, which were subjected to gas chromatography- mass spectrometry. compared to the rats fed the control diet, those fed ketogenic diets showed a significant reduction in the concentrations of 9-hexadecenoic and 9-octadecenoic acids, whereas those fed triheptanoin showed increased levels of octadecanoic acid. changes in the liver fatty acid profiles of the rats fed a triheptanoin-based or a soybean oil-based ketogenic diet did not seem to be related to the dietary fat source, but rather to the characteristics of the ketogenic diets themselves. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  10. [Non-alcoholic fatty liver disease--new view].

    Science.gov (United States)

    Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

    2008-06-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

  11. Preferential oxidation of linolenic acid compared to linoleic acid in the liver of catfish (Heteropneustes fossilis and Clarias batrachus)

    International Nuclear Information System (INIS)

    Bandyopadhyay, G.K.; Dutta, J.; Ghosh, S.

    1982-01-01

    The fate of [1(- 14 C] linoleic acid and [1( 14 C] linolenic acid in the liver slices and also in the liver tissues of live carnivorous catfish, Heteropneustes fossilis and Clarias batrachus, was studied. Incorporation of the fatty acids into different lipid classes in the live fish differed greatly from the tissue slices, indicating certain physiological control operative in vivo. The extent of desaturation and chain elongation of linoleic and linolenic acids into long-chain polyunsaturated fatty acids was low. Linolenic acid was oxidized (thus labeling the saturated fatty acid with liberated 14 C-acetyl-CoA) in preference to linoleic acid, and this oxidation also seemed to be under physiological control since both of the fatty acids were poorly oxidized in the tissue slices and in the killed fish. These fish can therefore recognize the difference in the acyl chain structures of linoleate and linolenate. The higher oxidation of linolenic acid and poor capacity for its conversion to longer chain, highly unsaturated derivatives indicates a higher demand for the dietary supply of these essential fatty acids in these two species

  12. CT appearance of focal fatty infiltration of the liver

    International Nuclear Information System (INIS)

    Halvorsen, R.A.; Korobkin, M.; Ram, P.C.; Thompson, W.M.

    1982-01-01

    Focal fatty infiltration of the liver is an entity that may be confused with liver metastasis on computed tomography (CT). The imaging results and medical records of 16 patients with CT appearance suggestive of focal fatty liver were reviewed, three of whom had the simultaneous presence of metastitic liver disease. Focal fatty liver often has a distinctive appearance with CT, usually with a nonspherical shape, absence of mass effect, and density close to water. Liver metastases are usually round or oval, and unless cystic or necrotic, they have CT attenuation values closer to normal liver parenchyma than water. A radionuclide liver scan almost always resolves any confusion about the differential diagnosis of focal fatty liver: a well defined focus of photon deficiency is due to neoplasm rather than focal fatty infiltration. Sonography sometimes helps to confirm the CT impression, but may be misleading if the diagnosis of focal or diffuse fatty infiltration is not suspected before the examination

  13. Dietary α-lactalbumin induced fatty liver by enhancing nuclear liver X receptor αβ/sterol regulatory element-binding protein-1c/PPARγ expression and minimising PPARα/carnitine palmitoyltransferase-1 expression and AMP-activated protein kinase α phosphorylation associated with atherogenic dyslipidaemia, insulin resistance and oxidative stress in Balb/c mice.

    Science.gov (United States)

    López-Oliva, María Elvira; Garcimartin, Alba; Muñoz-Martínez, Emilia

    2017-12-01

    The effect and the role played by dietary α-lactalbumin (α-LAC) on hepatic fat metabolism are yet to be fully elucidated. We reported previously that α-LAC intake induced atherogenic dyslipidaemia in Balb/c mice. The aim of the present study was to investigate if this atherogenic effect could be due to a possible α-LAC-induced hepatic steatosis. We examine the ability of dietary α-LAC to induce liver steatosis, identifying the molecular mechanisms underlying hepatic lipid metabolism in association with the lipid profile, peripheral insulin resistance (IR) and changes in the hepatic oxidative environment. Male Balb/c mice (n 6) were fed with diets containing either chow or 14 % α-LAC for 4 weeks. The α-LAC-fed mice developed abdominal adiposity and IR. Moderate liver steatosis with increased TAG and NEFA contents was correlated with atherogenic dyslipidaemia. There was increased nuclear expression of liver X receptor αβ (LXRαβ), sterol regulatory element-binding protein-1c (SREBP-1c) and PPARγ transcription factors and of the cytosolic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase involved in the hepatic de novo lipogenesis. The opposite was found for the nuclear receptor PPARα and the mitochondrial enzyme carnitine palmitoyltransferase-1 (CPT-1), leading to reduced fatty acid β-oxidation (FAO). These changes were associated with a significant decrease in both p-Thr172-AMP-activated protein kinase α (AMPKα) (inactivation) and p-Ser79-ACC1 (activation) and with a more oxidative liver environment increasing lipid peroxidation and protein oxidation and reducing GSH:GSSG ratio in the α-LAC-fed mice. In conclusion, 4 weeks of 14 % α-LAC feeding induced liver steatosis associated with atherogenic dyslipidaemia, IR and oxidative stress by enhancing nuclear LXRαβ/SREBP-1c/PPARγ expression and diminishing PPARα/CPT-1 expression and AMPKα phosphorylation shifting the hepatic FAO toward fatty acid synthesis in Balb/c mice.

  14. Fatty acid and sterol contents during tulip leaf senescence induced by methyl jasmonate

    Directory of Open Access Journals (Sweden)

    Marian Saniewski

    2013-12-01

    Full Text Available It has been shown previously that methyl jasmonate (JA-Me applied in lanolin paste on the bottom surface of intact tulip leaves causes a rapid and intense its senescence. The aim of this work was to study the effect of JA-Me on free and bound fatty acid and sterol contents during tulip leaf senescence. The main free and bound fatty acids of tulip leaf, in decreasing order of their abundance, were linolenic, linoleic, palmitic, oleic, stearic and myristic acids. Only the content of free linolenic acid decreased after treatment with JA-Me during visible stage of senescence. ß-Sitosterol (highest concentration, campesterol, stigmasterol and cholesterol were identified in tulip leaf. Methyl jasmonate evidently increased the level of ß-sitosterol, campesterol and stigmasterol during induced senescence. It is suggested that the increase in sterol concentrations under the influence of methyl jasmonate induced changes in membrane fluidity and permeability, which may be responsible for senescence.

  15. Chemoproteomic Profiling of Acetanilide Herbicides Reveals Their Role in Inhibiting Fatty Acid Oxidation.

    Science.gov (United States)

    Counihan, Jessica L; Duckering, Megan; Dalvie, Esha; Ku, Wan-Min; Bateman, Leslie A; Fisher, Karl J; Nomura, Daniel K

    2017-03-17

    Acetanilide herbicides are among the most widely used pesticides in the United States, but their toxicological potential and mechanisms remain poorly understood. Here, we have used chemoproteomic platforms to map proteome-wide cysteine reactivity of acetochlor (AC), the most widely used acetanilide herbicide, in vivo in mice. We show that AC directly reacts with >20 protein targets in vivo in mouse liver, including the catalytic cysteines of several thiolase enzymes involved in mitochondrial and peroxisomal fatty acid oxidation. We show that the fatty acids that are not oxidized, due to impaired fatty acid oxidation, are instead diverted into other lipid pathways, resulting in heightened free fatty acids, triglycerides, cholesteryl esters, and other lipid species in the liver. Our findings show the utility of chemoproteomic approaches for identifying novel mechanisms of toxicity associated with environmental chemicals like acetanilide herbicides.

  16. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  17. Effects of induced subacute ruminal acidosis on milk fat content and milk fatty acid profile.

    Science.gov (United States)

    Enjalbert, F; Videau, Y; Nicot, M C; Troegeler-Meynadier, A

    2008-06-01

    Two lactating dairy cows fitted with a rumen cannula received successively diets containing 0%, 20%, 34% and again 0% of wheat on a dry matter basis. After 5, 10 and 11 days, ruminal pH was measured between 8:00 and 16:00 hours, and milk was analysed for fat content and fatty acid profile. Diets with 20% and 34% wheat induced a marginal and a severe subacute ruminal acidosis respectively. After 11 days, diets with wheat strongly reduced the milk yield and milk fat content, increased the proportions of C8:0 to C13:0 even- or odd-chain fatty acids, C18:2 n-6 and C18:3 n-3 fatty acids but decreased the proportions of C18:0 and cis-9 C18:1 fatty acids. Wheat also increased the proportions of trans-5 to trans-10 C18:1, the latter exhibiting a 10-fold increase with 34% of wheat compared with value during the initial 0% wheat period. There was also an increase of trans-10, cis-12 C18:2 fatty acid and a decrease of trans-11 to trans-16 C18:1 fatty acids. The evolution during adaptation or after return to a 0% wheat diet was rapid for pH but much slower for the fatty acid profile. The mean ruminal pH was closely related to milk fat content, the proportion of odd-chain fatty acids (linear relationship) and the ratio of trans-10 C18:1/trans-11 C18:1 (nonlinear relationship). Such changes in fatty acid profile suggested a possible use for non-invasive diagnosis of subacute ruminal acidosis.

  18. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

    Directory of Open Access Journals (Sweden)

    Amanda Natália Lucchesi

    2015-01-01

    Full Text Available Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC and 30 untreated diabetic (UD rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

  19. Bifidobacterium breve with α-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome.

    Directory of Open Access Journals (Sweden)

    Eoin Barrett

    Full Text Available The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15 were orally gavaged with either B. breve DPC6330 (10(9 microorganisms/day alone or in combination with 0.5% (w/w linoleic acid & 0.5% (w/w α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11 in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05. Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11 in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05, whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05 compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01 and α-linolenic acid in adipose tissue (p<0.001, whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05, and α-linolenic acid in adipose tissue (p<0.001. B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated

  20. Hepatic fatty acid profile of rats fed a triheptanoin-based ketogenic diet

    OpenAIRE

    Meloi, Ingrid Sofia Vieira de; Ataidei, Terezinha da Rocha; Oliveirai, Suzana Lima de; Bezerra Buenoi, Nassib; Freitasi, Johnnatan Duarte de; Sant'Anai, Antônio Euzébio Goulart

    2015-01-01

    Objective: the aim of this study was to evaluate the influence of consumption of a ketogenic diet supplemented with triheptanoin, a medium-chain anaplerotic triacylglycerol, on the liver fatty acid profile of Wistar rats. Methods: three groups of male Wistar rats (n = 10) were submitted to an AIN-93 control diet, a triheptanoin- based ketogenic diet, or a soybean oil-based ketogenic diet for 60 days. Excised livers were subjected to lipid extraction and methylation to obtain fatty acids methy...

  1. Effect of essential fatty acids on glucose-induced cytotoxicity to retinal vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Shen Junhui

    2012-07-01

    Full Text Available Abstract Background Diabetic retinopathy is a major complication of dysregulated hyperglycemia. Retinal vascular endothelial cell dysfunction is an early event in the pathogenesis of diabetic retinopathy. Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by docosahexaenoic acid (DHA, 22:6 ω-3 and eicosapentaenoic acid (EPA, 20:5 ω-3. The influence of dietary omega-3 PUFA on brain zinc metabolism has been previously implied. Zn2+ is essential for the activity of Δ6 desaturase as a co-factor that, in turn, converts essential fatty acids to their respective long chain metabolites. Whether essential fatty acids (EFAs α-linolenic acid and linoleic acid have similar beneficial effect remains poorly understood. Methods RF/6A cells were treated with different concentrations of high glucose, α-linolenic acid and linoleic acid and Zn2+. The alterations in mitochondrial succinate dehydrogenase enzyme activity, cell membrane fluidity, reactive oxygen species generation, SOD enzyme and vascular endothelial growth factor (VEGF secretion were evaluated. Results Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by both linoleic acid (LA and α-linolenic acid (ALA, while the saturated fatty acid, palmitic acid was ineffective. A dose–response study with ALA showed that the activity of the mitochondrial succinate dehydrogenase enzyme was suppressed at all concentrations of glucose tested to a significant degree. High glucose enhanced fluorescence polarization and microviscocity reverted to normal by treatment with Zn2+ and ALA. ALA was more potent that Zn2+. Increased level of high glucose caused slightly increased ROS generation that correlated with corresponding decrease in SOD activity. ALA suppressed ROS generation to a significant degree in a dose dependent fashion and raised SOD activity significantly. ALA suppressed

  2. Effect of inulin supplementation and dietary fat source on performance, blood serum metabolites, liver lipids, abdominal fat deposition, and tissue fatty acid composition in broiler chickens.

    Science.gov (United States)

    Velasco, S; Ortiz, L T; Alzueta, C; Rebolé, A; Treviño, J; Rodríguez, M L

    2010-08-01

    A study was conducted to evaluate the effect of adding inulin to diets containing 2 different types of fat as energy sources on performance, blood serum metabolites, liver lipids, and fatty acids of abdominal adipose tissue and breast and thigh meat. A total of 240 one-day-old female broiler chicks were randomly allocated into 1 of 6 treatments with 8 replicates per treatment and 5 chicks per pen. The experiment consisted of a 3 x 2 factorial arrangement of treatments including 3 concentrations of inulin (0, 5, and 10 g/kg of diet) and 2 types of fat [palm oil (PO) and sunflower oil (SO)] at an inclusion rate of 90 g/kg of diet. The experimental period lasted from 1 to 34 d. Dietary fat type did not affect BW gain but impaired feed conversion (P abdominal fat deposition and serum lipid and glucose concentrations. Triacylglycerol contents in liver were higher in the birds fed PO diets. Dietary fat type also modified fatty acids of abdominal and i.m. fat, resulting in a higher concentration of C16:0 and C18:1n-9 and a lower concentration of C18:2n-6 in the birds fed PO diets. The addition of inulin to diets modified (P = 0.017) BW gain quadratically without affecting feed conversion. Dietary inulin decreased the total lipid concentration in liver (P = 0.003) and that of triacylglycerols and very low density lipoprotein cholesterol (up to 31%) in blood serum compared with the control groups. The polyunsaturated fatty acid:saturated fatty acid ratio increased in abdominal and i.m. fat when inulin was included in the SO-containing diets. The results from the current study suggest that the addition of inulin to broiler diets has a beneficial effect on blood serum lipids by decreasing triacylglyceride concentrations The results also support the use of inulin to increase the capacity of SO for enhancing polyunsaturated fatty acid:saturated fatty acid ratio of i.m. fat in broilers.

  3. Uptake of oleate by isolated rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut

    International Nuclear Information System (INIS)

    Schwieterman, W.; Sorrentino, D.; Potter, B.J.; Rand, J.; Kiang, C.L.; Stump, D.; Berk, P.D.

    1988-01-01

    A portion of the hepatocellular uptake of nonesterified long-chain fatty acids is mediated by a specific 40-kDa plasma membrane fatty acid binding protein, which has also been isolated from the gut. To investigate whether a similar transport process exists in other tissues with high transmembrane fatty acid fluxes, initial rates (V/sub O/) of [ 3 H]-oleate uptake into isolated rat adipocytes were studied as a function of the concentration of unbound [ 3 H]oleate in the medium. V/sub O/ reached a maximum as the concentration of unbound oleate was increased and was significantly inhibited both by phloretin and by prior incubation of the cells with Pronase. A rabbit antibody to the rat liver plasma membrane fatty acid binding protein inhibited adipocyte fatty acid uptake by up to 63% in dose-dependent fashion. Inhibition was noncompetitive; at an immunoglobulin concentration of 250 μg/ml V/sub max/ was reduced from 2480 /plus minus/ 160 to 1870 /plus minus/ 80 pmol/min per 5 /times/ 10 4 adipocytes, with no change in K/sub m/. A basic kDa adipocyte plasma membrane fatty acid binding protein, isolated from crude adipocyte plasma membrane fractions, reacted strongly in both agar gel diffusion and electrophoretic blots with the antibody raised against the corresponding hepatic plasma membrane protein. These data indicate that the uptake of oleate by rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut

  4. Fatty acid profiles in tissues of mice fed conjugated linoleic acid

    DEFF Research Database (Denmark)

    Gøttsche, Jesper; Straarup, Ellen Marie

    2006-01-01

    The incorporation of vaccenic acid (VA, 0.5 and 1.2%), conjugated linoleic acid (CLA, mixture of primarily c9,t11- and t10,c12-CLA, 1.2%), linoleic acid (LA, 1.2%) and oleic acid (OA, 1.2%) into different tissues of mice was examined. The effects on the fatty acid composition of triacylglycerols...... (TAG) and phospholipids (PL) in kidney, spleen, liver and adipose tissue were investigated. VA and CLA (c9,t11- and t10,c12-CLA) were primarily found in TAG, especially in kidney and adipose tissue, respectively. Conversion of VA to c9,t11-CLA was indicated by our results, as both fatty acids were...... incorporated into all the analyzed tissues when a diet containing VA but not c9,t11-CLA was fed. Most of the observed effects on the fatty acid profiles were seen in the CLA group, whereas only minor effects were observed in the VA groups compared with the CA group. Thus, CLA increased n-3 polyunsaturated...

  5. Fatty infiltration of the liver: evaluation by proton spectroscopic imaging

    International Nuclear Information System (INIS)

    Heiken, J.P.; Lee, J.K.; Dixon, W.T.

    1985-01-01

    The reliability of proton spectroscopic imaging in evaluating fatty infiltration of the liver was investigated in 35 subjects (12 healthy volunteers and 23 patients with fatty livers). With this modified spin-echo technique, fatty liver could be separated from normal liver both visually and quantitatively. On the opposed image, normal liver had an intermediate signal intensity, greater than that of muscle, whereas fatty liver had a lower signal intensity, equal to or less than that of muscle. In normal livers, the lipid signal fraction was less than 10%, while in fatty livers it was greater than 10% and usually exceeded 20%. With this technique, nonuniform fatty infiltration of the liver can be differentiated from hepatic metastases, and the technique may prove useful in the differentiation of some hepatic disorders

  6. Selective inhibition of type 2 fatty acid synthetase by the antibiotic thiolactomycin

    International Nuclear Information System (INIS)

    Nishida, Ikuo; Kawaguchi, Akihiko; Yamada, Mitsuhiro

    1984-01-01

    The antibiotic thiolactomycin inhibits the fatty acid synthesis from both [1- 14 C]-acetate and [2 14 C] malonyl-CoA of spinach leaves, developing castor bean endosperms and avocado mesocarp. On the other hand, fatty acid synthetases of Brevibacterium ammoniagenes and Corynebacterium glutamicum are much less sensitive to this antibiotic. As Hayashi et al. have indicated in their paper that thiolactomycin inhibits fatty acid synthetase of Escherichia coli but has little effect on the synthetases of yeast and rat liver, thiolactomycin is suggested to be a selective inhibitor of type 2 fatty acid synthetases. (author)

  7. Selective inhibition of type 2 fatty acid synthetase by the antibiotic thiolactomycin

    Energy Technology Data Exchange (ETDEWEB)

    Nishida, Ikuo; Kawaguchi, Akihiko; Yamada, Mitsuhiro (Tokyo Univ. (Japan). Faculty of Science)

    1984-03-01

    The antibiotic thiolactomycin inhibits the fatty acid synthesis from both (1-/sup 14/C)-acetate and (2/sup 14/C) malonyl-CoA of spinach leaves, developing castor bean endosperms and avocado mesocarp. On the other hand, fatty acid synthetases of Brevibacterium ammoniagenes and Corynebacterium glutamicum are much less sensitive to this antibiotic. As Hayashi et al. have indicated in their paper that thiolactomycin inhibits fatty acid synthetase of Escherichia coli but has little effect on the synthetases of yeast and rat liver, thiolactomycin is suggested to be a selective inhibitor of type 2 fatty acid synthetases.

  8. Whole Rye Consumption Improves Blood and Liver n-3 Fatty Acid Profile and Gut Microbiota Composition in Rats.

    Science.gov (United States)

    Ounnas, Fayçal; Privé, Florence; Salen, Patricia; Gaci, Nadia; Tottey, William; Calani, Luca; Bresciani, Letizia; López-Gutiérrez, Noelia; Hazane-Puch, Florence; Laporte, François; Brugère, Jean-François; Del Rio, Daniele; Demeilliers, Christine; de Lorgeril, Michel

    2016-01-01

    Whole rye (WR) consumption seems to be associated with beneficial health effects. Although rye fiber and polyphenols are thought to be bioactive, the mechanisms behind the health effects of WR have yet to be fully identified. This study in rats was designed to investigate whether WR can influence the metabolism of n-3 and n-6 long-chain fatty acids (LCFA) and gut microbiota composition. For 12 weeks, rats were fed a diet containing either 50% WR or 50% refined rye (RR). The WR diet provided more fiber (+21%) and polyphenols (+29%) than the RR diet. Fat intake was the same in both diets and particularly involved similar amounts of essential (18-carbon) n-3 and n-6 LCFAs. The WR diet significantly increased the 24-hour urinary excretion of polyphenol metabolites-including enterolactone-compared with the RR diet. The WR rats had significantly more n-3 LCFA-in particular, eicosapentanoic (EPA) and docosahexanoic (DHA) acids-in their plasma and liver. Compared with the RR diet, the WR diet brought significant changes in gut microbiota composition, with increased diversity in the feces (Shannon and Simpson indices), decreased Firmicutes/Bacteroidetes ratio and decreased proportions of uncultured Clostridiales cluster IA and Clostridium cluster IV in the feces. In contrast, no difference was found between groups with regards to cecum microbiota. The WR rats had lower concentrations of total short-chain fatty acids (SCFA) in cecum and feces (pconsumption results in major biological modifications-increased plasma and liver n-3 EPA and DHA levels and improved gut microbiota profile, notably with increased diversity-known to provide health benefits. Unexpectedly, WR decreased SCFA levels in both cecum and feces. More studies are needed to understand the interactions between whole rye (fiber and polyphenols) and gut microbiota and also the mechanisms of action responsible for stimulating n-3 fatty acid metabolism.

  9. Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis

    International Nuclear Information System (INIS)

    Chen, Xue; Ward, Stephen C.; Cederbaum, Arthur I.; Xiong, Huabao; Lu, Yongke

    2017-01-01

    Background & aims: Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5 −/− ) mice develop more severe alcoholic fatty liver than Cyp2a5 +/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα −/− ) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5 −/− mice. Methods: Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. Results: More severe alcoholic fatty liver disease was developed in Cyp2a5 −/− mice than in Cyp2a5 +/+ mice. Basal FGF21 levels were higher in Cyp2a5 −/− mice than in Cyp2a5 +/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5 −/− mice while FGF21 was induced by ethanol in Cyp2a5 +/+ mice. Basal levels of serum FGF21 were lower in Pparα −/− mice than in Pparα +/+ mice; ethanol induced FGF21 in Pparα +/+ mice but not in Pparα −/− mice, whereas ethanol induced hypertriglyceridemia in Pparα −/− mice but not in Pparα +/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα −/− mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα −/− /Cyp2a5 −/− ) mice developed more severe alcoholic fatty liver than Pparα +/+ /Cyp2a5 −/− mice. Conclusions: These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease.

  10. Focal sparing around the gallbladder in fatty liver

    International Nuclear Information System (INIS)

    Chen, Kemin; Hiramatsu, Yoshihiro; Yunoki, Masanori; Hirano, Yoko

    1989-01-01

    In evaluating fatty liver with CT, the residual normal liver tissues without fat deposits are occasionally detected on CT as high attenuation regions, especially surrounding the gallbladder. This study examined the incidence of this phenomenon in terms of the diagnostic value of CT in fatty liver. Fifty-seven patients with fatty liver were examined with CT. The incidence of focal sparing area was the highest in the gallbladder bed (42/57, 74%), followed by the interlobar fissure or subcapsular area (13, 23%), quadrate lobe (8, 14%), caudate lobe (2, 4%), and right lobe (one, 1.8%). These CT appearances were of spot, band, ring, and the mixed type. In 38 patients, fatty liver was too moderate to be detected without CT attenuation numbers. Among them, 27 patients (71%) had focal sparing area surrounding the gallbladder. This CT appearance seemed to be of significance in preventing the missing of moderate fatty liver. (Namekawa, K)

  11. Demonstration of diet-induced decoupling of fatty acid and cholesterol synthesis by combining gene expression array and 2H2O quantification.

    Science.gov (United States)

    Jensen, Kristian K; Previs, Stephen F; Zhu, Lei; Herath, Kithsiri; Wang, Sheng-Ping; Bhat, Gowri; Hu, Guanghui; Miller, Paul L; McLaren, David G; Shin, Myung K; Vogt, Thomas F; Wang, Liangsu; Wong, Kenny K; Roddy, Thomas P; Johns, Douglas G; Hubbard, Brian K

    2012-01-15

    The liver is a crossroad for metabolism of lipid and carbohydrates, with acetyl-CoA serving as an important metabolic intermediate and a precursor for fatty acid and cholesterol biosynthesis pathways. A better understanding of the regulation of these pathways requires an experimental approach that provides both quantitative metabolic flux measurements and mechanistic insight. Under conditions of high carbohydrate availability, excess carbon is converted into free fatty acids and triglyceride for storage, but it is not clear how excessive carbohydrate availability affects cholesterol biosynthesis. To address this, C57BL/6J mice were fed either a low-fat, high-carbohydrate diet or a high-fat, carbohydrate-free diet. At the end of the dietary intervention, the two groups received (2)H(2)O to trace de novo fatty acid and cholesterol synthesis, and livers were collected for gene expression analysis. Expression of lipid and glucose metabolism genes was determined using a custom-designed pathway focused PCR-based gene expression array. The expression analysis showed downregulation of cholesterol biosynthesis genes and upregulation of fatty acid synthesis genes in mice receiving the high-carbohydrate diet compared with the carbohydrate-free diet. In support of these findings, (2)H(2)O tracer data showed that fatty acid synthesis was increased 10-fold and cholesterol synthesis was reduced by 1.6-fold in mice fed the respective diets. In conclusion, by applying gene expression analysis and tracer methodology, we show that fatty acid and cholesterol synthesis are differentially regulated when the carbohydrate intake in mice is altered.

  12. Salicornia Extract Ameliorates Salt-Induced Aggravation of Nonalcoholic Fatty Liver Disease in Obese Mice Fed a High-Fat Diet.

    Science.gov (United States)

    Kim, Jae Hwan; Suk, Sujin; Jang, Woo Jung; Lee, Chang Hyung; Kim, Jong-Eun; Park, Jin-Kyu; Kweon, Mee-Hyang; Kim, Jong Hun; Lee, Ki Won

    2017-07-01

    High-fat and high-salt intakes are among the major risks of chronic diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Salicornia is a halophytic plant known to exert antioxidant, antidiabetic, and hypolipidemic effects, and Salicornia-extracted salt (SS) has been used as a salt substitute. In this study, the effects of SS and purified salt (PS) on the aggravation of NAFLD/NASH were compared. C57BL/6J male mice (8-wk-old) were fed a high-fat diet (HFD) for 6 mo and divided into 3 dietary groups, which were additionally fed HFD, HFD + SS, and HFD + PS for 13 wk. PS induced aggravation of NAFLD/NASH in HFD-fed mice. Although the actual salt intake was same between the PS and SS groups as 1% of the diet (extrapolated from the World Health Organization [WHO] guideline), SS induced less liver injury and hepatic steatosis compared to PS. The hepatic mRNA expressions of inflammatory cytokines and fibrosis marker were significantly lower in the SS group than the PS group. Oxidative stress is one of the major causes of inflammation in NAFLD/NASH. Results of the component analysis showed that the major polyphenols that exhibited antioxidant activity in the Salicornia water extract were ferulic acid, caffeic acid, and isorhamnetin. These results suggest that even the level of salt intake recommended by WHO can accelerate the progression of liver disease in obese individuals consuming HFD. It is proposed that SS can be a salt substitute for obese individuals who consume HFD. © 2017 Institute of Food Technologists®.

  13. Animal experimental studies on the influence of fatty infiltration of the liver on tissue relaxation times and signal changes in MRT

    International Nuclear Information System (INIS)

    Kreft, B.; Stark, D.; Schild, H.

    1995-01-01

    Using a spectrometer (n=60) in vitro and MRT imaging (n=8) in vivo, we studied the influence of fatty changes of liver cells on the relaxation times of the liver (two animal models of fatty liver disease/orotic acid, L-ethionine). Induction of fatty degeneration of the liver by means of an orotic acid diet resulted in pure deposition of fat in the liver without any histological or serological proof of inflammatory changes. Although accumulation of triglyceride in the liver reduced the T 1 relaxation time only relatively slightly (-15%), there was good correlation (r=0.88) between fat content and T 1 . There was also good correlation (r=0.92) between T 2 and histological fat content. Inflammatory changes besides fatty deposition were seen both serologically and histologically in the L-ethionine model, so that the fatty content did not correlate with T 1 . In-vivo MRT imaging showed that spin-echo sequences are inappropriate for diagnosing fatty infiltration of the liver despite the relaxation time changes produced by the fatty deposition. On the other hand, chemical-shift imaging sequences are very sensitive to identify fatty deposits, and are also independent of any additionally existing inflammatory changes. (orig.) [de

  14. Focus on Therapeutic Strategies of Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Marilena Durazzo

    2012-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common chronic liver disease in the Western world (it affects 30% of the general adult population. The NAFLD encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH, defined by steatosis, hepatocellular damage, and lobular inflammation in individuals without significant alcohol consumption and negative viral, congenital, and autoimmune liver disease markers. Currently, NAFLD is considered an emerging epidemic in light of the dramatic increase in obesity rates. With the progressive nature of NASH and its rising prevalence there is a significant need for a specific and targeted treatments since to date there has not been any validated therapies for NAFLD other than weight loss, which is well known to have a poor long-term success rate. In recent years, visceral adipose tissue has taken an important role in NAFLD pathogenesis, and current therapeutic approaches aim at reducing visceral obesity and free fatty acid overflow to the liver. This paper is focused on the treatments used for NAFLD and the potential new therapy.

  15. Effect of Combination Therapy with Atorvastatin and Ursodeoxycholic Acid on the Course of Ischemic Heart Disease with Co-Existent Non-Alcoholic Fatty Liver Disease and Obesity

    Directory of Open Access Journals (Sweden)

    Nataliya Karpyshyn

    2016-12-01

    Conclusions. The use of ursodeoxycholic acid in addition to atorvastatin in patients with ischemic heart disease, co-existent non-alcoholic fatty liver disease and obesity makes it possible to avoid the adverse effect of hypolipidemic therapy on the functional status of the liver.

  16. Content of non-esterified fatty acids in the blood plasma of rabbits with acute arginine pancreatitis and its correction

    Directory of Open Access Journals (Sweden)

    Y. F. Rivis

    2013-01-01

    Full Text Available The aim of this work was to study the content of non-esterified fatty acids in plasma and liver of rabbits with acute arginine pancreatitis and its correction by linseed oil. The experiment was carried out on male rabbits breed gray giant with live weight 3.8–4.0 kg. The material for the study was sampled from blood and liver. Lipids from plasma and liver were extracted with a mixture of chloroform and methanol. After that the non-esterified fatty acids were isolated and methylated. Methyl esters of fatty acids were studied by the gas-liquid chromatography with the chromatograph ''Chrom 5'' (Prague,CzechRepublic. We have found that the content of non-esterified fatty acids decreases in the blood plasma and liver of rabbits with the acute arginine pancreatitis. It takes place at the expense of a reduce of saturated fatty acids with odd and even number of carbon atoms in a chain, monounsaturated fatty acids of the families ω-7 and ω-9 and polyunsaturated fatty acids of the families ω-3 and ω-6. That may indicate a greater use of non-esterified fatty acids for energy metabolism and esterification of lipids. We suppose that this is a consequence of the probable increase in content of non-esterified and esterified cholesterol in the rabbits’ blood plasma. Those processes provoke the cholesterol deposits in blood vessels and therefore cardiovascular diseases. We tried to influence on the processes by addition of linseed oil to the rabbits diet. We have found that in the linseed oil-fed rabbits the content of non-esterified fatty acids decreases at the expense of saturated fatty acids with odd and even number of carbon atoms in a chain and monounsaturated fatty acids of the families ω-7 and ω-9 inblood plasma and liver of the rabbits with acute arginine pancreatitis. Furthermore the levels of non-esterified polyunsaturated fatty acids of ω-3 family increase in the rabbits’ plasma and liver. As this takes place the ratio of non

  17. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Yi, E-mail: yi.luo@pfizer.com; Rana, Payal; Will, Yvonne

    2012-06-01

    Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity attenuated

  18. Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Sunny, Nishanth E; Kalavalapalli, Srilaxmi; Bril, Fernando; Garrett, Timothy J; Nautiyal, Manisha; Mathew, Justin T; Williams, Caroline M; Cusi, Kenneth

    2015-08-15

    Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD.

  19. Inhibition of 5-Lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model

    Directory of Open Access Journals (Sweden)

    Kuifen Ma

    2017-11-01

    Full Text Available Objective(s: Arachidonic Acid/5-lipoxygenase (AA/5-LOX pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD. Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD. Liver function, HE staining, NAFLD activity score (NAS were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA and AA, products: cysteinyl-leukotrienes (CysLTs, and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-ylethyl]-1-hydroxyurea was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

  20. Quantitative evaluation of 99mTc-GSA for fatty liver and ischemia-reperfusion injury in rats

    International Nuclear Information System (INIS)

    Kimoto, Mitsunori

    1996-01-01

    99m Tc-GSA (GSA) liver scintigraphy was performed in rats with fatty liver and ischemia-reperfusion injury to study the usefulness of GSA in evaluating these pathological processes. Fatty liver was produced by feeding rats a choline-deficient diet. The rats with fatty liver were divided into five groups according to the length of the diet (controls, two weeks, six weeks, 10 weeks, and 12 weeks). In the rats dieted for two weeks and six weeks, regional hepatic ischemia was also induced by clamping the left hepatic artery and the left portal vein for 10 minutes, then reperfusion was performed for 15 minutes. GSA was administered via the IVC. t 90 , or the time at which the liver time activity curve reached ninety percent of its peak value, was used as an index of GSA hepatic uptake, Ku and Kd, determined by two compartment analysis, were also used as indices. In rats of the fatty liver group, we confirmed microscopically that various degrees of fatty infiltration existed according to the diet period, and t 90 became significantly longer according to the severity of fatty infiltration. Ku and Kd also decreased according to the severity of fatty infiltration. In the rats with fatty infiltration and ischemia-reperfusion injury, t 90 also increased according to the severity of fatty infiltration, becoming longer than in the rats without ischemia-reperfusion injury. Quantitative analysis of GSA liver scintigraphy was useful for evaluating fatty liver and ischemia-reperfusion injury. (author)

  1. Essential fatty acid-rich diets protect against striatal oxidative damage induced by quinolinic acid in rats.

    Science.gov (United States)

    Morales-Martínez, Adriana; Sánchez-Mendoza, Alicia; Martínez-Lazcano, Juan Carlos; Pineda-Farías, Jorge Baruch; Montes, Sergio; El-Hafidi, Mohammed; Martínez-Gopar, Pablo Eliasib; Tristán-López, Luis; Pérez-Neri, Iván; Zamorano-Carrillo, Absalom; Castro, Nelly; Ríos, Camilo; Pérez-Severiano, Francisca

    2017-09-01

    Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive- or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive- or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/µl) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARγ expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive- and fish-oil-rich diets exert neuroprotective effects.

  2. Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls

    DEFF Research Database (Denmark)

    Heebøll, Sara; Poulsen, Marianne Kjær; Ørnstrup, Marie Juul

    2017-01-01

    BACKGROUND AND OBJECTIVE: CD36 is implicated in fatty acid uptake in multiple tissues, including hepatocytes and adipocytes. Circulating CD36 (sCD36) is increased in non-alcoholic fatty liver disease (NAFLD).We explored this association further by investigating correlations between sCD36 levels...... resonance imaging (n=94, subcutaneous and visceral adipose tissue) and liver biopsy (n=28 NAFLD patients) performed. Plasma sCD36 was assessed by ELISA. RESULTS: NAFLD patients had elevated sCD36 levels compared to controls (0.68 (0.12-2.27) versus 0.43 (0.10-1.18), P.... An unhealthy and unbalanced CD36 expression in adipose and hepatic tissue may shift the fatty acid load to the liver.Clinical Trials.gov (NCT01464801, NCT01412645, NCT01446276).International Journal of Obesity accepted article preview online, 05 December 2016. doi:10.1038/ijo.2016.223....

  3. Fructose as a key player in the development of fatty liver disease.

    Science.gov (United States)

    Basaranoglu, Metin; Basaranoglu, Gokcen; Sabuncu, Tevfik; Sentürk, Hakan

    2013-02-28

    We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver. The prevalence of nonalcoholic steatohepatitis (NASH) is 3% and 20% in nonobese and obese subjects, respectively. Obesity is a low-grade chronic inflammatory condition and obesity-related cytokines such as interleukin-6, adiponectin, leptin, and tumor necrosis factor-α may play important roles in the development of nonalcoholic fatty liver disease (NAFLD). Additionally, the prevalence of NASH associated with both cirrhosis and hepatocellular carcinoma was reported to be high among patients with type 2 diabetes with or without obesity. Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in mice, the American Lifestyle-Induced Obesity Syndrome model, which included consumption of a high-fructose corn syrup in amounts relevant to that consumed by some Americans. The observation reinforces the concerns about the role of fructose in the obesity epidemic. Increased availability of fructose (e.g., high-fructose corn syrup) increases not only abnormal glucose flux but also fructose metabolism in the hepatocyte. Thus, the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and amino acids. Fructose was previously accepted as a beneficial dietary component because it does not stimulate insulin secretion. However, since insulin signaling plays an important role in central mechanisms of NAFLD, this property of fructose may be undesirable. Fructose has a selective hepatic metabolism, and provokes a hepatic stress response involving activation of c-Jun N-terminal kinases and subsequent reduced hepatic insulin signaling. As high fat diet alone produces obesity, insulin resistance, and some degree of fatty liver with minimal inflammation and no fibrosis, the fast food diet which includes fructose and fats produces

  4. Analysis of fatty liver by CT values in obese children

    International Nuclear Information System (INIS)

    Naganuma, Yoshihiro; Tomizawa, Shuichi; Ikarashi, Kozo; Tohyama, Jun; Ozawa, Kanzi; Uchiyama, Makoto.

    1996-01-01

    Liver attenuation values were measured by CT in 97 (183 times) obese children with ages 3 to 18 years and a diagnosis of fatty liver was made in 42 subjects. Liver/spleen ration from CT measurements showed a significant negative correlation with the percentage of standard body weight, and with the systolic pressure. In children with fatty liver, systolic pressure and serum GOT, GPT, ChE, TC, TG, ApoB and insulin were significantly higher than those in children without fatty liver. After a low-calorie dietary regimen and exercise therapy, the liver/spleen ratio and GPT improved in all children. The diagnosis of fatty infiltration (fatty liver) was made with a liver/spleen ratio of less than 1.0 as determined by the number of measurements taken, a reasonable criterion for the diagnosis of fatty liver by CT in children. There were some children with elevated GPT who showed normal CT findings. This may be caused by overnutrition which was associated with fatty infiltration, since GPT decreased in all these children after treatment. The present study suggests that CT is a useful procedure in diagnosing fatty liver, and in monitoring and determining efficacy of treatment in obese children. (author)

  5. Conjugated linoleic acid or omega 3 fatty acids increase mitochondrial biosynthesis and metabolism in skeletal muscle cells

    Directory of Open Access Journals (Sweden)

    Vaughan Roger A

    2012-10-01

    Full Text Available Abstract Background Polyunsaturated fatty acids are popular dietary supplements advertised to contribute to weight loss by increasing fat metabolism in liver, but the effects on overall muscle metabolism are less established. We evaluated the effects of conjugated linoleic acid (CLA or combination omega 3 on metabolic characteristics in muscle cells. Methods Human rhabdomyosarcoma cells were treated with either DMSO control, or CLA or combination omega 3 for 24 or 48 hours. RNA was determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Mitochondrial content was determined using flow cytometry and immunohistochemistry. Metabolism was quantified by measuring extracellular acidification and oxygen consumption rates. Results Omega 3 significantly induced metabolic genes as well as oxidative metabolism (oxygen consumption, glycolytic capacity (extracellular acidification, and metabolic rate compared with control. Both treatments significantly increased mitochondrial content. Conclusion Omega 3 fatty acids appear to enhance glycolytic, oxidative, and total metabolism. Moreover, both omega 3 and CLA treatment significantly increase mitochondrial content compared with control.

  6. Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress

    OpenAIRE

    Merritt II, J Lawrence; Sun,Angela

    2015-01-01

    Angela Sun, J Lawrence Merritt II Department of Pediatrics, University of Washington, Seattle, WA, USA Abstract: Fatty acid oxidation disorders are inborn errors of metabolism resulting in failure of ß-oxidation within or transport of fatty acids into the mitochondria. The long-chain fatty acid oxidation disorders are characterized by variable presentations ranging from newborn cardiomyopathy, to infantile hypoketotic hypoglycemia resulting from liver involvement, to skeletal myopa...

  7. Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment (II). The treatment of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández-Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

    Disease nonalcoholic fatty liver disease (NAFLD) comprises a series of histologically similar to those induced by alcohol consumption in people with very little or no liver damage same. The importance of NAFLD is its high prevalence in our Western societies, from the point of view liver in its progressive evolution from steatosis to steatohepatitis, cirrhosis and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with accelerated atherosclerosis and cardiovascular events, the leading cause of morbidity and mortality. This updated January 2016 revision consists of two parts. In this second part, the treatment of NAFLD and its influence on cardiovascular disease and drugs used in the control of cardiovascular risk factors showing a beneficial effect on the liver disease will be reviewed. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition

    International Nuclear Information System (INIS)

    Kim, Seok-Joo; Lee, Sun-Mee

    2012-01-01

    Alcoholic fatty liver is susceptible to secondary stresses such as ischemia/reperfusion (I/R). Baicalin is an active component extracted from Scutellaria baicalensis, which is widely used in herbal preparations for treatment of hepatic diseases and inflammatory disorders. This study evaluated the potential beneficial effect of baicalin on I/R injury in alcoholic fatty liver. Rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Baicalin (200 mg/kg) was intraperitoneally administered 24 and 1 h before ischemia. After reperfusion, baicalin attenuated the increases in serum alanine aminotransferase activity, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in alcoholic fatty liver. The increased levels of TNF-α and IL-6 mRNA expression and inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions increased after reperfusion, which were higher in ethanol-fed animals, were attenuated by baicalin. In ethanol-fed animals, baicalin attenuated the increases in toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expressions and the nuclear translocation of NF-κB after reperfusion. In conclusion, our findings suggest that baicalin ameliorates I/R-induced hepatocellular damage by suppressing TLR4-mediated inflammatory responses in alcoholic fatty liver. -- Highlights: ► Baicalin attenuates hepatic I/R-induced inflammation in alcoholic fatty liver. ► Baicalin downregulates TLR4, MyD88 expression during I/R in alcoholic fatty liver. ► Baicalin attenuates NF-κB nuclear translocation during I/R in alcoholic fatty liver.

  9. Endogenous n-3 polyunsaturated fatty acids attenuate T cell-mediated hepatitis via autophagy activation

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    Yanli Li

    2016-09-01

    Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFAs exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A was administered intravenously to wild-type (WT and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase (ALT activity, and inhibited production of pro-inflammatory cytokines (e.g. TNF-α, IL-6, IL-17A and IFN-γ. In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism, and could be exploited as a new therapeutic approach for autoimmune hepatitis.

  10. Human germline hedgehog pathway mutations predispose to fatty liver.

    Science.gov (United States)

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2 +/- ) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 +/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 +/- mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  11. Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake and De Novo Fatty Acid Synthesis

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    Fengxia Ge

    2012-01-01

    Full Text Available A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD and db/db and ob/ob mice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers. By echocardiography, ejection fraction (EF and fractional shortening (FS of left ventricular diameter during systole were significantly reduced. The Vmax for saturable fatty acid uptake was increased and significantly correlated with cardiac triglycerides and insulin concentrations. Vmax also correlated with expression of genes for the cardiac fatty acid transporters Cd36 and Slc27a1. Genes for de novo fatty acid synthesis (Fasn, Scd1 were also upregulated. Ten oxidative phosphorylation pathway genes were downregulated, suggesting that a decrease in cardiomyocyte ATP synthesis might explain the decreased contractile function in obese hearts.

  12. Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

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    Griffett, Kristine; Burris, Thomas P.

    2016-01-01

    The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inverse agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression. - Highlights: • The LXR antagonist GSK2033 suppresses the expression of lipogenic genes FASN and SREBF1 in HepG2 cells. • GSK2033 exhibits sufficient exposure to perform animal experiments targeting the liver. • GSK2033 has fails to suppress hepatic Fasn and Srebf1 expression in an animal model of non-alcoholic fatty liver disease. • GSK2033 may regulate the activity of several nuclear receptors.

  13. Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans.

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    Van Oudenhove, Lukas; McKie, Shane; Lassman, Daniel; Uddin, Bilal; Paine, Peter; Coen, Steven; Gregory, Lloyd; Tack, Jan; Aziz, Qasim

    2011-08-01

    Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression.

  14. Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Pparα).

    Science.gov (United States)

    Shi, Li-juan; Shi, Lei; Song, Guang-yao; Zhang, He-fang; Hu, Zhi-juan; Wang, Chao; Zhang, Dong-hui

    2013-08-15

    The aim of this study was to examine the therapeutic effect of oxymatrine, a monomer isolated from the medicinal plant Sophora flavescens Ait, on the hepatic lipid metabolism in non-alcoholic fatty liver (NAFLD) rats and to explore the potential mechanism. Rats were fed with high fructose diet for 8 weeks to establish the NAFLD model, then were given oxymatrine treatment (40, 80, and 160 mg/kg, respectively) for another 8 weeks. Body weight gain, liver index, serum and liver lipids, and histopathological evaluation were measured. Enzymatic activity and gene expression of the key enzymes involved in the lipogenesis and fatty acid oxidation were assayed. The results showed that oxymatrine treatment reduced body weight gain, liver weight, liver index, dyslipidemia, and liver triglyceride level in a dose dependant manner. Importantly, the histopathological examination of liver confirmed that oxymatrine could decrease the liver lipid accumulation. The treatment also decreased the fatty acid synthase (FAS) enzymatic activity and increased the carnitine palmitoyltransferase 1A (CPT1A) enzymatic activity. Besides, oxymatrine treatment decreased the mRNA expression of sterol regulatory element binding transcription factor 1(Srebf1), fatty acid synthase (Fasn), and acetyl CoA carboxylase (Acc), and increased the mRNA expression of peroxisome proliferator activated receptor alpha (Pparα), carnitine palmitoyltransferase 1A (Cpt1a), and acyl CoA oxidase (Acox1) in high fructose diet induced NAFLD rats. These results suggested that the therapeutic effect of oxymatrine on the hepatic steatosis in high fructose diet induced fatty liver rats is partly due to down-regulating Srebf1 and up-regulating Pparα mediated metabolic pathways simultaneously. © 2013 Elsevier B.V. All rights reserved.

  15. The effect of endogenous essential and nonessential fatty acids on the uptake and subsequent agonist-induced release of arachidonate

    International Nuclear Information System (INIS)

    Furth, E.E.; Hurtubise, V.; Schott, M.A.; Laposata, M.

    1989-01-01

    We have demonstrated that the uptake and agonist-induced release of a pulse of arachidonate are influenced by the size and composition of preexisting endogenous fatty acid pools. EFD-1 cells, an essential fatty acid-deficient mouse fibrosarcoma cell line, were incubated with radiolabeled (14C or 3H) arachidonate, linoleate, eicosapentaenoate (EPA), palmitate, or oleate in concentrations of 0-33 microM for 24 h. After 24 h, the cells were pulsed with 0.67 microM radiolabeled (3H or 14C, opposite first label) arachidonate for 15 min and then stimulated with 10 microM bradykinin for 4 min. Because EFD-1 cells contain no endogenous essential fatty acids, we were able to create essential fatty acid-repleted cells for which the specific activity of the newly constructed endogenous essential fatty acid pool was known. Loading the endogenous pool with the essential fatty acids arachidonate, eicosapentaenoate, or linoleate (15-20 nmol of fatty acid incorporated/10(6) cells) decreased the uptake of a pulse of arachidonate from 200 to 100 pmol/10(6) cells but had no effect on palmitate uptake. The percent of arachidonate incorporated during the pulse which was released upon agonist stimulation increased 2-fold (4-8%) as the endogenous pool of essential fatty acids was increased from 0 to 15-20 nmol/10(6) cells. This 8% release was at least 3-fold greater than the percent release from the various endogenous essential fatty acid pools. In contrast, loading the endogenous pool with the nonessential fatty acids oleate or palmitate to more than 2-3 times their preexisting cellular level had no effect on the uptake of an arachidonate pulse. Like the essential fatty acids, increasing endogenous oleate increased (by 2-fold) the percent release of arachidonate incorporated during the pulse, whereas endogenous palmitate had no effect on subsequent agonist-induced release from this arachidonate pool

  16. Omega-3 Polyunsaturated Fatty Acids Attenuate Radiation-induced Oxidative Stress and Organ Dysfunctions in Rats

    International Nuclear Information System (INIS)

    Abdel Aziz, N.; Yacoub, S.F.

    2013-01-01

    The Aim of the present study was to determine the possible protective effect of omega-3 polyunsaturated fatty acids (omega-3 PUFA) against radiation-induced oxidative stress associated with organ dysfunctions. Omega-3 PUFA was administered by oral gavages to male albino rats at a dose of 0.4 g/ kg body wt daily for 4 weeks before whole body γ-irradiation with 4Gy. Significant increase of serum lipid peroxidation end product as malondialdehyde (MDA) along with the reduction in blood glutathione (GSH) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) enzyme activities were recorded on 3rd and 8th days post-irradiation. Oxidative stress was associated with a significant increase in lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) enzyme activities, markers of heart damage, significant increases in uric acid, urea and creatinine levels, markers of kidney damage, significant increases of alkaline phosphatase (ALP) and transaminases (ALT and AST) activities, markers of liver damage. Moreover significant increases in total cholesterol and triglycerides levels were recorded. Omega-3 PUFA administration pre-irradiation significantly attenuated the radiation-induced oxidative stress and organ dysfunctions tested in this study. It could be concluded that oral supplementation of omega-3 PUFA before irradiation may afford protection against radiation-induced oxidative stress and might preserve the integrity of tissue functions of the organs under investigations.

  17. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study.

    Science.gov (United States)

    Scorletti, Eleonora; Bhatia, Lokpal; McCormick, Keith G; Clough, Geraldine F; Nash, Kathryn; Hodson, Leanne; Moyses, Helen E; Calder, Philip C; Byrne, Christopher D

    2014-10-01

    There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (β=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, β=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).

  18. The Role of Lipid and Lipoprotein Metabolism in Non‐Alcoholic Fatty Liver Disease

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    Francesco Massimo Perla

    2017-06-01

    Full Text Available Due to the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD has become one of the most prevalent chronic liver disorders in children and adolescents. NAFLD comprises a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. The mechanism of the liver injury in NAFLD is currently thought to be a “multiple-hit process” where the first “hit” is an increase in liver fat, followed by multiple additional factors that trigger the inflammatory activity. At the onset of disease, NAFLD is characterized by hepatic triglyceride accumulation and insulin resistance. Liver fat accumulation is associated with increased lipotoxicity from high levels of free fatty acids, free cholesterol and other lipid metabolites. As a consequence, mitochondrial dysfunction with oxidative stress and production of reactive oxygen species and endoplasmic reticulum stress-associated mechanisms, are activated. The present review focuses on the relationship between intra-cellular lipid accumulation and insulin resistance, as well as on lipid and lipoprotein metabolism in NAFLD.

  19. Non-alcoholic fatty liver disease: An expanded review

    Science.gov (United States)

    Benedict, Mark; Zhang, Xuchen

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the “magic bullet” in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients. PMID:28652891

  20. Comparing the effects of different dietary organic acids on the growth, intestinal short-chain fatty acids, and liver histopathology of red hybrid tilapia (Oreochromis sp.) and potential use of these as preservatives.

    Science.gov (United States)

    Ebrahimi, Mahdi; Daeman, Nor Hafizah; Chong, Chou Min; Karami, Ali; Kumar, Vikas; Hoseinifar, Seyed Hossein; Romano, Nicholas

    2017-08-01

    Dietary organic acids are increasingly being investigated as a potential means of improving growth and nutrient utilization in aquatic animals. A 9-week study was performed to compare equal amounts (2%) of different organic acids (sodium butyrate, acetate, propionate, or formate) on the growth, muscle proximate composition, fatty acid composition, cholesterol and lipid peroxidation, differential cell counts, plasma biochemistry, intestinal short-chain fatty acid (SCFA) level, and liver histopathology to red hybrid tilapia (Oreochromis sp.) (initial mean weight of 2.87 g). A second experiment was performed to determine their effects on lipid peroxidation and trimethylamine (TMA) when added at 1% to tilapia meat and left out for 24 h. The results of the first experiment showed no treatment effect to growth, feeding efficiencies, or muscle fatty acid composition, but all dietary organic acids significantly decreased intestinal SCFA. Dietary butyrate and propionate significantly decreased muscle lipid peroxidation compared to the control group, but the dietary formate treatment had the lowest lipid peroxidation compared to all treatments. Muscle crude protein and lipid in tilapia fed the formate diet were significantly lower and higher, respectively, and showed evidence of stress based on the differential cell counts, significantly higher plasma glucose and liver glycogen, as well as inflammatory responses in the liver. Although a potential benefit of dietary organic acids was a reduction to lipid peroxidation, this could be accomplished post-harvest by direct additions to the meat. In addition, inclusions of butyrate and propionate to tilapia meat significantly decreased TMA, which might be a more cost-effective option to improve the shelf life of tilapia products.

  1. Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver

    International Nuclear Information System (INIS)

    Lee, Min-Ho; Kim, Mingoo; Lee, Byung-Hoon; Kim, Ju-Han; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-Il; Chung, Heekyoung; Kong, Gu; Lee, Mi-Ock

    2008-01-01

    Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P 1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid β-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity

  2. Correlation of hepatic 18F-fluorodeoxyglucose uptake with fatty liver

    International Nuclear Information System (INIS)

    An, Young Sil; Yoon, Joon Kee; Hong, Seon Pyo; Joh, Chul Woo; Yoon, Seok Nam

    2006-01-01

    Liver demonstrates heterogeneous FDG uptake and sometimes it shows abnormally increased uptake even though there is no malignant tissue. However, there was no previous study to correlate these various pattern of hepatic FDG uptake with benign liver disease. Therefore, we evaluated the significance of hepatic FDG uptake associated with various clinical factors including fatty liver, liver function tests and lipid profiles. We reviewed a total of 188 patients (male/female: 120/68, mean age: 50 ± 9) who underwent PET/CT for screening of malignancy. Patients with DM, impaired glucose tolerance, previous severe hepatic disease or long-term medication history were excluded. The FDG uptake in liver was analyzed semi-quantitatively using ROI on transaxial images (segment 8) and we compared mean standardized uptake value (SUV) between fatty liver and non-fatty liver group. We also evaluated the correlation between hepatic FDG uptake and various clinical factors including serum liver function test (ALT, AST), γ -GT, total cholesterol and triglyceride concentration. The effect of alcoholic history and body mass index on hepatic FDG uptake was analyzed within the fatty liver patients. The hepatic FDG uptake of fatty liver group was significantly higher than that of non-fatty liver group. Serum total cholesterol and triglyceride concentration showed significant correlation with hepatic FDG uptake. However, there was no significant correlation between other factors (ALT, AST, and γ -GT) and FDG uptake. Also there was no difference of mean SUV between normal and abnormal groups on the basis of alcoholic history and body mass index within fatty liver patients. Fatty liver and high serum triglyceride concentration were the independent factors affecting hepatic FDG uptake according to multivariate analysis. In conclusion, hepatic FDG uptake was strongly correlated with fatty liver and serum triglyceride concentration

  3. Long-chain α,ω-dioic acids as inducers of cyclosporin A-insensitive nonspecific permeability of the inner membrane of liver mitochondria loaded with calcium or strontium ions.

    Science.gov (United States)

    Dubinin, M V; Adakeeva, S I; Samartsev, V N

    2013-04-01

    Long-chain saturated monocarboxylic fatty acids can induce nonspecific permeability of the inner membrane (open pores) of liver mitochondria loaded with Ca2+ or Sr(2+) by the mechanism insensitive to cyclosporin A. In this work we investigated the effect of their metabolites - α,ω-dioic (dicarboxylic) acids - as potential inducers of pore opening by a similar mechanism. It was established that the addition of α,ω-hexadecanedioic acid (HDA) at a concentration of 10-30 µM to liver mitochondria loaded with Ca2+ or Sr(2+) leads to swelling of the organelles and release of these ions from the matrix. The maximum effect of HDA is observed at 50 µM Ca2+ concentration. Cyclosporin A at a concentration of 1 µM, previously added to the mitochondria, did not inhibit the observed processes. The calcium uniporter inhibitor ruthenium red, which blocks influx of Ca2+ and Sr(2+) to the matrix of mitochondria, prevented HDA-induced swelling. The effect of HDA as inducer of swelling of mitochondria was compared with similar effects of α,ω-tetradecanedioic and α,ω-dodecanedioic acids whose acyl chains are two and four carbon atoms shorter than HDA, respectively. It was found that the efficiency of these α,ω-dioic acids decreases with reducing number of carbon atoms in their acyl chains. It was concluded that in the presence of Ca2+ or Sr(2+) long-chain saturated α,ω-dioic acids can induce a cyclosporin A-insensitive permeability of the inner membrane (open pores) of liver mitochondria as well as their monocarboxylic analogs.

  4. Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY

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    Takumi Hirata

    2013-01-01

    Full Text Available Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n=12 or losartan at a dose of 50 mg once a day (n=7 for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA level (from 0.87±0.26 to 0.59±0.22 mEq/L (mean ± SD, P=0.005 and a significant increase in L/S ratio (P=0.049 evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

  5. Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels.

    Science.gov (United States)

    Horton, J D; Cuthbert, J A; Spady, D K

    1993-01-01

    The concentration of LDL in plasma is strongly influenced by the amount and the type of lipid in the diet. Recent studies in the hamster have shown that dietary fatty acids differentially affect circulating LDL levels primarily by altering receptor-dependent LDL uptake in the liver. To investigate the mechanistic basis of this effect, rates of receptor-dependent LDL transport in the liver were correlated with LDL receptor protein and mRNA levels in hamsters fed safflower oil or coconut oil and varying amounts of cholesterol. Hepatic LDL receptor activity was significantly lower in animals fed coconut oil than in animals fed safflower oil at all levels of cholesterol intake (26, 53, and 61% lower at cholesterol intakes of 0, 0.06, and 0.12%, respectively). These fatty acid-induced changes in hepatic LDL receptor activity were accompanied by parallel changes in hepatic LDL receptor protein and mRNA levels, suggesting that dietary fatty acids regulate the LDL receptor pathway largely at the mRNA level. Images PMID:8349814

  6. Diagnostic methods of fatty liver disease; Diagnostik der Fettleber

    Energy Technology Data Exchange (ETDEWEB)

    Kukuk, Guido Matthias; Sprinkart, Alois Martin; Traeber, Frank [Radiologische Universitaetsklinik Bonn (Germany). FE MRT

    2017-09-15

    Fatty liver disease is defined as an abnormal accumulation of lipids into the cytoplasm of hepatocytes. Different kinds of fatty liver diseases are becoming the most important etiologies of end-stage liver disease in the western world. Because fatty liver is a theoretically reversible process, timely and accurate diagnosis is a prerequisite for potential therapeutic options. This work describes major diagnostic methods and discusses particular advantages and disadvantages of various techniques.

  7. Plasma membrane fatty acid-binding protein and mitochondrial glutamic-oxaloacetic transaminase of rat liver are related

    International Nuclear Information System (INIS)

    Berk, P.D.; Potter, B.J.; Sorrentino, D.; Zhou, S.L.; Isola, L.M.; Stump, D.; Kiang, C.L.; Thung, S.; Wada, H.; Horio, Y.

    1990-01-01

    The hepatic plasma membrane fatty acid-binding protein (h-FABP PM ) and the mitochondrial isoenzyme of glutamic-oxaloacetic transaminase (mGOT) of rat liver have similar amino acid compositions and identical amino acid sequences for residues 3-24. Both proteins migrate with an apparent molecular mass of 43 kDa on SDS/polyacrylamide gel electrophoresis, have a similar pattern of basic charge isomers on isoelectric focusing, are eluted similarly from four different high-performance liquid chromatographic columns, have absorption maxima at 435 nm under acid conditions and 354 nm at pH 8.3, and bind oleate. Sinusoidally enriched liver plasma membranes and purified h-FABP PM have GOT enzymatic activity. Monospecific rabbit antiserum against h-FABP PM reacts on Western blotting with mGOT, and vice versa. Antisera against both proteins produce plasma membrane immunofluorescence in rat hepatocytes and selectively inhibit the hepatocellular uptake of [ 3 H]oleate but not that of [ 35 S]sulfobromophthalein or [ 14 C]taurocholate. The inhibition of oleate uptake produced by anti-h-FABP PM can be eliminated by preincubation of the antiserum with mGOT; similarly, the plasma membrane immunofluorescence produced by either antiserum can be eliminated by preincubation with the other antigen. These data suggest that h-FABP PM and mGOT are closely related

  8. Tailored fatty acid synthesis via dynamic control of fatty acid elongation

    Energy Technology Data Exchange (ETDEWEB)

    Torella, JP; Ford, TJ; Kim, SN; Chen, AM; Way, JC; Silver, PA

    2013-07-09

    Medium-chain fatty acids (MCFAs, 4-12 carbons) are valuable as precursors to industrial chemicals and biofuels, but are not canonical products of microbial fatty acid synthesis. We engineered microbial production of the full range of even-and odd-chain-length MCFAs and found that MCFA production is limited by rapid, irreversible elongation of their acyl-ACP precursors. To address this limitation, we programmed an essential ketoacyl synthase to degrade in response to a chemical inducer, thereby slowing acyl-ACP elongation and redirecting flux from phospholipid synthesis to MCFA production. Our results show that induced protein degradation can be used to dynamically alter metabolic flux, and thereby increase the yield of a desired compound. The strategy reported herein should be widely useful in a range of metabolic engineering applications in which essential enzymes divert flux away from a desired product, as well as in the production of polyketides, bioplastics, and other recursively synthesized hydrocarbons for which chain-length control is desired.

  9. Tailored fatty acid synthesis via dynamic control of fatty acid elongation

    Science.gov (United States)

    Torella, Joseph P.; Ford, Tyler J.; Kim, Scott N.; Chen, Amanda M.; Way, Jeffrey C.; Silver, Pamela A.

    2013-01-01

    Medium-chain fatty acids (MCFAs, 4–12 carbons) are valuable as precursors to industrial chemicals and biofuels, but are not canonical products of microbial fatty acid synthesis. We engineered microbial production of the full range of even- and odd-chain–length MCFAs and found that MCFA production is limited by rapid, irreversible elongation of their acyl-ACP precursors. To address this limitation, we programmed an essential ketoacyl synthase to degrade in response to a chemical inducer, thereby slowing acyl-ACP elongation and redirecting flux from phospholipid synthesis to MCFA production. Our results show that induced protein degradation can be used to dynamically alter metabolic flux, and thereby increase the yield of a desired compound. The strategy reported herein should be widely useful in a range of metabolic engineering applications in which essential enzymes divert flux away from a desired product, as well as in the production of polyketides, bioplastics, and other recursively synthesized hydrocarbons for which chain-length control is desired. PMID:23798438

  10. Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

    Science.gov (United States)

    Jaeger, Doris; Schoiswohl, Gabriele; Hofer, Peter; Schreiber, Renate; Schweiger, Martina; Eichmann, Thomas O.; Pollak, Nina M.; Poecher, Nadja; Grabner, Gernot F.; Zierler, Kathrin A.; Eder, Sandra; Kolb, Dagmar; Radner, Franz P.W.; Preiss-Landl, Karina; Lass, Achim; Zechner, Rudolf; Kershaw, Erin E.; Haemmerle, Guenter

    2015-01-01

    Background & Aims Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Methods Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. Results Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. Conclusions AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. PMID:25733154

  11. Nonalcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Patrick-Melin, A J; Kalinski, M I; Kelly, K R

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging chronic liver disease and is reported to affect up to 70-80% of overweight and obese individuals. NAFLD represents a spectrum of liver diseases that range from simple hepatic steatosis, to a more severe and treatment resistant stage...... that features steatosis plus inflammation, termed nonalcoholic steatohepatitis (NASH), which may in turn progress to hepatic fibrosis, cirrhosis, and sub-acute liver failure. Thus, NAFLD and its subsequent complications create a significant health burden, and currently there is no effective treatment strategy...

  12. The Polyunsaturated Fatty Acids Arachidonic Acid and Docosahexaenoic Acid Induce Mouse Dendritic Cells Maturation but Reduce T-Cell Responses In Vitro

    Science.gov (United States)

    Carlsson, Johan A.; Wold, Agnes E.; Sandberg, Ann-Sofie; Östman, Sofia M.

    2015-01-01

    Long-chain polyunsaturated fatty acids (PUFAs) might regulate T-cell activation and lineage commitment. Here, we measured the effects of omega-3 (n-3), n-6 and n-9 fatty acids on the interaction between dendritic cells (DCs) and naïve T cells. Spleen DCs from BALB/c mice were cultured in vitro with ovalbumin (OVA) with 50 μM fatty acids; α-linolenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid or oleic acid and thereafter OVA-specific DO11.10 T cells were added to the cultures. Fatty acids were taken up by the DCs, as shown by gas chromatography analysis. After culture with arachidonic acid or DHA CD11c+ CD11b+ and CD11c+ CD11bneg DCs expressed more CD40, CD80, CD83, CD86 and PDL-1, while IAd remained unchanged. However, fewer T cells co-cultured with these DCs proliferated (CellTrace Violetlow) and expressed CD69 or CD25, while more were necrotic (7AAD+). We noted an increased proportion of T cells with a regulatory T cell (Treg) phenotype, i.e., when gating on CD4+ FoxP3+ CTLA-4+, CD4+ FoxP3+ Helios+ or CD4+ FoxP3+ PD-1+, in co-cultures with arachidonic acid- or DHA-primed DCs relative to control cultures. The proportion of putative Tregs was inversely correlated to T-cell proliferation, indicating a suppressive function of these cells. With arachidonic acid DCs produced higher levels of prostaglandin E2 while T cells produced lower amounts of IL-10 and IFNγ. In conclusion arachidonic acid and DHA induced up-regulation of activation markers on DCs. However arachidonic acid- and DHA-primed DCs reduced T-cell proliferation and increased the proportion of T cells expressing FoxP3, indicating that these fatty acids can promote induction of regulatory T cells. PMID:26619195

  13. Neutrophil depletion improves diet-induced non-alcoholic fatty liver disease in mice.

    Science.gov (United States)

    Ou, Rongying; Liu, Jia; Lv, Mingfen; Wang, Jingying; Wang, Jinmeng; Zhu, Li; Zhao, Liang; Xu, Yunsheng

    2017-07-01

    Non-alcoholic fatty liver disease is highly associated with morbidity and mortality in population. Although studies have already demonstrated that the immune response plays a pivotal role in the development of non-alcoholic fatty liver disease, the comprehensive regulation is unclear. Therefore, present study was carried out to investigate the non-alcoholic