WorldWideScience

Sample records for lipoprotein receptor-related protein-10

  1. The low-density lipoprotein receptor-related protein 10 is a negative regulator of the canonical Wnt/{beta}-catenin signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Young-Hee; Sekiya, Manami; Hirata, Michiko; Ye, Mingjuan; Yamagishi, Azumi [Department of Molecular and Biochemical Nutrition, Graduate School of Human Life Science, Osaka City University, Osaka 558-8585 (Japan); Lee, Sang-Mi; Kang, Man-Jong [Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Hosoda, Akemi; Fukumura, Tomoe; Kim, Dong-Ho [Department of Molecular and Biochemical Nutrition, Graduate School of Human Life Science, Osaka City University, Osaka 558-8585 (Japan); Saeki, Shigeru, E-mail: saeki@life.osaka-cu.ac.jp [Department of Molecular and Biochemical Nutrition, Graduate School of Human Life Science, Osaka City University, Osaka 558-8585 (Japan)

    2010-02-19

    Wnt signaling pathways play fundamental roles in the differentiation, proliferation and functions of many cells as well as developmental, growth, and homeostatic processes in animals. Low-density lipoprotein receptor (LDLR)-related protein (LRP) 5 and LRP6 serve as coreceptors of Wnt proteins together with Frizzled receptors, triggering activation of canonical Wnt/{beta}-catenin signaling. Here, we found that LRP10, a new member of the LDLR gene family, inhibits the canonical Wnt/{beta}-catenin signaling pathway. The {beta}-catenin/T cell factor (TCF) transcriptional activity in HEK293 cells was activated by transfection with Wnt3a or LRP6, which was then inhibited by co-transfection with LRP10. Deletion of the extracellular domain of LRP10 negated its inhibitory effect. The inhibitory effect of LRP10 was consistently conserved in HEK293 cells even when GSK3{beta} phosphorylation was inhibited by incubation with lithium chloride and co-transfection with constitutively active S33Y-mutated {beta}-catenin. Nuclear {beta}-catenin accumulation was unaffected by LRP10. The present studies suggest that LRP10 may interfere with the formation of the {beta}-catenin/TCF complex and/or its binding to target DNA in the nucleus, and that the extracellular domain of LRP10 is critical for inhibition of the canonical Wnt/{beta}-catenin signaling pathway.

  2. Low-density lipoprotein receptor-related protein-1 facilitates heme scavenging after intracerebral hemorrhage in mice.

    Science.gov (United States)

    Wang, Gaiqing; Manaenko, Anatol; Shao, Anwen; Ou, Yibo; Yang, Peng; Budbazar, Enkhjargal; Nowrangi, Derek; Zhang, John H; Tang, Jiping

    2017-04-01

    Heme-degradation after erythrocyte lysis plays an important role in the pathophysiology of intracerebral hemorrhage. Low-density lipoprotein receptor-related protein-1 is a receptor expressed predominately at the neurovascular interface, which facilitates the clearance of the hemopexin and heme complex. In the present study, we investigated the role of low-density lipoprotein receptor-related protein-1 in heme removal and neuroprotection in a mouse model of intracerebral hemorrhage. Endogenous low-density lipoprotein receptor-related protein-1 and hemopexin were increased in ipsilateral brain after intracerebral hemorrhage, accompanied by increased hemoglobin levels, brain water content, blood-brain barrier permeability and neurological deficits. Exogenous human recombinant low-density lipoprotein receptor-related protein-1 protein reduced hematoma volume, brain water content surrounding hematoma, blood-brain barrier permeability and improved neurological function three days after intracerebral hemorrhage. The expression of malondialdehyde, fluoro-Jade C positive cells and cleaved caspase 3 was increased three days after intracerebral hemorrhage in the ipsilateral brain tissues and decreased with recombinant low-density lipoprotein receptor-related protein-1. Intracerebral hemorrhage decreased and recombinant low-density lipoprotein receptor-related protein-1 increased the levels of superoxide dismutase 1. Low-density lipoprotein receptor-related protein-1 siRNA reduced the effect of human recombinant low-density lipoprotein receptor-related protein-1 on all outcomes measured. Collectively, our findings suggest that low-density lipoprotein receptor-related protein-1 contributed to heme clearance and blood-brain barrier protection after intracerebral hemorrhage. The use of low-density lipoprotein receptor-related protein-1 as supplement provides a novel approach to ameliorating intracerebral hemorrhage brain injury via its pleiotropic neuroprotective effects.

  3. Segments in the C-terminal folding domain of lipoprotein lipase important for binding to the low density lipoprotein receptor-related protein and to heparan sulfate proteoglycans

    DEFF Research Database (Denmark)

    Nielsen, Morten Schallburg; Brejning, Jeanette; García, R.;

    1997-01-01

    Lipoprotein lipase (LpL) can mediate cellular uptake of chylomicron and VLDL remnants via binding to heparan sulfate proteoglycans (HSPG) and the endocytic alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR/LRP). Whereas it is established that the C-terminal ......Lipoprotein lipase (LpL) can mediate cellular uptake of chylomicron and VLDL remnants via binding to heparan sulfate proteoglycans (HSPG) and the endocytic alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR/LRP). Whereas it is established that the C...

  4. Giardia lamblia low-density lipoprotein receptor-related protein is involved in selective lipoprotein endocytosis and parasite replication.

    Science.gov (United States)

    Rivero, Maria R; Miras, Silvana L; Quiroga, Rodrigo; Rópolo, Andrea S; Touz, Maria C

    2011-03-01

    As Giardia lamblia is unable to synthesize cholesterol de novo, this steroid might be obtained from the host's intestinal milieu by endocytosis of lipoproteins. In this work, we identified a putative Giardia lamblia low-density lipoprotein receptor-related proteins (GlLRP), a type I membrane protein, which shares the substrate N-terminal binding domain and a FXNPXY-type endocytic motif with human LRPs. Expression of tagged GlLRP showed that it was localized predominantly in the endoplasmic reticulum, lysosomal-like peripheral vacuoles and plasma membrane. However, the FXNPXY-deleted GlLRP was retained at the plasma membrane suggesting that it is abnormally transported and processed. The low-density lipoprotein and chylomicrons interacted with GlLRP, with this interaction being necessary for lipoprotein internalization and cell proliferation. Finally, we show that GlLRP binds directly to the medium subunit of Giardia adaptor protein 2, indicating that receptor-mediated internalization occurs through an adaptin mechanism.

  5. Low density lipoprotein receptor-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter

    DEFF Research Database (Denmark)

    Wicher, Grzegorz; Larsson, Mårten; Svenningsen, Åsa Fex

    2006-01-01

    Lipoprotein receptor-related protein-2 (LRP2)/megalin is a member of the low density lipoprotein receptor (LDLR) family, and is essential in absorptive epithelia for endocytosis of lipoproteins, low molecular weight proteins, cholesterol and vitamins, as well as in cellular signaling. Previous st...... that spinal cord oligodendrocytes are phenotypically different from those in the brain, and indicate that megalin translocates signals from the cell membrane to the nucleus of oligodendrocytes during the formation and maintenance of myelin of long spinal cord pathways....

  6. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization

    Science.gov (United States)

    Barmina, O. Y.; Walling, H. W.; Fiacco, G. J.; Freije, J. M.; Lopez-Otin, C.; Jeffrey, J. J.; Partridge, N. C.

    1999-01-01

    We have previously identified a specific receptor for collagenase-3 that mediates the binding, internalization, and degradation of this ligand in UMR 106-01 rat osteoblastic osteosarcoma cells. In the present study, we show that collagenase-3 binding is calcium-dependent and occurs in a variety of cell types, including osteoblastic and fibroblastic cells. We also present evidence supporting a two-step mechanism of collagenase-3 binding and internalization involving both a specific collagenase-3 receptor and the low density lipoprotein receptor-related protein. Ligand blot analysis shows that (125)I-collagenase-3 binds specifically to two proteins ( approximately 170 kDa and approximately 600 kDa) present in UMR 106-01 cells. Western blotting identified the 600-kDa protein as the low density lipoprotein receptor-related protein. Our data suggest that the 170-kDa protein is a specific collagenase-3 receptor. Low density lipoprotein receptor-related protein-null mouse embryo fibroblasts bind but fail to internalize collagenase-3, whereas UMR 106-01 and wild-type mouse embryo fibroblasts bind and internalize collagenase-3. Internalization, but not binding, is inhibited by the 39-kDa receptor-associated protein. We conclude that the internalization of collagenase-3 requires the participation of the low density lipoprotein receptor-related protein and propose a model in which the cell surface interaction of this ligand requires a sequential contribution from two receptors, with the collagenase-3 receptor acting as a high affinity primary binding site and the low density lipoprotein receptor-related protein mediating internalization.

  7. Segments in the C-terminal folding domain of lipoprotein lipase important for binding to the low density lipoprotein receptor-related protein and to heparan sulfate proteoglycans

    DEFF Research Database (Denmark)

    Nielsen, Morten Schallburg; Brejning, Jeanette; García, R.

    1997-01-01

    Lipoprotein lipase (LpL) can mediate cellular uptake of chylomicron and VLDL remnants via binding to heparan sulfate proteoglycans (HSPG) and the endocytic alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR/LRP). Whereas it is established that the C......L-(347-448) in Escherichia coli. In addition to binding to alpha2MR/LRP, LpL-(313-448) displayed binding to heparin with an affinity similar to that of the LpL monomer, whereas it bound poorly to lipoprotein particles. Moreover, LpL-(313-448) displayed heparin sensitive binding to normal, but not to HSPG...

  8. Roles oflow-density lipoprotein receptor-related protein 1 intumors

    Institute of Scientific and Technical Information of China (English)

    PeipeiXing; ZhichaoLiao; ZhiwuRen; JunZhao; FengjuSong; GuowenWang; KexinChen; Jilong Yang

    2016-01-01

    Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, ifbroblasts, neu-rons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging invitro and invivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation ofLRP1 CpG islands. Furthermore, a novel fusion gene,LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

  9. Polymorphism of the low-density lipoprotein receptor-related protein 5 gene and fracture risk.

    Science.gov (United States)

    Wang, Chao; Zhang, Gang; Gu, Mingyong; Zhou, Zhenyu; Cao, Xuecheng

    2014-01-01

    Several molecular epidemiological studies have been conducted to examine the association between low-density lipoprotein receptor-related proteins (LRP5) Ala1330Val polymorphism and fracture; however, the conclusions remained controversial. We therefore performed an extensive meta-analysis on 10 published studies with 184479 subjects. Electronic databases, including PubMed, Excerpta Medica Database (EMBASE), Cochrane, Elsevier Science Direct and China National Knowledge Infrastructure (CNKI) databases were searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. LRP5 Ala1330Val polymorphism was associated with a significantly increased risk of fracture (OR = 1.10; 95% CI, 1.06-1.14; I(2) = 29%). We also found that this polymorphism increased fracture risk in Caucasians. In the subgroup analysis according to gender, women was significantly associated with risk of fracture. In the subgroup analysis by type of fracture, LRP5 Ala1330Val polymorphism showed increased osteoporotic fracture risk. In conclusion, this meta-analysis suggested that an increased risk of fracture was associated with the LRP5 Ala1330Val polymorphism.

  10. Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk.

    Science.gov (United States)

    Harriott, A M; Heckman, M G; Rayaprolu, S; Soto-Ortolaza, A I; Diehl, N N; Kanekiyo, T; Liu, C-C; Bu, G; Malik, R; Cole, J W; Meschia, J F; Ross, O A

    2015-08-01

    Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted. © 2015 EAN.

  11. The multiligand α2-macroglobulin receptor/low density lipoprotein receptor-related protein

    DEFF Research Database (Denmark)

    Gliemann, Jørgen; Nykjær, Anders; Petersen, Claus Munck

    1994-01-01

    The fusion of separate lines of research has greatly helped in elucidating the function of the giant members of the low density lipoprotein (LDL) receptor (LDLR) supergene family. The cDNA encoding a large protein structurally closely related to LDLR, and hence named LDLR-related protein (LRP......), was cloned by Herz et al. in 1988.'Evidence was provided demonstrating that LRP can function as a receptor for chylomicron remnants@-migrating very low density lipoproteins (P-VLDL) rich in apolipoprotein E (apoE)?' The a2-macroglobulin (a2M) receptor (a2MR) was purified from rat livep and human p l a~e n t...

  12. Low density lipoprotein receptor related protein 1 variant interacts with saturated fatty acids in Puerto Ricans

    Science.gov (United States)

    Low density lipoprotein related receptor protein 1 (LRP1) is a multi-functional endocytic receptor that is highly expressed in adipocytes and the hypothalamus. Animal models and in vitro studies support a role for LRP1 in adipocyte metabolism and leptin signaling, but genetic polymorphisms have not ...

  13. ASSOCIATION BETWEEN LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN GENE, BUTYRYLCHOLINESTERASE GENE AND ALZHEIMER'S DISEASE IN CHINESE

    Institute of Scientific and Technical Information of China (English)

    毕胜; 张昱; 吴江; 王德生; 赵庆杰

    2001-01-01

    Objective. To research the relations between low-density lipoprotein receptor-related protein gene (LRP)polymorphism, butyrylcholinesterase gene (BchE) polymorphism and Alzheimer's disease (AD) in Chinese. Methods. The gene polymorphisms of LRP and BchE were genotyped in 38 AD eases and 40 controls withpolymerase chain reaction-restrictian fragment length polymorphism (PCR-RFLP) methods. AD groups were classi-fled according to the LRP C/C genotype and compared with matched controls. Resu/ts. AD group had higher frequencies ofC/C homozygote (81.6% vs 60. 0%, P <0. 05) and of C allele (89.5% vs 76. 3%, P < 0. 05), with no significant difference between any of these LRP genotypes classi-fied AD groups and their respective control groups. Conclusions. A positive correlation was found between LRP gene polymorphism and AD, but not betweenBchE gene polymorphism and AD in Chinese AD cases.

  14. ASSOCIATION BETWEEN LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN GENE, BUTYRYLCHOLINESTERASE GENE AND ALZHEIMER'S DISEASE IN CHINESE

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To research the relations between low-density lipoprotein receptor-related protein gene (LRP) polymorphism, butyrylcholinesterase gene (BchE) polymorphism and Alzheimer's disease (AD) in Chinese. Methods. The gene polymorphisms of LRP and BchE were genotyped in 38 AD cases and 40 controls with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. AD groups were classified according to the LRP C/C genotype and compared with matched controls. Results. AD group had higher frequencies of C/C homozygote (81.6% vs 60.0% , P<0.05) and of C allele (89.5% vs 76.3% , P< 0.05),with no significant difference between any of these LRP genotypes classified AD groups and their respective control groups.? Conclusions. A positive correlation was found between LRP gene polymorphism and AD, but not between BchE gene polymorphism and AD in Chinese AD cases.

  15. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor

    DEFF Research Database (Denmark)

    Kristensen, T; Moestrup, Søren Kragh; Gliemann, Jørgen;

    1990-01-01

    these polypeptides, and analysis of a 1772 bp cDNA encoding part of the 500 kDa polypeptide provide evidence that the 500 kDa and 85 kDa chains are the alpha- and beta-subunits, respectively, of a recently cloned hepatic membrane protein, termed the low density lipoprotein receptor related protein (LRP) (Herz, J......The human placental receptor (alpha 2MR) for alpha 2-macroglobulin-proteinase complexes contains 3 polypeptides of approx. 500 kDa, 85 kDa, and 40 kDa. N-terminal sequence analysis of the 500 kDa and 85 kDa polypeptides, analysis of a random selection of peptides convering 536 residues from...

  16. Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function

    Directory of Open Access Journals (Sweden)

    Loic Auderset

    2016-01-01

    Full Text Available The central nervous system (CNS is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions.

  17. Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Yinyuan Ding

    2016-05-01

    Full Text Available Low-density lipoprotein receptor-related protein-1 (LRP1 is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2 translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL triglyceride secretion.

  18. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A.

    Science.gov (United States)

    Kounnas, M Z; Morris, R E; Thompson, M R; FitzGerald, D J; Strickland, D K; Saelinger, C B

    1992-06-25

    The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2 MR/LRP) is a large cell-surface glycoprotein consisting of a 515-kDa and an 85-kDa polypeptide; this receptor is thought to be responsible for the binding and endocytosis of activated alpha 2-macroglobulin and apoE-enriched beta-very low density lipoprotein. A similar high molecular weight glycoprotein has been identified as a potential receptor for Pseudomonas exotoxin A (PE). We demonstrate that the alpha 2 MR/LRP and the PE-binding glycoprotein have a similar mobility upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis and are immunologically indistinguishable. Furthermore, affinity-purified alpha 2 MR/LRP binds specifically to PE but not to a mutant toxin defective in its ability to bind cells. The 39-kDa receptor-associated protein, which blocks binding of ligands to alpha 2 MR/LRP, also prevents binding and subsequent toxicity of PE for mouse fibroblasts. The concentration of receptor-associated protein that was required to reduce binding and toxicity to 50% was approximately 14 nM, a value virtually identical to the KD measured for the interaction of receptor-associated protein with the purified receptor. Overall, the studies strongly suggest that the alpha 2 MR/LRP is responsible for internalizing PE.

  19. Polymorphisms in the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Gene Are Associated with Peak Bone Mass in Non-sedentary Men

    DEFF Research Database (Denmark)

    Brixen, K; Beckers, S; Peeters, A

    2007-01-01

    PURPOSE: To investigate the impact of the Ala1330Val (rs3736228, exon 18) and Val667Met (rs4988321, exon 9) polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene on peak bone mass in young men. METHODS: The Odense Androgen Study (OAS) is a population-based study...

  20. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor

    DEFF Research Database (Denmark)

    Kristensen, Torsten; Moestrup, Søren Kragh; Gliemann, Jørgen;

    1990-01-01

    The human placental receptor (α2MR) for α2-macroglobulin-proteinase complexes contains 3 polypeptides of approx. 500 kDa, 85 kDa, and 40 kDa. N-terminal sequence analysis of the 500 kDa and 85 kDa polypeptides, analysis of a random selection of peptides covering 536 residues from these polypeptides......, and analysis of a 1772 bp cDNA encoding part of the 500 kDa polypeptide provide evidence that the 500 kDa and 85 kDa chains are the α- and β-subunits, respectively, of a recently cloned hepatic membrane protein, termed the low density lipoprotein receptor related protein (LRP) (Herz, J., Hamann, U., Rogne, S......., Myklebost, O., Gausepohl, H. and Stanley, K.K. (1988) EMBO J. 7, 4119-4127; Herz, J., Kowal, R.C., Goldstein, J.L. and Brown, M.S. (1990) EMBO J. 9, 1769-1776). N-terminal sequence analysis of the 40 kDa polypeptide shows that it is of distinct genetic origin. It is suggested that LRP is the functional...

  1. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor

    DEFF Research Database (Denmark)

    Kristensen, T; Moestrup, Søren Kragh; Gliemann, Jørgen;

    1990-01-01

    The human placental receptor (alpha 2MR) for alpha 2-macroglobulin-proteinase complexes contains 3 polypeptides of approx. 500 kDa, 85 kDa, and 40 kDa. N-terminal sequence analysis of the 500 kDa and 85 kDa polypeptides, analysis of a random selection of peptides convering 536 residues from...... these polypeptides, and analysis of a 1772 bp cDNA encoding part of the 500 kDa polypeptide provide evidence that the 500 kDa and 85 kDa chains are the alpha- and beta-subunits, respectively, of a recently cloned hepatic membrane protein, termed the low density lipoprotein receptor related protein (LRP) (Herz, J......., Hamann, U., Rogne, S., Myklebost, O., Gausepohl, H. and Stanley, K.K. (1988) EMBO J. 7, 4119-4127; Herz, J., Kowal, R.C., Goldstein, J.L. and Brown, M.S. (1990) EMBO J. 9, 1769-1776). N-terminal sequence analysis of the 40 kDa polypeptide shows that it is of distinct genetic origin. It is suggested...

  2. Protein interactions among Fe65, the low-density lipoprotein receptor-related protein, and the amyloid precursor protein.

    Science.gov (United States)

    Mulvihill, Melinda M; Guttman, Miklos; Komives, Elizabeth A

    2011-07-19

    The adapter protein Fe65 has been proposed to be the link between the intracellular domains of the amyloid precursor protein, APP (AICD), and the low-density lipoprotein receptor-related protein (LRP-CT). Functional linkage between these two proteins has been established, and mutations within LRP-CT affect the amount of Aβ produced from APP. Previous work showed that AICD binds to protein interaction domain 2 (PID2) of Fe65. Although the structure of PID1 was determined recently, all attempts to demonstrate LRP-CT binding to this domain failed. We used biophysical experiments and binding studies to investigate the binding among these three proteins. Full-length Fe65 bound more weakly to AICD than did N-terminally truncated forms; however, the intramolecular domain-domain interactions that had been proposed to inhibit binding could not be observed using amide H-D exchange. Surprisingly, when LRP-CT is phosphorylated at Tyr4507, it bound to Fe65 PID1 despite the fact that this domain belongs to the Dab-like subclass of PIDs that are not supposed to be phosphorylation-dependent. Mutation of a critical arginine abolished binding, providing further proof of the phosphorylation dependence. Fe65 PID1 thus provides a link between the Dab-like class and the IRS-like class of PIDs and is the first Dab-like family member to show phosphorylation-dependent binding.

  3. Helicobacter pylori-induced activation of β-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled

    Directory of Open Access Journals (Sweden)

    Lendeckel Uwe

    2010-02-01

    Full Text Available Abstract Background The human microbial pathogen Helicobacter pylori resides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/β-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6 and Dishevelled (Dvl in the activation of β-catenin early after infection of gastric epithelial cells with H. pylori. Results Infection of gastric epithelial NCI-N87 cells with H. pylori induces rapid phosphorylation of the Wnt/β-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA or vacuolating cytotoxin A (VacA. However, bacteria lacking a functional type 4 secretion system (T4SS failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation. H. pylori-induced nuclear accumulation of β-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3. Conclusion We analysed the H. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of β-catenin.

  4. Association between low density lipoprotein receptor-related protein 2 gene polymorphisms and bone mineral density variation in Chinese population.

    Directory of Open Access Journals (Sweden)

    Chun Wang

    Full Text Available Low density lipoprotein receptor-related protein 2 gene (LRP2 is located next to the genomic region showing suggestive linkage with both hip and wrist bone mineral density (BMD phenotypes. LRP2 knockout mice showed severe vitamin D deficiency and bone disease, indicating the involvement of LRP2 in the preservation of vitamin D metabolites and delivery of the precursor to the kidney for the generation of 1α,25(OH(2D(3. In order to investigate the contribution of LRP2 gene polymorphisms to the variation of BMD in Chinese population, a total of 330 Chinese female-offspring nuclear families with 1088 individuals and 400 Chinese male-offspring nuclear families with 1215 individuals were genotyped at six tagSNPs of the LRP2 gene (rs2389557, rs2544381, rs7600336, rs10210408, rs2075252 and rs4667591. BMD values at the lumbar spine 1-4 (L1-4 and hip sites were measured by DXA. The association between LRP2 polymorphisms and BMD phenotypes was assessed by quantitative transmission disequilibrium tests (QTDTs in female- and male-offspring nuclear families separately. In the female-offspring nuclear families, rs2075252 and haplotype GA of rs4667591 and rs2075252 were identified in the nominally significant total association with peak BMD at L1-4; however, no significant within-family association was found between peak BMD at the L1-4 and hip sites and six tagSNPs or haplotypes. In male-offspring nuclear families, neither the six tagSNPs nor the haplotypes was in total association or within-family association with the peak BMD variation at the L1-4 and hip sites by QTDT analysis. Our findings suggested that the polymorphisms of LRP2 gene is not a major factor that contributes to the peak BMD variation in Chinese population.

  5. Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration.

    Science.gov (United States)

    Landowski, Lila M; Pavez, Macarena; Brown, Lachlan S; Gasperini, Robert; Taylor, Bruce V; West, Adrian K; Foa, Lisa

    2016-01-15

    The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.

  6. Mechanisms of Cellular Uptake of Thrombin-Antithrombin II Complexes Role of the Low-Density Lipoprotein Receptor-Related Protein as a Serpin-Enzyme Complex Receptor.

    Science.gov (United States)

    Strickland, D K; Kounnas, M Z

    1997-01-01

    Serine proteinase inhibitors (serpins) such as antithrombin III inhibit target proteinases by forming a stable complexwith the enzyme. Once formed, several serpin-enzyme complexes (SECs) are removed from the circulation by a receptor, termed the SEC receptor, that is present in the liver. Until recently, the identity of this clearance receptor remained unknown; however, data are now available that strongly implicates one member of the low-density lipoprotein (LDL) receptor family as a candidate for the SEC receptor. This receptor, known as the LDL receptor-related protein (LRP), is a prominent liver receptor that is known to bind numerous ligands that include proteinase-inhibitor complexes, matrix proteins, and certain apolipoprotein E- and lipoprotein lipase-enriched lipoproteins. © 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:9-16).

  7. Pseudomonas exotoxin-mediated selection yields cells with altered expression of low-density lipoprotein receptor-related protein.

    Science.gov (United States)

    FitzGerald, D J; Fryling, C M; Zdanovsky, A; Saelinger, C B; Kounnas, M; Winkles, J A; Strickland, D; Leppla, S

    1995-06-01

    The alpha 2-macroglobulin (alpha 2M) receptor/low-density lipoprotein receptor-related protein (LRP) is important for the clearance of proteases, protease-inhibitor complexes, and various ligands associated with lipid metabolism. While the regulation of receptor function is poorly understood, the addition of high concentrations of the 39-kD receptor-associated protein (RAP) to cells inhibits the binding and/or uptake of many of these ligands. Previously, we (Kounnas, M.Z., R.E. Morris, M.R. Thompson, D.J. FitzGerald, D.K. Strickland, and C.B. Saelinger. 1992. J. Biol. Chem. 267:12420-12423) [corrected] showed that Pseudomonas exotoxin (PE) could bind immobilized LRP. Also, the addition of RAP blocked toxin-mediated cell killing. These findings suggested that PE might use LRP to gain entry into toxin-sensitive cells. Here we report on a strategy to select PE-resistant lines of Chinese hamster ovary cells that express altered amounts of LRP. An important part of this strategy is to screen PE-resistant clones for those that retain sensitivity to both diphtheria toxin and to a fusion protein composed of lethal factor (from anthrax toxin) fused to the adenosine diphosphate-ribosylating domain of PE. Two lines, with obvious changes in their expression of LRP, were characterized in detail. The 14-2-1 line had significant amounts of LRP, but in contrast to wild-type cells, little or no receptor was displayed on the cell surface. Instead, receptor protein was found primarily within cells, much of it apparently in an unprocessed state. The 14-2-1 line showed no uptake of chymotrypsin-alpha 2M and was 10-fold resistant to PE compared with wild-type cells. A second line, 13-5-1, had no detectable LRP mRNA or protein, did not internalize alpha 2M-chymotrypsin, and exhibited a 100-fold resistance to PE. Resistance to PE appeared to be due to receptor-specific defects, since these mutant lines showed no resistance to a PE chimeric toxin that was internalized via the transferrin

  8. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

    DEFF Research Database (Denmark)

    Bown, Matthew J; Jones, Gregory T; Harrison, Seamus C

    2011-01-01

    additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p lipoprotein...... p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies...

  9. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4.

    Science.gov (United States)

    Verschuuren, Jan J G M; Huijbers, Maartje G; Plomp, Jaap J; Niks, Erik H; Molenaar, Peter C; Martinez-Martinez, Pilar; Gomez, Alejandro M; De Baets, Marc H; Losen, Mario

    2013-07-01

    Myasthenia gravis is caused by antibodies to the acetylcholine receptor, muscle-specific kinase, low-density lipoprotein receptor-related protein 4, or possibly yet unidentified antibodies. The mechanisms by which these antibodies interfere with the function of postsynaptic proteins include complement activation, antigenic modulation by crosslinking of the target proteins, competition with ligand binding sites, or steric hindrance which inhibits conformational changes or binding to associated proteins. Screening for auto-antibodies to different postsynaptic targets, and also for low-affinity antibodies, is contributing to a more accurate diagnosis of MG patients. Further studies into the specific pathophysiological pathways of the several MG subforms might help to develop new, more antigen specific, therapies. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6 Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Gwang-woong Go

    2015-06-01

    Full Text Available Low-density lipoprotein receptor-related protein 6 (LRP6 is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention.

  11. Association between Low-density Lipoprotein Receptor-related Protein 5 Polymorphisms and Type 2 Diabetes Mellitus in Han Chinese:a Case-control Study

    Institute of Scientific and Technical Information of China (English)

    YOU Hai Fei; WANG Yan; WANG Qian; WANG Bing Yuan; REN Yong Cheng; HU Dong Sheng; ZHAO Jing Zhi; ZHAI Yu Jia; YIN Lei; PANG Chao; LUO Xin Ping; ZHANG Ming; WANG Jin Jin; LI Lin Lin

    2015-01-01

    Objective To investigate the association between low-density lipoprotein receptor-related protein 5 (LRP5) variants (rs12363572 and rs4930588) and type 2 diabetes mellitus (T2DM) in Han Chinese. Methods A total of 1842 T2DM cases (507 newly diagnosed cases and 1335 previously diagnosed cases) and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms (SNPs). Odds ratios (ORs) and 95%confidence intervals (95%CIs) were calculated to describe the strength of the association by logistic regression. Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index (BMI), the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype TT was associated with reduced risk of T2DM (OR 0.820, 95% CI 0.732-0.919). In addition, rs12363572 was associated with BMI (P Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.

  12. Association between Low-density Lipoprotein Receptor-related Protein 5 Polymorphisms and Type 2 Diabetes Mellitus in Han Chinese: a Case-control Study.

    Science.gov (United States)

    You, Hai Fei; Zhao, Jing Zhi; Zhai, Yu Jia; Yin, Lei; Pang, Chao; Luo, Xin Ping; Zhang, Ming; Wang, Jin Jin; Li, Lin Lin; Wang, Yan; Wang, Qian; Wang, Bing Yuan; Ren, Yong Cheng; Hu, Dong Sheng

    2015-07-01

    To investigate the association between low-density lipoprotein receptor-related protein 5 (LRP5) variants (rs12363572 and rs4930588) and type 2 diabetes mellitus (T2DM) in Han Chinese. A total of 1842 T2DM cases (507 newly diagnosed cases and 1335 previously diagnosed cases) and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms (SNPs). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to describe the strength of the association by logistic regression. In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index (BMI), the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype TT was associated with reduced risk of T2DM (OR 0.820, 95% CI 0.732-0.919). In addition, rs12363572 was associated with BMI (P<0.001) and rs4930588 was associated with triglyceride levels (P=0.043) in 507 newly diagnosed T2DM cases but not in healthy controls. No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  13. Acceleration of Lung Regeneration by Platelet-Rich Plasma Extract through the Low-Density Lipoprotein Receptor-Related Protein 5-Tie2 Pathway.

    Science.gov (United States)

    Mammoto, Tadanori; Chen, Zhao; Jiang, Amanda; Jiang, Elisabeth; Ingber, Donald E; Mammoto, Akiko

    2016-01-01

    Angiogenesis, the growth of new blood vessels, plays a key role in organ development, homeostasis, and regeneration. The cooperation of multiple angiogenic factors, rather than a single factor, is required for physiological angiogenesis. Recently, we have reported that soluble platelet-rich plasma (PRP) extract, which contains abundant angiopoietin-1 and multiple other angiogenic factors, stimulates angiogenesis and maintains vascular integrity in vitro and in vivo. In this report, we have demonstrated that mouse PRP extract increases phosphorylation levels of the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) and thereby activates angiogenic factor receptor Tie2 in endothelial cells (ECs) and accelerates EC sprouting and lung epithelial cell budding in vitro. PRP extract also increases phosphorylation levels of Tie2 in the mouse lungs and accelerates compensatory lung growth and recovery of exercise capacity after unilateral pneumonectomy in mice, whereas soluble Tie2 receptor or Lrp5 knockdown attenuates the effects of PRP extract. Because human PRP extract is generated from autologous peripheral blood and can be stored at -80°C, our findings may lead to the development of novel therapeutic interventions for various angiogenesis-related lung diseases and to the improvement of strategies for lung regeneration.

  14. Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro.

    Science.gov (United States)

    Hou, Huayan; Habib, Ahsan; Zi, Dan; Tian, Kathy; Tian, Jun; Giunta, Brian; Sawmiller, Darrell; Tan, Jun

    2017-06-13

    Previous studies have demonstrated that the low-density lipoprotein receptor-related protein-1 (LRP1) plays conflicting roles in Alzheimer's disease (AD) pathogenesis, clearing β-amyloid (Aβ) from the brain while also enhancing APP endocytosis and resultant amyloidogenic processing. We have recently discovered that co-expression of mutant LRP1 C-terminal domain (LRP1-CT C4408R) with Swedish mutant amyloid precursor protein (APPswe) in Chinese hamster ovary (CHO) cells decreases Aβ production, while also increasing sAPPα and APP α-C-terminal fragment (α-CTF), compared with CHO cells expressing APPswe alone. Surprisingly, the location of this mutation on LRP1 corresponded with the α-secretase cleavage site of APP. Further experimentation confirmed that in CHO cells expressing APPswe or wild-type APP (APPwt), co-expression of LRP1-CT C4408R decreases Aβ and increases sAPPα and α-CTF compared with co-expression of wild-type LRP1-CT. In addition, LRP1-CT C4408R enhanced the unglycosylated form of LRP1-CT and reduced APP endocytosis as determined by flow cytometry. This finding identifies a point mutation in LRP1 which slows LRP1-CT-mediated APP endocytosis and amyloidogenic processing, while enhancing APP α-secretase cleavage, thus demonstrating a potential novel target for slowing AD pathogenesis.

  15. Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pires, L.A. [Laboratório de Metabolismo de Lípides, Instituto do Coração, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Departamento de Ginecologia, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Hegg, R. [Departamento de Ginecologia, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Freitas, F.R.; Tavares, E.R.; Almeida, C.P. [Laboratório de Metabolismo de Lípides, Instituto do Coração, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Baracat, E.C. [Departamento de Ginecologia, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Maranhão, R.C. [Laboratório de Metabolismo de Lípides, Instituto do Coração, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP (Brazil); Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-05-04

    Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

  16. Low level of low-density lipoprotein receptor-related protein 1 predicts an unfavorable prognosis of hepatocellular carcinoma after curative resection.

    Directory of Open Access Journals (Sweden)

    Xiao-Yong Huang

    Full Text Available BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1 is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC. METHODS: LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP, the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens. RESULTS: Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set. CONCLUSIONS: LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy.

  17. Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.

    Science.gov (United States)

    Yang, Wei-Na; Ma, Kai-Ge; Qian, Yi-Hua; Zhang, Jian-Shui; Feng, Gai-Feng; Shi, Li-Li; Zhang, Zhi-Chao; Liu, Zhao-Hui

    2015-07-01

    Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aβ). Reuptake of extracellular Aβ is believed to contribute significantly to the intraneuronal Aβ pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aβ1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aβ internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aβ1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aβ internalization in neurons. We found that extracellular Aβ1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aβ1-42 and LRP1 were also found co-localized in neurons during Aβ1-42 internalization, and they could form Aβ1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aβ1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aβ1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aβ1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aβ levels and served a potential therapeutic target for AD.

  18. Association of polymorphisms in low-density lipoprotein receptor- related protein 5 gene with bone mineral density in postmenopausal Chinese women

    Institute of Scientific and Technical Information of China (English)

    Zhen-lin ZHANG; Yue-juan QIN; Jin-wei HE; Qi-ren HUANG; Miao LI; Yun-qiu HU; Yu-juan LIU

    2005-01-01

    Aim: To investigate the possible association of Q89R, N740N and A1330V polymorphisms in low-density lipoprotein receptor-related protein 5 (LRP5) gene with bone mineral density (BMD) in postmenopausal Chinese women. Methods: Q89R,N740N and A1330V genotypes were determined by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) in 647 unrelated healthy postmenopausal Han Chinese women aged 43-76 years in Shanghai. BMD at lumbar spine 1-4 and the left proximal femur including the femoral neck, trochanter and Ward's triangle were measured by dual-energy X-ray absorptionmetry in all subjects. Results: The distribution of the Q89R, N740N and A1330V genotypes in this population was as follows: QQ 80.5%, QR 18.7%, and RR 0.8%; TT 66.9%,TC 31.1%, and CC 2.0%; AA 68.0%, AV 29.7%, and VV 2.3%. The frequencies of the Q89R, N740N and A1330V genotypes and alleles did not deviate from the HardyWeinberg equilibrium. We found that the Q89R and A1330V polymorphisms were in linkage disequilibrium in our population (x2= 13.50, P<0.01). Both before and after adjusting for age, years since menopause, height, and weight, the Q89R or N740N genotypes were significantly associated with BMD at the femoral neck (P<0.05).Subjects with the Q89R QQ genotype or the N740N TT genotype had a significantly higher BMD at the femoral neck, compared with those with the QR/RR or TC/CC genotypes, respectively. No significant association was found between A1330V polymorphism and BMD at any site. Conclusion: Our findings suggest that the LRP5 gene is a candidate for the genetic determination of BMD in postmenopausal Chinese women.

  19. Generation of a Potent Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Antagonist by Engineering a Stable Form of the Receptor-associated Protein (RAP) D3 Domain.

    Science.gov (United States)

    Prasad, Joni M; Migliorini, Mary; Galisteo, Rebeca; Strickland, Dudley K

    2015-07-10

    The low density lipoprotein receptor-related protein 1 (LRP1) is a member of the low density lipoprotein receptor family and plays important roles in a number of physiological and pathological processes. Expression of LRP1 requires the receptor-associated protein (RAP), a molecular chaperone that binds LRP1 and other low density lipoprotein receptor family members in the endoplasmic reticulum and traffics with them to the Golgi where the acidic environment causes its dissociation. Exogenously added RAP is a potent LRP1 antagonist and binds to LRP1 on the cell surface, preventing ligands from binding. Following endocytosis, RAP dissociates in the acidic endosome, allowing LRP1 to recycle back to the cell surface. The acid-induced dissociation of RAP is mediated by its D3 domain, a relatively unstable three-helical bundle that denatures at pH RAP D3 domain. By combining this disulfide bond with elimination of key histidine residues, we generated a stable RAP molecule that is resistant to both pH- and heat-induced denaturation. This molecule bound to LRP1 with high affinity at both neutral and acidic pH and proved to be a potent inhibitor of LRP1 function both in vitro and in vivo, suggesting that our stable RAP molecule may be useful in multiple pathological settings where LRP1 blockade has been shown to be effective. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Generation of a Potent Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Antagonist by Engineering a Stable Form of the Receptor-associated Protein (RAP) D3 Domain*

    Science.gov (United States)

    Prasad, Joni M.; Migliorini, Mary; Galisteo, Rebeca; Strickland, Dudley K.

    2015-01-01

    The low density lipoprotein receptor-related protein 1 (LRP1) is a member of the low density lipoprotein receptor family and plays important roles in a number of physiological and pathological processes. Expression of LRP1 requires the receptor-associated protein (RAP), a molecular chaperone that binds LRP1 and other low density lipoprotein receptor family members in the endoplasmic reticulum and traffics with them to the Golgi where the acidic environment causes its dissociation. Exogenously added RAP is a potent LRP1 antagonist and binds to LRP1 on the cell surface, preventing ligands from binding. Following endocytosis, RAP dissociates in the acidic endosome, allowing LRP1 to recycle back to the cell surface. The acid-induced dissociation of RAP is mediated by its D3 domain, a relatively unstable three-helical bundle that denatures at pH RAP D3 domain. By combining this disulfide bond with elimination of key histidine residues, we generated a stable RAP molecule that is resistant to both pH- and heat-induced denaturation. This molecule bound to LRP1 with high affinity at both neutral and acidic pH and proved to be a potent inhibitor of LRP1 function both in vitro and in vivo, suggesting that our stable RAP molecule may be useful in multiple pathological settings where LRP1 blockade has been shown to be effective. PMID:26013822

  1. Up-regulation of hepatic low-density lipoprotein receptor-related protein 1: a possible novel mechanism of antiatherogenic activity of hydroxymethylglutaryl-coenzyme A reductase inhibitor Atorvastatin and hepatic LRP1 expression.

    Science.gov (United States)

    Moon, Jae Hoon; Kang, Saet Byol; Park, Jong Suk; Lee, Byung Wan; Kang, Eun Seok; Ahn, Chul Woo; Lee, Hyun Chul; Cha, Bong Soo

    2011-07-01

    Low-density lipoprotein receptor-related protein 1 (LRP1) binds to apolipoprotein E and serves as a receptor for remnant lipoproteins in the liver, thus playing an important role in clearing these atherogenic particles. In this study, we investigated the effect of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, on hepatic LRP1 expression. We used HepG2 and Hep3B cells for in vitro study, and Otsuka Long-Evans Tokushima fatty and Sprague-Dawley rats for in vivo study. We used relatively high pharmacologic dose of atorvastatin in this study (in vitro, 0.5 μmol/L in culture media, for 48 hours; in vivo, 20 mg/[kg d], for 6 weeks). Atorvastatin increased LRP1 and low-density lipoprotein (LDL) receptor expression in HepG2 and Hep3B cells and induced hepatic LRP1 and LDL receptor expression in chow diet-fed Sprague-Dawley rats and high-fat diet-fed Otsuka Long-Evans Tokushima fatty rats. Atorvastatin decreased intracellular sterol level and increased the amount of the nuclear form of sterol response element-binding protein-2 (SREBP-2) in both HepG2 and Hep3B cells as well as in two animal models. Treatment of HepG2 cells with LDL increased intracellular sterol level and reduced LRP1, LDL receptor, and SREBP-2. When SREBP-2 in HepG2 cells was knocked down by small interfering RNA, the induction of LRP1 expression by atorvastatin did not take place. In conclusion, up-regulation of hepatic LRP1 might be a novel mechanism by which statin treatment decreases remnant lipoproteins. In addition, SREBP-2 acts as a mediator of atorvastatin-induced up-regulation of hepatic LRP1. Future studies using standard doses of atorvastatin in humans are needed to elucidate clinical relevance of these findings.

  2. Specificity of binding of the low density lipoprotein receptor-related protein to different conformational states of the clade E serpins plasminogen activator inhibitor-1 and proteinase nexin-1.

    Science.gov (United States)

    Jensen, Jan K; Dolmer, Klavs; Gettins, Peter G W

    2009-07-03

    The low density lipoprotein receptor-related protein (LRP) is the principal clearance receptor for serpins and serpin-proteinase complexes. The ligand binding regions of LRP consist of clusters of cysteine-rich approximately 40-residue complement-like repeats (CR), with cluster II being the principal ligand-binding region. To better understand the specificity of binding at different sites within the cluster and the ability of LRP to discriminate in vivo between uncomplexed and proteinase-complexed serpins, we have systematically examined the affinities of plasminogen activator inhibitor-1 (PAI-1) and proteinase nexin-1 (PN-1) in their native, cleaved, and proteinase-complexed states to (CR)(2) and (CR)(3) fragments of LRP cluster II. A consistent blue shift of the CR domain tryptophan fluorescence suggested a common mode of serpin binding, involving lysines on the serpin engaging the acidic region around the calcium binding site of the CR domain. High affinity binding of non-proteinase-complexed PAI-1 and PN-1 occurred to all fragments containing three CR domains (3-59 nm) and most that contain only two CR domains, although binding energies to different (CR)(3) fragments differed by up to 18% for PAI-1 and 9% for PN-1. No detectable difference in affinity was seen between native and cleaved serpin. However, the presence of proteinase in complex with the serpin enhanced affinity modestly and presumably nonspecifically. This may be sufficient to give preferential binding of such complexes in vivo at the relevant physiological concentrations.

  3. Association of type 2 diabetes mellitus with the interaction between low-density lipoprotein receptor-related protein 5 (LRP5) polymorphisms and overweight and obesity in rural Chinese adults.

    Science.gov (United States)

    Zhang, Lu; Wang, Jinjin; Zhang, Ming; Wang, Guo'an; Shen, Yanxia; Wu, Dongting; Wang, Chongjian; Li, Linlin; Ren, Yongcheng; Wang, Bingyuan; Zhang, Hongyan; Yang, Xiangyu; Zhao, Yang; Han, Chengyi; Zhou, Junmei; Pang, Chao; Yin, Lei; Zhao, Jingzhi; Luo, Xinping; Hu, Dongsheng

    2017-01-09

    Low-density lipoprotein receptor-related protein 5 (LRP5) plays an important role in glucose and cholesterol metabolism. The present cohort study evaluated associations of LRP5 variants with the incidence of type 2 diabetes mellitus (T2DM) in a rural adult Chinese population. In all, 7751 subjects aged ≥18 years without T2DM underwent genotyping at baseline; 6326 subjects (81.62%) were followed-up, and 5511 with a clear disease outcome were eligible for analysis. The same questionnaire was administered and the same anthropometric and blood biochemical examinations were performed at baseline and follow-up. Association analysis was performed for five single nucleotide polymorphisms and haplotypes of LRP5. Cox proportional hazards testing of three different genetic models found no significant association between T2DM and LRP5 after adjusting for potential risk factors (P > 0.05). However, the incidence of T2DM in subjects with LRP5 mutational genotypes was higher in the overweight/obese than normal weight population. Under the dominant model, the risk of T2DM was increased with an interaction between rs11228303 and the waist-to-height ratio adjusted for baseline age, sex, and family history of T2DM (synergy index [SI] = 4.172; 95% confidence interval [CI] 1.014-17.166)], and body mass index (SI = 3.237; 95% CI 1.102-9.509). Furthermore, the A allele of rs3758644 was related to decreased fasting plasma insulin and homeostatic model assessment of β-cell function levels, whereas the T allele of rs12363572 was related to increased high-density lipoprotein cholesterol levels in new-onset diabetes patients (P < 0.05). The risk of T2DM may be associated with interactions between the LRP5 gene and overweight and obesity. Polymorphisms of LRP5 are related to β-cell function and lipid metabolism. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  4. The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated β-amyloid protein internalization in mouse brain.

    Science.gov (United States)

    Ma, Kai-Ge; Lv, Jia; Hu, Xiao-Dan; Shi, Li-Li; Chang, Ke-Wei; Chen, Xin-Lin; Qian, Yi-Hua; Yang, Wei-Na; Qu, Qiu-Min

    2016-07-01

    Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular β-amyloid protein (Aβ) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control Aβ internalization may provide new insight for regulating Aβ levels. In the present study, the regulation of Aβ internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that Aβ1-42 were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. Aβ1-42-LRP1 complex was formed during Aβ1-42 internalization, and the p38 MAPK signaling pathway was activated by Aβ1-42 via LRP1. Aβ1-42 and LRP1 were co- localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in Aβ1-42 internalization in mouse brain. The results of this investigation demonstrated that Aβ1-42 induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of Aβ1-42. These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of Aβ1-42 internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo.

  5. The High Affinity Binding Site on Plasminogen Activator Inhibitor-1 (PAI-1) for the Low Density Lipoprotein Receptor-related Protein (LRP1) Is Composed of Four Basic Residues.

    Science.gov (United States)

    Gettins, Peter G W; Dolmer, Klavs

    2016-01-08

    Plasminogen activator inhibitor 1 (PAI-1) is a serpin inhibitor of the plasminogen activators urokinase-type plasminogen activator (uPA) and tissue plasminogen activator, which binds tightly to the clearance and signaling receptor low density lipoprotein receptor-related protein 1 (LRP1) in both proteinase-complexed and uncomplexed forms. Binding sites for PAI-1 within LRP1 have been localized to CR clusters II and IV. Within cluster II, there is a strong preference for the triple CR domain fragment CR456. Previous mutagenesis studies to identify the binding site on PAI-1 for LRP1 have given conflicting results or implied small binding contributions incompatible with the high affinity PAI-1/LRP1 interaction. Using a highly sensitive solution fluorescence assay, we have examined binding of CR456 to arginine and lysine variants of PAI-1 and definitively identified the binding site as composed of four basic residues, Lys-69, Arg-76, Lys-80, and Lys-88. These are highly conserved among mammalian PAI-1s. Individual mutations result in a 13-800-fold increase in Kd values. We present evidence that binding involves engagement of CR4 by Lys-88, CR5 by Arg-76 and Lys-80, and CR6 by Lys-69, with the strongest interactions to CR5 and CR6. Collectively, the individual binding contributions account quantitatively for the overall PAI-1/LRP1 affinity. We propose that the greater efficiency of PAI-1·uPA complex binding and clearance by LRP1, compared with PAI-1 alone, is due solely to simultaneous binding of the uPA moiety in the complex to its receptor, thereby making binding of the PAI-1 moiety to LRP1 a two-dimensional surface-localized association.

  6. Receptor-associated protein (RAP) has two high-affinity binding sites for the low-density lipoprotein receptor-related protein (LRP): consequences for the chaperone functions of RAP.

    Science.gov (United States)

    Jensen, Jan K; Dolmer, Klavs; Schar, Christine; Gettins, Peter G W

    2009-06-26

    RAP (receptor-associated protein) is a three domain 38 kDa ER (endoplasmic reticulum)-resident protein that is a chaperone for the LRP (low-density lipoprotein receptor-related protein). Whereas RAP is known to compete for binding of all known LRP ligands, neither the location, the number of binding sites on LRP, nor the domains of RAP involved in binding is known with certainty. We have systematically examined the binding of each of the three RAP domains (D1, D2 and D3) to tandem and triple CRs (complement-like repeats) that span the principal ligand-binding region, cluster II, of LRP. We found that D3 binds with low nanomolar affinity to all (CR)2 species examined. Addition of a third CR domain increases the affinity for D3 slightly. A pH change from 7.4 to 5.5 gave only a 6-fold increase in Kd for D3 at 37 degrees C, whereas temperature change from 22 degrees C to 37 degrees C has a similar small effect on affinity, raising questions about the recently proposed D3-destabilization mechanism of RAP release from LRP. Surprisingly, and in contrast to literature suggestions, D1 and D2 also bind to most (CR)2 and (CR)3 constructs with nanomolar affinity. Although this suggested that there might be three high-affinity binding sites in RAP for LRP, studies with intact RAP showed that only two binding sites are available in the intact chaperone. These findings suggest a new model for RAP to function as a folding chaperone and also for the involvement of YWTD domains in RAP release from LRP in the Golgi.

  7. 软骨细胞膜蛋白低密度脂蛋白受体相关蛋白1低表达的意义%Knockdown of low density lipoprotein receptor-related protein 1 in chondrocytes

    Institute of Scientific and Technical Information of China (English)

    杨二平; 彭飞; 梁杰; 杜远立

    2016-01-01

    BACKGROUND:Tumor necrosis factor α, as a pathogenic factor, induces the inflammatory reaction mainlyvia the activation of the nuclear factor kappa B signaling pathway. Low density lipoprotein receptor-related protein 1 (LRP1) is involved in the regulation of the inflammatory reaction induced by cytokines. OBJECTIVE:To study the effect of knockdown of LRP1 on tumor necrosis factor α-induced inflammatory reaction. METHODS: Primary cultured rat chondrocytes were transfected with lentivirus-mediated RNA interference to knockdown LRP1 gene. Three days after lentivirus transfection, chondrocytes were pretreated with Bay 11-7082 (10 μmol/L) for 30 minutes prior to the addition of tumor necrosis factor α (30 μg/L) for 30 minutes. Signaling protein and mRNA expressions in chondrocytes were detected by western blot assay and real-time PCR analysis, respectively. Chondrocytes were pretreated with or not Bay 11-7082 (10 μmol/L) 30 minutes prior to the addition of tumor necrosis factor α (30 μg/L) for 12 hours after starvation in DMEM for overnight, and the culture medium was colected for ELISA determination of matrix metaloproteinase 13 level. RESULTS AND CONCLUSION:Tumor necrosis factor α receptor 1 expression was upregulated in chondrocytes after lentivirus-induced knockdown of LRP1. Increased expression of inducible nitric oxide synthase and activation of the nuclear factor kappa B signaling pathway were found after the addition of tumor necrosis factor α in shLRP1 group. Moreover, increased level of matrix metaloproteinase 13 was determined by ELISA. Taken together, knockdown of LRP1 up-regulates the expression of tumor necrosis factor α-induced inducible nitric oxide synthase and matrix metaloproteinase 13 through the activation of the nuclear factor kappa B signaling pathway.%背景:肿瘤坏死因子α是骨关节炎主要致病因子,主要通过激活核因子KB信号通路活性实现软骨细胞炎症反应。细胞膜蛋白低密

  8. Lentivirus-induced knockdown of low density lipoprotein receptor-related protein 1 aggravates cartilage damage in a rat model of osteoarthritis%慢病毒介导shRNA关节腔注射可加重骨关节炎的软骨破坏

    Institute of Scientific and Technical Information of China (English)

    杨二平; 彭飞; 梁杰; 杜远立

    2016-01-01

    BACKGROUND:Emerging evidence demonstrates that low density lipoprotein receptor-related protein 1 (LRP1)isinvolved in lipid metabolism and regulation of inflammatory reaction. OBJECTIVE:To explore the effectof lentivirus-induced knockdown of low density lipoprotein receptor-related protein 1 on cartilage damage and matrix metaloproteinase 13 in a rat model of osteoarthritis, so as to assess the role of low density lipoprotein receptor-related protein 1 in the pathogenesis of osteoarthritis. METHODS:Sixty-fourSprague-Dawleyratswere included andramdomlydivided into four groups (n=16 for each): negative control group, no surgery; sham-surgery group, onlythearticular cavity of the knee was exposed; osteoarthritisplus shLRP1 group, rat osteoarthritis models were established by cutting anterior cruciate ligament and removing the medial meniscus partly folowed by an intra-articular injection of lentivirus-mediated siRNA at 2 days after surgery, once a week for 2 consecutive weeks; osteoarthritis group,an intra-articular injection of the negative control lentivirus was performed after surgery. Rats inthe four groups started running on theself-made electric treadmil from 5 days after modeling, 30 minutes per day,totaly 500 meters. Cartilage damage and matrix metaloproteinase 13 expression in cartilage tissues were determined at 2, 4, 6 weeks after surgery. RESULTS AND CONCLUSION:Gross and pathological observations showed that lentivirus-induced knockdown of lowdensity lipoprotein receptor-related protein 1 aggravatedcartilage damage intherat model of osteoarthritis. At 6 weeks after surgery, Mankin’s scoreand matrix metaloproteinase 13 expression inthecartilage tissues in osteoarthritis plus shLRP1 groupweresignificantly increased compared with other three groups (P  目的:观察慢病毒介导的低密度脂蛋白受体相关蛋白1-shRNA对大鼠骨关节炎模型软骨破坏的影响,以及对软骨组织中基质金属蛋白酶13表达的作用,初步判

  9. What are lipoproteins doing in the brain?

    Science.gov (United States)

    Wang, Hong; Eckel, Robert H

    2014-01-01

    Lipoproteins in plasma transport lipids between tissues, however, only high-density lipoproteins (HDL) appear to traverse the blood-brain barrier (BBB); thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes, and are found on HDL. In the hippocampus and other brain regions, lipoproteins help to regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, acting through lipoprotein lipase (LPL) and the low-density lipoprotein (LDL) receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. 血液透析患者低密度脂蛋白受体相关蛋白5'端四核苷酸重复序列基因多态性与血脂水平检测%The detection of the gene polymorphism of low density lipoprotein receptor related protein tetranucleotide and serum lipid level in hemodialysis patients

    Institute of Scientific and Technical Information of China (English)

    王晓鸿; 李清芹; 李怀富; 陆元善; 徐琴君; 王玉新

    2011-01-01

    Objective To investigate characteristics of dislipidemia and the effect of gene polymorphism of low density lipoprotein receptor related protein (LRP) tetranucleotide on hemodialysis patients. Methods Serum total cholesterol (TC),triglyceride (TG),low density lipoprotein cholesterol (LDLC),high density lipoprotein cholesterol (HDLC),apolipoproteins (Apo A1,B,E) and lipoprotein(a) [Lp(a)] were measured;polymerase chain reaction-restriction fragment length polymophism (PCR-RFLP) was used to detect LRP gene polymorphism in hemodialysis patients. Results Serum levels of TG and ApoB were significantly higher in the hemodialysis patients than those in contrals,and the levels of TC,LDLC,HDLC were lower compare to those in contrals. Patients with cardiovascular disease had higher TG level comparing to the patients without cardiovascular disease. The data of LRP polymorphism detected by PCR-RFLP showed that the allele frequency and the distribution of the LRP genotype of tetranucleotide reapeat sequence did not differ significantly between controls and hemodialysis patients. There was no statistic difference of serum lipid levels among hemodialysis patients with different genotype of LRP tetranucleotide.Conclusions Hemodialysis patients can develop hypertrglyeridemia and hypocholesteroldemia. TG level might be related to the development of cardiovascular disease in hemodialysis patients. The gene polymorphisms of LRP tetranucleotide dose not affect the lipid levels significantly in hemodialysis patients.%目的 探讨血液透析患者脂代谢紊乱的临床特征及低密度脂蛋白受体相关蛋白(LRp)5'端四核苷酸重复序列基因多态性对脂代谢的影响.方法 比较血液透析组患者(112例)与对照组(372例)血清TC、TG、HDL-C、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白(Apo)A1、ApoB、ApoE及脂蛋白(Lp)(a)水平,聚合酶链反应-限制性片断长度方法检测LRP5'端四核苷酸重复序列基因多态性.结果 血液透析组

  11. Detection of Rsa Ⅰ gene polimorphism of low density lipoprotein receptor related protein and its influence on serum lipid level in hemodialysis patients%血液透析患者低密度脂蛋白受体相关蛋白Rsa Ⅰ位点基因多态性对血脂水平的影响

    Institute of Scientific and Technical Information of China (English)

    王玉新; 张以勤; 叶婧; 陆元善; 徐琴君; 邹和群

    2012-01-01

    Objectives To investigate the characteristics of dislipidemia and influence by low density lipoprotein receptor related protein (LRP) exon 3 Rsa Ⅰ gene polymorphism in hemodialysis patients.Methods serum total cholesterol (TC),triglyceride (TG),low density lipoprotein cholesterol (LDLC),high density lipoprotein cholesterol ( HDLC),apolipoproteins ( Apo A1,B,E) and lipoprotein (a) [Lp (a)] were measured,polymerase chain reaction - restriction fragment length polymophism ( PCR - RFLP) was used to detect LRP gene polymorphism in hemodialysis patients.Results The serum levels of TG and ApoB were higher significantly in the hemodialysis patients compared to contrals,and the levels of TC,LDLC,HDLC were lower compared to controls.Patients with cardiovascular disorder had higher TG level compared to patients without the disorder.The data of LRP polymorphism detected by PCR - RFLP showed that the allele frequency and the distribution of the LRP genotype of tetranucleotide reapeat sequence and exon 3 did not differ significantly between controls and hemodialysis patients.There was no statistic difference in serum lipid level between hemodialysis patients with different genotype of LRP exon 3.Conclusions Hemodialysis patients were liable to develop hypertrglyeridemia and hypocholesteroldemia.TG level might related to the development of cardiovascular disorder in hemodialysis patients.There is different influence of LRP Rsa Ⅰ gene polymorphism on lipid levels between controls and hemodialysis patients.%目的 探讨血液透析患者脂代谢紊乱的临床特征及低密度脂蛋白受体相关蛋白(LRP)外显子3RsaⅠ位点基因多态性对脂代谢的影响.方法 生化方法检测血液透析患者血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDLC)、低密度脂蛋白胆固醇(LDLC)、载脂蛋白(Apo)A1、ApoB、ApoE及脂蛋白(Lp)(a)水平,多聚合酶链反应-限制性片断长度多态性方法( PCR - RFLP)检测LRP外显子3Rsa

  12. Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

    NARCIS (Netherlands)

    Espirito Santo, S.M.S.; Rensen, P.C.N.; Goudriaan, J.R.; Bensadoun, A.; Bovenschen, N.; Voshol, P.J.; Havekes, L.M.; Vlijmen, B.J.M. van

    2005-01-01

    The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma.

  13. LDL Receptor-Related Protein-1 (LRP1 Regulates Cholesterol Accumulation in Macrophages.

    Directory of Open Access Journals (Sweden)

    Anna P Lillis

    Full Text Available Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the in vivo contribution of the LDL receptor-related protein 1 (LRP1 to this process is not known [corrected]. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR-deficient background (macLRP1-/-. After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis.

  14. 敲低低密度脂蛋白受体相关蛋白1抑制C3H10T1/2多潜能干细胞定向成脂%Knock Down of Low Density Lipoprotein Receptor-related Protein 1(Lrp1) by RNAi Inhibits The Commitment of C3H10T1/2 Pluripotent Stem Cells to Preadipocyte

    Institute of Scientific and Technical Information of China (English)

    陈婧文; 郭亮

    2012-01-01

    C3H10T1/2多潜能干细胞成脂过程分为定向和分化两个阶段,骨形成蛋白4(BMP4)可以诱导其定向成前脂肪细胞.已有的研究表明,脂肪组织特异性敲除低密度脂蛋白受体相关蛋白1 (Lrp1)的小鼠体重减轻,脂肪组织含量减少,揭示此基因对成脂具有重要作用.然而,目前尚不清楚Lrp1是否在成脂定向过程中发挥作用.采用小干扰RNA技术(RNAi),在体外水平研究低密度脂蛋白Lrp1对C3H10T1/2多潜能干细胞成脂定向的作用.分别在C3H10T1/2成脂的定向期和脂滴成熟期敲低Lrp1,通过显微镜下观察、油红O染色、Western blotting等实验证实,定向期而非脂滴成熟期敲低Lrp1显著抑制C3H10T1/2多潜能干细胞成脂.BMP4通过激活下游Smad1/5/8信号通路发挥作用,而敲低Lrp1显著抑制BMP4诱导的Smad1/5/8磷酸化.这些结果说明:敲低Lrp1通过下调Smad信号通路,抑制BMP4诱导的C3H10T1/2多潜能干细胞成脂定向.%The adipocyte development process of C3H10T1/2 pluripotent stem cells includes two stages: the commitment stage and the differentiation stage. There are evidences that BMP4 commits C3H10T1/2 cells into preadipocytes. Previous studies have shown that mice lacking adipocyte Lrpl(adLrpl-/-) displays reduced body weight and smaller fat stores which highlights the important role of Lrpl in adipogenesis. However, little is known about the role of Lrpl in preadipocyte commitment. RNAi was used to study the effect of low density lipoprotein receptor-related protein l(Lrpl) on commitment of C3H10T1/2 to preadipocyte. Through microscopic examination, Oil red O staining, Western blotting, it is demonstrated that Lrpl RNAi inhibits C3H10T1/2 adipogenesis in commitment stage, rather than in lipid maturation period. BMP4 signals through Smadl/5/8 and Lrpl RNAi significantly suppresses the BMP4-triggered phosphorylation of Smadl/5/8. These data suggest that Lrpl RNAi has inhibitory effects on the BMP4-induced of C3H10T1

  15. Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss

    NARCIS (Netherlands)

    K.A. Berk (Kirsten); R. Vongpromek (Ranitha); M. Jiang (Meizi); W.J. Schneider (Wolfgang); R. Timman (Reinier); A.J.M. Verhoeven; H. Bujo (Hideaki); E.J.G. Sijbrands (Eric); M.T. Mulder (Monique)

    2016-01-01

    markdownabstract__Background and aims__ Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of

  16. Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss

    NARCIS (Netherlands)

    K.A. Berk (Kirsten Ac); R. Vongpromek (Ranitha); M. Jiang (Meizi); W.J. Schneider (Wolfgang); R. Timman (Reinier); A.J.M. Verhoeven; H. Bujo (Hideaki); E.J.G. Sijbrands (Eric); M. Mulder (Monique)

    2016-01-01

    markdownabstract__Background and aims__ Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of at

  17. Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.

    NARCIS (Netherlands)

    Wilhelmus, M.M.; Otte-Holler, I.; Triel, J.J. van; Veerhuis, R.; Maat-Schieman, M.L.; Bu, G.; Waal, R.M.W. de; Verbeek, M.M.

    2007-01-01

    Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of r

  18. Molecular interactions between coagulation factor IX and low density lipoprotein receptor-related protein

    NARCIS (Netherlands)

    Rohlena, Jakub

    2004-01-01

    Factor IX is an essential blood haemostatic protein, which is apparent from the observation that the absence of functional FIX is associated with the severe bleeding disorder haemophilia B. To achieve its full enzymatic activity, the serine protease precursor factor IX must first be activated into

  19. Familial lipoprotein lipase deficiency

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000408.htm Familial lipoprotein lipase deficiency To use the sharing features on this page, please enable JavaScript. Familial lipoprotein lipase deficiency is a group of rare genetic ...

  20. Lipoprotein-a

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007262.htm Lipoprotein-a To use the sharing features on this page, please enable JavaScript. Lipoproteins are molecules made of proteins and fat. They ...

  1. Lipoprotein(a) metabolism

    Science.gov (United States)

    Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein. The metabolism of this lipoprotein is still not well understood. It has long been known that the plasma concentration of Lp(a) is highly heritable, with its genetic determinants located in the apo(a) locus and regulating the rate of hepatic apo(a...

  2. Lipoproteins of Bacterial Pathogens▿

    Science.gov (United States)

    Kovacs-Simon, A.; Titball, R. W.; Michell, S. L.

    2011-01-01

    Bacterial lipoproteins are a set of membrane proteins with many different functions. Due to this broad-ranging functionality, these proteins have a considerable significance in many phenomena, from cellular physiology through cell division and virulence. Here we give a general overview of lipoprotein biogenesis and highlight examples of the roles of lipoproteins in bacterial disease caused by a selection of medically relevant Gram-negative and Gram-positive pathogens: Mycobacterium tuberculosis, Streptococcus pneumoniae, Borrelia burgdorferi, and Neisseria meningitidis. Lipoproteins have been shown to play key roles in adhesion to host cells, modulation of inflammatory processes, and translocation of virulence factors into host cells. As such, a number of lipoproteins have been shown to be potential vaccines. This review provides a summary of some of the reported roles of lipoproteins and of how this knowledge has been exploited in some cases for the generation of novel countermeasures to bacterial diseases. PMID:20974828

  3. Lipoprotein(a)

    DEFF Research Database (Denmark)

    Langsted, Anne; Kamstrup, Pia R; Nordestgaard, Børge G

    2014-01-01

    tested whether normal food intake or inflammation influenced lipoprotein(a)'s ability to predict ischemic heart disease. METHODS: We studied 34 829 individuals from the Danish general population using the Copenhagen General Population Study and the Copenhagen City Heart Study. RESULTS: Lipoprotein......(a) levels did not change in response to normal food intake: median fasting levels were 17.3 mg/dL, while median levels at 3-4 h since last meal were 19.4 mg/dL(p = 0.38). Lipoprotein(a) levels increased minimally with increasing levels of C-reactive protein(CRP): median lipoprotein(a) levels at CRP

  4. Glycosaminoglycan-lipoprotein interaction.

    Science.gov (United States)

    Olsson, U; Ostergren-Lundén, G; Moses, J

    2001-10-01

    Glycosaminoglycans (GAGs) bound to various proteoglycans (PGs) present in the cardiovascular system have been proposed to perform a wide range of functions. These include conferring viscoelastic properties; interacting with and modulating growth factors and enzymes; and as receptors and co-receptors in lipoprotein metabolism. Binding of apoB-100 lipoproteins, particularly low density lipoproteins (LDL), to GAGs of extracellular matrix PGs in arteries has been proposed to be an initiating event in development of atherosclerosis. This study was initiated with the aim of getting an overview of the binding patterns of different lipoprotein subclasses with individual GAG categories. We thus evaluated the interaction of lipoproteins with GAGs commonly found in the cardiovascular system using a gel mobility-shift assay developed for this purpose. The same procedure was used to measure lipoproteins binding to metabolically [(35)S]-labeled whole PGs prepared from three cell types, arterial smooth muscle cells, THP-1 macrophages and from HepG2 cells. The effect of GAG composition on PGs on lipoprotein binding was evaluated by enzymatic degradation of the carbohydrate chains. Heparan sulfate was found to bind beta very low density lipoproteins (beta-VLDL) and a chylomicron remnant model (beta-VLDL+apoE), but not LDL. Dermatan sulfate was found to bind LDL, but not beta-VLDL or the chylomicron remnant model. Chondroitin sulfate and heparin were found to bind all lipoproteins tested (LDL, beta-VLDL and beta-VLDL+apoE) although with different affinities. We can conclude that each lipoprotein subclass tested binds a specific assortment of the GAGs tested. The observations made contribute to the understanding of new and complex mechanisms by which carbohydrate and lipid metabolism may be linked.

  5. Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation.

    Science.gov (United States)

    El Asmar, Zeina; Terrand, Jérome; Jenty, Marion; Host, Lionel; Mlih, Mohamed; Zerr, Aurélie; Justiniano, Hélène; Matz, Rachel L; Boudier, Christian; Scholler, Estelle; Garnier, Jean-Marie; Bertaccini, Diego; Thiersé, Danièle; Schaeffer, Christine; Van Dorsselaer, Alain; Herz, Joachim; Bruban, Véronique; Boucher, Philippe

    2016-03-04

    The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (α) chain of LRP1 mediates TGFβ-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (β) chain of LRP1 suffices to limit cholesterol accumulation in LRP1(-/-) cells. Through binding of Erk2 to the second of its carboxyl-terminal NPXY motifs, LRP1 β-chain positively regulates the expression of ATP binding cassette transporter A1 (ABCA1) and of neutral cholesterol ester hydrolase (NCEH1). These results highlight the unexpected functions of LRP1 and the canonical Wnt5a pathway and new therapeutic potential in cholesterol-associated disorders including cardiovascular diseases.

  6. Cellular uptake of lipoproteins and Persistent Organic Compounds - An update and new data

    DEFF Research Database (Denmark)

    Hjelmborg, Philip Sebastian; Andreassen, Thomas Kjærgaard; Bonefeld-Jørgensen, Eva Cecilie

    2008-01-01

    including the pesticide DDT (p,p'-dichlorodiphenyltrichloroethane), and especially its metabolite DDE (p,p'-dichlorodiphenyldichloroethene), interacts with nuclear hormone receptors causing these to malfunction, which in turn results in a range of deleterious health effects in humans. The aim of the present...... study was to determine the role of lipoprotein receptors in mouse embryonic fibroblast (MEF) cells in conjunction with uptake of DDT-lipoprotein complexes from supplemented media in vitro. Uptake of DDT by MEF cells was investigated using MEF1 cells carrying the receptors LRP (low-density lipoprotein...... receptor-related protein) and LDLR (low density lipoprotein receptor) present and MEF4 cells with no LRP and LDLR expression. Cells were incubated together with the complex of LDL and [14C]DDT. The receptor function was further evaluated by adding the 40 kDa receptor-associated protein (RAP) which blocks...

  7. Sex steroids and lipoprotein metabolism

    NARCIS (Netherlands)

    Gevers Leuven, J.A.

    1994-01-01

    Lipoprotein metabolism is involved in atherogenesis. Female sex-hormones have substantial effects on both lipoprotein metabolism and the vessel wall. Cholesterol, one of the major lipids in lipoproteins, is both the substrate for, and the target of, the steroidal sex hormones.

  8. Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4

    Directory of Open Access Journals (Sweden)

    Höltershinken Martin

    2007-02-01

    Full Text Available Abstract Background Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds. Results We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families. Conclusion We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly.

  9. Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

    DEFF Research Database (Denmark)

    Jen, Angela; Parkyn, Celia J; Mootoosamy, Roy C

    2010-01-01

    clusters 2 and 4, PrP(C) and PrP(Sc) fibrils bind only to receptor cluster 4. PrP(Sc) fibrils out-compete PrP(C) for internalization. When endocytosed, PrP(Sc) fibrils are routed to lysosomes, rather than recycled to the cell surface with PrP(C). Thus, although LRP1 binds both forms of PrP, it traffics...

  10. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

    DEFF Research Database (Denmark)

    Bown, Matthew J; Jones, Gregory T; Harrison, Seamus C

    2011-01-01

    Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value ... demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might...

  11. Lipoproteins and lipoprotein mimetics for imaging and drug delivery.

    Science.gov (United States)

    Thaxton, C Shad; Rink, Jonathan S; Naha, Pratap C; Cormode, David P

    2016-11-15

    Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites. Lipoproteins can be modified to act as contrast agents in many ways, such as by insertion of gold cores to provide contrast for computed tomography. They can be loaded with drugs, nucleic acids, photosensitizers or boron to act as therapeutics. Attachment of ligands can re-route lipoproteins to new targets. These attributes render lipoproteins attractive and versatile delivery vehicles. In this review we will provide background on lipoproteins, then survey their roles as contrast agents, in drug and nucleic acid delivery, as well as in photodynamic therapy and boron neutron capture therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Lipoprotein marker for hypertriglyceridemia

    Energy Technology Data Exchange (ETDEWEB)

    Cubicciotti, Roger S. (El Cerrito, CA); Karu, Alexander E. (Kensington, CA); Krauss, Ronald M. (Berkeley, CA)

    1986-01-01

    Methods and compositions are provided for the detection of a particular low density lipoprotein which has been found to be a marker for patients suffering from type IV hypertriglyceridemia. A monoclonal antibody capable of specifically binding to a characteristic epitopic site on this LDL subspecies can be utilized in a wide variety of immunoassays. Hybridoma cell line SPL.IVA5A1 was deposited at the American Type Culture Collection on Mar. 29, 1984, and granted accession no. HB 8535.

  13. Expression of interferon inducible protein-10 in pancreas of mice

    Institute of Scientific and Technical Information of China (English)

    Dong Li; Su-Wen Zhu; Dong-Juan Liu; Guo-Liang Liu

    2005-01-01

    AIM: To investigate the expression of interferon inducible protein-10 (IP-10) in pancreas of mice and to discuss its possible role in the pathogenesis of type 1 diabetes.METHODS: Non-obese diabetic (NOD) mice were used as experiment group and BALB/c mice as non-diabetic prone model. Immunohistochemistry method was used to evaluate the expression of IP-10 in the pancreas of NOD mice and BALB/c mice. Immunoelectron microscope was used to show the location of IP-10 in pancreatic islet β cells.RESULTS: Pancreatic islets were positively stained in all the NOD mice. Insulitis could be found in mice at the age of 4 wk. The weakly positive results were found in control group with no insulitis. Immunoelectron microscopy further demonstrated that IP-10 was produced by pancreatic β cells and stored in cytoplasm of the cells.CONCLUSION: IP-10 can be largely produced in pancreatic islets of NOD mice at the age of 2 wk when there is no significant insulitis, and may play an important part in the pathogenesis of type 1 diabetes by attracting immune cells to infiltrate the pancreatic islets.

  14. Interferon-γ-induced protein 10 in Lyme disease.

    Science.gov (United States)

    Fallahi, P; Elia, G; Bonatti, A

    2017-01-01

    Lyme disease is an infectious disease caused by bacteria of the Borrelia type, that affects about 300,000 people a year in the USA and 65,000 people a year in Europe. Borrelia infection, and Lyme disease, following occupational exposure has been frequently reported in USA, Europe and Asia. The manifestations of Lyme disease include erythema migrans (EM), arthritis, neuroborrelliosis (NB), and others. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of Borrelia infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of interferon (IFN)-γ and IFN-γ dependent chemokines. In EM high levels of T helper (Th) 1 cells chemoattranctants [monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP- 10), and IFN-inducible T cell alpha chemoattractant (I-TAC)] have been shown. Synovial tissues and fluids of patients with Lyme Arthritis (LA) (overall with antibiotic-refractory LA) contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly MIG and IFN-γ. In NB concentrations of IP-10 and I-TAC in the cerebrospinal fluid (CSF) were significantly higher, suggesting that IP-10 and I-TAC create a chemokine gradient between the CSF and serum and recruite C-X-C chemokine receptor 3-expressing memory CD4+ T-cells into the CSF of these patients. A positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction has also been shown. These results suggest that IFN-γ dependent chemokines are important biomarkers to monitor the progression and diffusion of the disease in patients with Borrelia infection; further larger studies are needed.

  15. Oxidized lipoprotein lipids and atherosclerosis.

    Science.gov (United States)

    Ahotupa, Markku

    2017-04-01

    Plasma lipoproteins contain variable amounts of lipid oxidation products (LOP), which are known to impair normal physiological functions and stimulate atherosclerotic processes. Recent evidence indicates that plasma lipoproteins are active carriers of LOP, low-density lipoprotein (LDL) directing transport toward peripheral tissues, and high-density lipoprotein (HDL) being active in the reverse transport. It has been proposed that the lipoprotein-specific transport of LOP could play a role in atherosclerosis-related effects of LDL and HDL. This article gives an overview of the present knowledge of lipoprotein LOP transport and its association with the risk of atherosclerosis and cardiovascular diseases (CVD). Evidence of the significance of lipoprotein LOP transport comes mainly from studies of physiological oxidative stress and is supported by studies of the functionality apolipoprotein A-1 mimetic peptides. A large body of data has accumulated indicating that lipoprotein LOP transport is connected to the risk of atherosclerosis. While high levels of LOP carried by LDL are indicative of elevated risk, high LOP level in HDL appears to associate with protection. If confirmed, the proposed lipoprotein LOP transport function would affect conception of the etiology of atherosclerosis, but would not conflict current views of the pathophysiological mechanisms. It could open new perspectives, such as the dietary origin of LOP, and the protective function of HDL in clearance of LOP. Focusing on LOP could give additional tools especially for prevention and diagnosis, but would not radically change the management of atherosclerosis and CVD.

  16. Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease

    DEFF Research Database (Denmark)

    Roeseler, Eberhard; Julius, Ulrich; Heigl, Franz

    2016-01-01

    OBJECTIVE: Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correl...

  17. Lipoprotein metabolism indicators improve cardiovascular risk prediction

    Science.gov (United States)

    Background: Cardiovascular disease risk increases when lipoprotein metabolism is dysfunctional. We have developed a computational model able to derive indicators of lipoprotein production, lipolysis, and uptake processes from a single lipoprotein profile measurement. This is the first study to inves...

  18. Lipoprotein metabolism indicators improve cardiovascular risk prediction

    NARCIS (Netherlands)

    Schalkwijk, D.B. van; Graaf, A.A. de; Tsivtsivadze, E.; Parnell, L.D.; Werff-van der Vat, B.J.C. van der; Ommen, B. van; Greef, J. van der; Ordovás, J.M.

    2014-01-01

    Background: Cardiovascular disease risk increases when lipoprotein metabolism is dysfunctional. We have developed a computational model able to derive indicators of lipoprotein production, lipolysis, and uptake processes from a single lipoprotein profile measurement. This is the first study to inves

  19. Genetics of non-conventional lipoprotein fractions

    Science.gov (United States)

    Lipoprotein subclass measures associate with cardiometabolic disease risk. Currently the information that lipoproteins convey on disease risk over that of traditional demographic and lipid measures is minimal, and so their use is clinics is limited. However, lipoprotein subclass perturbations repres...

  20. Functional Roles of the Interaction of APP and Lipoprotein Receptors

    Science.gov (United States)

    Pohlkamp, Theresa; Wasser, Catherine R.; Herz, Joachim

    2017-01-01

    The biological fates of the key initiator of Alzheimer’s disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density lipoprotein (LDL) receptor-related proteins (LRPs) and their molecular roles in the neurodegenerative disease process are inseparably interwoven. Not only does APP bind tightly to the extracellular domains (ECDs) of several members of the LRP group, their intracellular portions are also connected through scaffolds like the one established by FE65 proteins and through interactions with adaptor proteins such as X11/Mint and Dab1. Moreover, the ECDs of APP and LRPs share common ligands, most notably Reelin, a regulator of neuronal migration during embryonic development and modulator of synaptic transmission in the adult brain, and Agrin, another signaling protein which is essential for the formation and maintenance of the neuromuscular junction (NMJ) and which likely also has critical, though at this time less well defined, roles for the regulation of central synapses. Furthermore, the major independent risk factors for AD, Apolipoprotein (Apo) E and ApoJ/Clusterin, are lipoprotein ligands for LRPs. Receptors and ligands mutually influence their intracellular trafficking and thereby the functions and abilities of neurons and the blood-brain-barrier to turn over and remove the pathological product of APP, the amyloid-β peptide. This article will review and summarize the molecular mechanisms that are shared by APP and LRPs and discuss their relative contributions to AD.

  1. Physiological regulation of lipoprotein lipase

    NARCIS (Netherlands)

    Kersten, A.H.

    2014-01-01

    The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich lipoproteins VLDL and chylomicrons. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities such as the heart, skele

  2. Congenital β-lipoprotein deficiency

    NARCIS (Netherlands)

    Buchem, F.S.P. van; Pol, G.; Gier, J. de; Böttcher, C.J.F.; Pries, C.

    1966-01-01

    There are several degrees of β-lipoprotein deficiency. If there is no β-lipoprotein present, or if there are only traces of it, the Bassen-Kornzweig syndrome develops. A constant feature of this syndrome is disturbed fat absorption with accumulation of fat in the epithelium of intestinal mucosa and

  3. Phytosterols, Phytostanols, and Lipoprotein Metabolism

    Directory of Open Access Journals (Sweden)

    Helena Gylling

    2015-09-01

    Full Text Available The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%–10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein

  4. Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.

    Directory of Open Access Journals (Sweden)

    Martin F Dietrich

    Full Text Available BACKGROUND: The low-density lipoprotein (LDL receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL receptor-related protein 1b (LRP1B was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD is fully viable with no apparent phenotype. METHODS AND PRINCIPAL FINDINGS: Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b-deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteases and gamma-secretase cleavage. We further demonstrate negative regulation of the Wnt signaling pathway by the soluble extracellular domain. CONCLUSIONS AND SIGNIFICANCE: Our results underline a crucial role for Lrp1b in development. The expression in mice of truncated alleles of Lrp1b and Lrp4 with deletions of the transmembrane and intracellular domains leads to release of the extracellular domain into the extracellular space, which is sufficient to confer viability. In contrast, null mutations are embryonically (Lrp1b or perinatally (Lrp4 lethal. These findings suggest that the extracellular domains of both proteins may function as a scavenger for

  5. Synthetic Lipoproteins as Carriers for Drug Delivery.

    Science.gov (United States)

    Huang, Gangliang; Liu, Yang; Huang, Hualiang

    2016-01-01

    Synthetic lipoprotein is an effective carrier of targeted delivery for drugs. It has the very small size, good biocompatibility, suitable half-life, and specific lipoprotein receptorbinding capacity. Compared with the traditional natural lipoprotein, synthetic lipoprotein not only retains the original biological characteristics and functions, but also exhibits the excellent characteristics in drug delivery. Herein, the advantages, development, applications, and prospect of synthetic lipoproteins as drug carriers were summarized.

  6. Classifying lipoproteins based on their polar profiles.

    Science.gov (United States)

    Polanco, Carlos; Castañón-González, Jorge Alberto; Buhse, Thomas; Uversky, Vladimir N; Amkie, Rafael Zonana

    2016-01-01

    The lipoproteins are an important group of cargo proteins known for their unique capability to transport lipids. By applying the Polarity index algorithm, which has a metric that only considers the polar profile of the linear sequences of the lipoprotein group, we obtained an analytical and structural differentiation of all the lipoproteins found in UniProt Database. Also, the functional groups of lipoproteins, and particularly of the set of lipoproteins relevant to atherosclerosis, were analyzed with the same method to reveal their structural preference, and the results of Polarity index analysis were verified by an alternate test, the Cumulative Distribution Function algorithm, applied to the same groups of lipoproteins.

  7. Ion mobility analysis of lipoproteins

    Science.gov (United States)

    Benner, W. Henry; Krauss, Ronald M.; Blanche, Patricia J.

    2007-08-21

    A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

  8. Aerosol preparation of intact lipoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Benner, W. Henry (Danville, CA); Krauss, Ronald M (Berkeley, CA); Blanche, Patricia J (Berkeley, CA)

    2012-01-17

    A medical diagnostic method and instrumentation system for analyzing noncovalently bonded agglomerated biological particles is described. The method and system comprises: a method of preparation for the biological particles; an electrospray generator; an alpha particle radiation source; a differential mobility analyzer; a particle counter; and data acquisition and analysis means. The medical device is useful for the assessment of human diseases, such as cardiac disease risk and hyperlipidemia, by rapid quantitative analysis of lipoprotein fraction densities. Initially, purification procedures are described to reduce an initial blood sample to an analytical input to the instrument. The measured sizes from the analytical sample are correlated with densities, resulting in a spectrum of lipoprotein densities. The lipoprotein density distribution can then be used to characterize cardiac and other lipid-related health risks.

  9. Transendothelial lipoprotein exchange and microalbuminuria

    DEFF Research Database (Denmark)

    Jensen, Jan Skov; Feldt-Rasmussen, Bo; Jensen, Kurt Svarre

    2004-01-01

    OBJECTIVE: Microalbuminuria associates with increased risk of atherosclerosis in individuals without diabetes. We hypothesized that transendothelial lipoprotein exchange is elevated among such individuals, possibly explaining increased intimal lipoprotein accumulation and thus atherosclerosis....... METHODS: Using an in vivo isotope technique, transendothelial exchange of low density lipoprotein (LDL) was measured in 77 non-diabetic individuals. Autologous 131-iodinated LDL was reinjected intravenously, and the 1-h fractional escape rate was calculated as index of transendothelial exchange. RESULTS...... transformed) plasma insulin: beta=0.6 (95% CI: 0.1-1.1); R=0.22; Plipoproteins, LDL size, body mass index, plasma volume, and use of medicine, and it was unlikely caused by altered hepatic LDL receptor expression...

  10. Single-Particle Tracking of Human Lipoproteins.

    Science.gov (United States)

    de Messieres, Michel; Ng, Abby; Duarte, Cornelio J; Remaley, Alan T; Lee, Jennifer C

    2016-01-05

    Lipoproteins, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low density lipoprotein (VLDL), play a critical role in heart disease. Lipoproteins vary in size and shape as well as in their apolipoprotein content. Here, we developed a new experimental framework to study freely diffusing lipoproteins from human blood, allowing analysis of even the smallest HDL with a radius of 5 nm. In an easily constructed confinement chamber, individual HDL, LDL, and VLDL particles labeled with three distinct fluorophores were simultaneously tracked by wide-field fluorescence microscopy and their sizes were determined by their motion. This technique enables studies of individual lipoproteins in solution and allows characterization of the heterogeneous properties of lipoproteins which affect their biological function but are difficult to discern in bulk studies.

  11. Relationship among sera lipoprotein abnormalities in healthy ...

    African Journals Online (AJOL)

    Relationship among sera lipoprotein abnormalities in healthy individuals with background of diabetic sibling. ... As the prevalence of lipoprotein abnormalities in adolescents is increasing dramatically, the identification of ... Article Metrics.

  12. Computational modeling of lipoprotein metabolism

    NARCIS (Netherlands)

    Schalkwijk, Daniël Bernardus van

    2013-01-01

    This PhD thesis contains the following chapters. The first part, containing chapter 2 and 3 mainly concerns model development. Chapter 2 describes the development of a mathematical modeling framework within which different diagnostic models based on lipoprotein profiles can be developed, and a first

  13. Butter, margarine and serum lipoproteins.

    NARCIS (Netherlands)

    Zock, P.L.; Katan, M.B.

    1997-01-01

    Intake of trans fatty acids unfavorably affects blood lipoproteins. As margarines are a major source of trans, claims for the advantages of margarines over butter need to be scrutinized. Here we review dietary trials that directly compared the effects of butter and margarine on blood lipids. We iden

  14. Revisiting the gram-negative lipoprotein paradigm

    Science.gov (United States)

    The processing of lipoproteins (lpps) in Gram-negative bacteria is generally considered to be an essential pathway. Mature lipoproteins in these bacteria are triacylated, with the final fatty acid addition performed by Lnt, an apolipoprotein n-acyltransferase. The mature lipoproteins are then sorted...

  15. Lipoprotein(a) and dietary proteins: casein lowers lipoprotein(a) concentrations as compared with soy protein1-3

    DEFF Research Database (Denmark)

    Nilausen, Karin Johanne; Meinertz, H.

    1999-01-01

    Lipoprotein(a), plasma lipoproteins, dietary proteins, soy protein, casein, liquid-formula, coronary artery disease, men, Denmark......Lipoprotein(a), plasma lipoproteins, dietary proteins, soy protein, casein, liquid-formula, coronary artery disease, men, Denmark...

  16. [Lipoprotein receptors. Old acquaintances and newcomers].

    Science.gov (United States)

    Ducobu, J

    1997-02-01

    Lipoprotein receptors are plasma membrane proteins of high affinity which interact with circulating lipoprotein particles. The well characterized LDL receptor continues to be analysed and some new findings on its intracellular mechanisms of action have emerged. New lipoprotein receptors have recently been described: the chylomicron remnant receptor or LDL-related protein (LRP), the lipolysis stimulated receptor (LSR), the very low density lipoprotein receptor (VLDLR), the HDL receptor (HDLR) and the scavenger receptor (SR). The molecular details of the receptors will facilitate the development of new therapeutic means to improve receptor-mediated clearance of lipoproteins.

  17. Effects of hormones on lipids and lipoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Krauss, R.M.

    1991-12-01

    Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women. In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause- Cross-sectional and longitudinal studies have suggested increases in levels of cholesterol, low density lipoproteins (LDL) and triglyceride-rich lipoproteins associated with menopause. High density lipoproteins (HDL), which are higher in women than men and are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause, although small, and perhaps transient reductions in the HDL{sub 2} subfraction have been reported in relation to reduced estradiol level following menopause. Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. While there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, it is not dear to what extent exogenous hormone-induced lipoprotein changes contribute to the reduced incidence of cardiovascular disease with hormone replacement therapy.

  18. Lipoprotein (a: Structure, Pathophysiology and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Raul Cavalcante Maranhão

    2014-07-01

    Full Text Available The chemical structure of lipoprotein (a is similar to that of LDL, from which it differs due to the presence of apolipoprotein (a bound to apo B100 via one disulfide bridge. Lipoprotein (a is synthesized in the liver and its plasma concentration, which can be determined by use of monoclonal antibody-based methods, ranges from 1,000 mg/dL. Lipoprotein (a levels over 20-30 mg/dL are associated with a two-fold risk of developing coronary artery disease. Usually, black subjects have higher lipoprotein (a levels that, differently from Caucasians and Orientals, are not related to coronary artery disease. However, the risk of black subjects must be considered. Sex and age have little influence on lipoprotein (a levels. Lipoprotein (a homology with plasminogen might lead to interference with the fibrinolytic cascade, accounting for an atherogenic mechanism of that lipoprotein. Nevertheless, direct deposition of lipoprotein (a on arterial wall is also a possible mechanism, lipoprotein (a being more prone to oxidation than LDL. Most prospective studies have confirmed lipoprotein (a as a predisposing factor to atherosclerosis. Statin treatment does not lower lipoprotein (a levels, differently from niacin and ezetimibe, which tend to reduce lipoprotein (a, although confirmation of ezetimibe effects is pending. The reduction in lipoprotein (a concentrations has not been demonstrated to reduce the risk for coronary artery disease. Whenever higher lipoprotein (a concentrations are found, and in the absence of more effective and well-tolerated drugs, a more strict and vigorous control of the other coronary artery disease risk factors should be sought.

  19. Lipoprotein apheresis: present and future uses.

    Science.gov (United States)

    Moriarty, Patrick M

    2015-12-01

    For the past 40 years, apheresis, in particular, lipoprotein apheresis, has been the therapy of choice to lower LDL-C for familial hypercholesterolemia patients with uncontrolled dyslipidemia and cardiovascular disease. With the advent of recent and future lipid-modifying agents and their ability to lower LDL-C, the question arises on what will be the future of lipoprotein apheresis. Lipoprotein apheresis lowers not only plasma levels of apolipoprotein B lipoproteins but also markers of vascular inflammation and blood rheology. Other vascular diseases, not necessarily associated with familial hypercholesterolemia, such as nephrotic syndrome and peripheral arterial disease have profited from lipoprotein apheresis therapy. In 2013, the Food and Drug Administration approved lipoprotein apheresis therapy for patients with focal segmental glomerulosclerosis. Since 2010, the German healthcare ministry has approved lipoprotein apheresis therapy for patients with an elevated lipoprotein(a) and ongoing cardiovascular disease irrespective of LDL-C levels. Recent and future lipid-modifying therapies will most likely reduce the practice of lipoprotein apheresis therapy for familial hypercholesterolemia patients. Future implications for lipoprotein apheresis will involve vascular diseases that are at present lacking clinically effective therapy, whereas acute and chronic reductions of lipids, vascular inflammation, and/or rheology may improve the clinical outcome.

  20. Recent advances in physiological lipoprotein metabolism.

    Science.gov (United States)

    Ramasamy, Indra

    2014-12-01

    Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and post-transcriptional level. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDL-cholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several

  1. Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice

    DEFF Research Database (Denmark)

    Gordts, Philip L S M; Bartelt, Alexander; Nilsson, Stefan K;

    2012-01-01

    Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.......Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE....

  2. Impact of gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) on glucose and lipid homeostasis

    DEFF Research Database (Denmark)

    Foer, D; Zhu, M; Cardone, R L

    2017-01-01

    potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia. Studies in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis; however, whether it plays a similar role in humans is unclear. As current literature links loss-of-function LRP5...... kindreds with HBM-causing LRP5 mutations and included 9 males and 2 females. Two subjects that were being treated with insulin for type 2 diabetes were excluded from our analysis, as this would have obscured our ability to determine the impact of gain-of-function LRP5 mutations on glucose metabolism...

  3. Diagnostic markers based on a computational model of lipoprotein metabolism

    NARCIS (Netherlands)

    Schalkwijk, D.B. van; Ommen, B. van; Freidig, A.P.; Greef, J. van der; Graaf, A.A. de

    2011-01-01

    Abstract Background: Dyslipidemia is an important risk factor for cardiovascular disease and type II diabetes. Lipoprotein diagnostics, such as LDL cholesterol and HDL cholesterol, help to diagnose these diseases. Lipoprotein profile measurements could improve lipoprotein diagnostics, but interpreta

  4. Lipoprotein lipase gene variants: Association with acute myocardial ...

    African Journals Online (AJOL)

    Lipoprotein lipase gene variants: Association with acute myocardial infarction and lipid profiles. ... Therefore, genes involved in lipid and lipoprotein metabolism pathways such as lipoprotein lipase (LPL), are proper candidates ... Article Metrics.

  5. Variations in plasma lipids and lipoproteins among cardiovascular ...

    African Journals Online (AJOL)

    Variations in plasma lipids and lipoproteins among cardiovascular disease patients in ... This study was designed to assess the changes in plasma lipids and lipoproteins, in particular highdensity lipoprotein (HDLC) in patients ... Article Metrics.

  6. Lrp13 is a novel vertebrate lipoprotein receptor that binds vitellogenins in teleost fishes.

    Science.gov (United States)

    Reading, Benjamin J; Hiramatsu, Naoshi; Schilling, Justin; Molloy, Katelyn T; Glassbrook, Norm; Mizuta, Hiroko; Luo, Wenshu; Baltzegar, David A; Williams, Valerie N; Todo, Takashi; Hara, Akihiko; Sullivan, Craig V

    2014-11-01

    Transcripts encoding a novel member of the lipoprotein receptor superfamily, termed LDL receptor-related protein (Lrp)13, were sequenced from striped bass (Morone saxatilis) and white perch (Morone americana) ovaries. Receptor proteins were purified from perch ovary membranes by protein-affinity chromatography employing an immobilized mixture of vitellogenins Aa and Ab. RT-PCR revealed lrp13 to be predominantly expressed in striped bass ovary, and in situ hybridization detected lrp13 transcripts in the ooplasm of early secondary growth oocytes. Quantitative RT-PCR confirmed peak lrp13 expression in the ovary during early secondary growth. Quantitative mass spectrometry revealed peak Lrp13 protein levels in striped bass ovary during late-vitellogenesis, and immunohistochemistry localized Lrp13 to the oolemma and zona radiata of vitellogenic oocytes. Previously unreported orthologs of lrp13 were identified in genome sequences of fishes, chicken (Gallus gallus), mouse (Mus musculus), and dog (Canis lupus familiaris). Zebrafish (Danio rerio) and Nile tilapia (Oreochromis niloticus) lrp13 loci are discrete and share genomic synteny. The Lrp13 appears to function as a vitellogenin receptor and may be an important mediator of yolk formation in fishes and other oviparous vertebrates. The presence of lrp13 orthologs in mammals suggests that this lipoprotein receptor is widely distributed among vertebrates, where it may generally play a role in lipoprotein metabolism.

  7. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family

    DEFF Research Database (Denmark)

    Nilsson, Stefan K; Lookene, Aivar; Beckstead, Jennifer A;

    2007-01-01

    Apolipoprotein A-V is a potent modulator of plasma triacylglycerol levels. To investigate the molecular basis for this phenomenon we explored the ability of apolipoprotein A-V, in most experiments complexed to disks of dimyristoylphosphatidylcholine, to interact with two members of the low densit...... to receptor-covered sensor chips. Our results indicate that apolipoprotein A-V may influence plasma lipid homeostasis by enhancing receptor-mediated endocytosis of triacylglycerol-rich lipoproteins. Udgivelsesdato: 2007-Mar-27......Apolipoprotein A-V is a potent modulator of plasma triacylglycerol levels. To investigate the molecular basis for this phenomenon we explored the ability of apolipoprotein A-V, in most experiments complexed to disks of dimyristoylphosphatidylcholine, to interact with two members of the low density...... lipoprotein receptor family, the low density lipoprotein receptor-related protein and the mosaic type-1 receptor, SorLA. Experiments using surface plasmon resonance showed specific binding of both free and lipid-bound apolipoprotein A-V to both receptors. The binding was calcium dependent and was inhibited...

  8. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    NARCIS (Netherlands)

    Kersten, A.H.

    2008-01-01

    Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that

  9. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    NARCIS (Netherlands)

    Kersten, A.H.

    2008-01-01

    Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that

  10. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    Directory of Open Access Journals (Sweden)

    Sander Kersten

    2008-01-01

    Full Text Available Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs. Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARα is the molecular target for the fibrate class of drugs. Activation of PPARα in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL-cholesterol levels are increased upon PPARα activation in humans. PPARγ is the molecular target for the thiazolidinedione class of drugs. Activation of PPARγ in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.

  11. Computational studies of plasma lipoprotein lipids.

    Science.gov (United States)

    Pan, Lurong; Segrest, Jere P

    2016-10-01

    Plasma lipoproteins are macromolecular assemblies of proteins and lipids found in the blood. The lipid components of lipoproteins are amphipathic lipids such as phospholipids (PLs), and unesterified cholesterols (UCs) and hydrophobic lipids such as cholesteryl esters (CEs) and triglycerides (TGs). Since lipoproteins are soft matter supramolecular assemblies easily deformable by thermal fluctuations and they also exist in varying densities and protein/lipid components, a detailed understanding of their structure/function is experimentally difficult. Molecular dynamics (MD) simulation has emerged as a particularly promising way to explore the structure and dynamics of lipoproteins. The purpose of this review is to survey the current status of computational studies of the lipid components of the lipoproteins. Computational studies aim to explore three levels of complexity for the 3-dimensional structural dynamics of lipoproteins at various metabolic stages: (i) lipoprotein particles consist of protein with minimal lipid; (ii) lipoprotein particles consist of PL-rich discoidal bilayer-like lipid particles; (iii) mature circulating lipoprotein particles consist of CE-rich or TG-rich spheroidal lipid-droplet-like particles. Due to energy barriers involved in conversion between these species, other biomolecules also participate in lipoprotein biological assembly. For example: (i) lipid-poor apolipoprotein A-I (apoA-I) interacts with ATP-binding cassette transporter A1 (ABCA1) to produce nascent discoidal high density lipoprotein (dHDL) particles; (ii) lecithin-cholesterol acyltransferase (LCAT) mediates the conversion of UC to CE in dHDL, driving spheroidal HDL (sHDL) formation; (iii) transfer proteins, cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP), transfer both CE and TG and PL, respectively, between lipoprotein particles. Computational studies have the potential to explore different lipoprotein particles at each metabolic stage in

  12. The iron-regulated staphylococcal lipoproteins

    Directory of Open Access Journals (Sweden)

    Jessica eSheldon

    2012-04-01

    Full Text Available Lipoproteins fulfill diverse roles in antibiotic resistance, adhesion, protein secretion, signaling and sensing, and many also serve as the substrate binding protein (SBP partner to ABC transporters for the acquisition of a diverse array of nutrients including peptides, sugars, and scarcely abundant metals. In the staphylococci, the iron-regulated SBPs are significantly upregulated during iron starvation and function to sequester and deliver iron into the bacterial cell, enabling staphylococci to circumvent iron restriction imposed by the host environment. Accordingly, this subset of lipoproteins has been implicated in staphylococcal pathogenesis and virulence. Lipoproteins also activate the host innate immune response, triggered through Toll-like receptor-2 (TLR2 and, notably, the iron-regulated subset of lipoproteins are particularly immunogenic. In this review, we discuss the iron-regulated staphylococcal lipoproteins with regard to their biogenesis, substrate specificity, and impact on the host innate immune response.

  13. The pathophysiology of intestinal lipoprotein production

    Directory of Open Access Journals (Sweden)

    Antonina eGiammanco

    2015-03-01

    Full Text Available Intestinal lipoprotein production is a multistep process, essential for the absorption of dietary fats and fat-soluble vitamins. Chylomicron assembly begins in the endoplasmic reticulum with the formation of primordial, phospholipids-rich particles that are then transported to the Golgi for secretion. Several classes of transporters play a role in the selective uptake and/or export of lipids through the villus enterocytes. Once secreted in the lymph stream, triglyceride-rich lipoproteins (TRLs are metabolized by Lipoprotein lipase (LPL, which catalyzes the hydrolysis of triacylglycerols of very low density lipoproteins (VLDLs and chylomicrons, thereby delivering free fatty acids to various tissues. Genetic mutations in the genes codifying for these proteins are responsible of different inherited disorders affecting chylomicron metabolism.This review focuses on the molecular pathways that modulate the uptake and the transport of lipoproteins of intestinal origin and it will highlight recent findings on TRLs assembly.

  14. A Computational Model for the Analysis of Lipoprotein Distributions in the Mouse : Translating FPLC Profiles to Lipoprotein Metabolism

    NARCIS (Netherlands)

    Sips, Fianne L. P.; Tiemann, Christian A.; Oosterveer, Maaike H.; Groen, Albert K.; Hilbers, Peter A. J.; van Riel, Natal A. W.

    Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions,

  15. A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome.

    Science.gov (United States)

    Jones, Jennifer L; Comperatore, Michael; Barona, Jacqueline; Calle, Mariana C; Andersen, Catherine; McIntosh, Mark; Najm, Wadie; Lerman, Robert H; Fernandez, Maria Luz

    2012-03-01

    The objective was to assess the impact of a Mediterranean-style, low-glycemic-load diet (control group, n = 41) and the same diet plus a medical food (MF) containing phytosterols, soy protein, and extracts from hops and Acacia (MF group, n = 42) on lipoprotein atherogenicity in women with metabolic syndrome. Plasma lipids, apolipoproteins (apos), lipoprotein subfractions and particle size, low-density lipoprotein (LDL) oxidation, and lipoprotein (a) were measured at baseline, week 8, and week 12 of the intervention. Three-day dietary records were collected at the same time points to assess compliance. Compared with baseline, women decreased energy intake from carbohydrate (P lipoproteins, large very low-density lipoprotein (P lipoprotein to smaller high-density lipoprotein particles was increased (P lipoprotein (a) (P lipoproteins, oxidized LDL, and apo B. Inclusion of an MF may have an additional effect in reducing apo B. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

    Directory of Open Access Journals (Sweden)

    Miloslava Hodúlová

    Full Text Available The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain and two progenitor strains SHR-Lx (n = 13 and BXH2/Cub (n = 18 were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG and cholesterol (C concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl. We have identified 14 loci (encompassing 1 to 65 genes on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b. Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant

  17. The majority of lipoprotein lipase in plasma is bound to remnant lipoproteins: A new definition of remnant lipoproteins.

    Science.gov (United States)

    Sato, Koichi; Okajima, Fumikazu; Miyashita, Kazuya; Imamura, Shigeyuki; Kobayashi, Junji; Stanhope, Kimber L; Havel, Peter J; Machida, Tetsuo; Sumino, Hiroyuki; Murakami, Masami; Schaefer, Ernst; Nakajima, Katsuyuki

    2016-10-01

    Lipoprotein lipase (LPL) is a multifunctional protein and a key enzyme involved in the regulation of lipoprotein metabolism. We determined the lipoproteins to which LPL is bound in the pre-heparin and post-heparin plasma. Tetrahydrolipstatin (THL), a potent inhibitor of serine lipases, was used to block the lipolytic activity of LPL, thereby preventing changes in the plasma lipoproteins due to ex vivo lipolysis. Gel filtration was performed to obtain the LPL elution profiles in plasma and the isolated remnant lipoproteins (RLP). When ex vivo lipolytic activity was inhibited by THL in the post-heparin plasma, majority of the LPL was found in the VLDL elution range, specifically in the RLP as inactive dimers. However, in the absence of THL, most of the LPL was found in the HDL elution range as active dimers. Furthermore, majority of the LPL in the pre-heparin plasma was found in the RLP as inactive form, with broadly diffused lipoprotein profiles in the presence and absence of THL. It is suggested that during lipolysis in vivo, the endothelial bound LPL dimers generates RLP, forming circulating RLP-LPL complexes in an inactive form that subsequently binds and initiates receptor-mediated catabolism. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Understanding Lipoproteins as Transporters of Cholesterol and Other Lipids

    Science.gov (United States)

    Biggerstaff, Kyle D.; Wooten, Joshua S.

    2004-01-01

    A clear picture of lipoprotein metabolism is essential for understanding the pathophysiology of atherosclerosis. Many students are taught that low-density lipoprotein-cholesterol is "bad" and high-density lipoprotein-cholesterol is "good." This misconception leads to students thinking that lipoproteins are types of cholesterol rather than…

  19. Low-density lipoprotein analysis in microchip capillary electrophoresis systems

    NARCIS (Netherlands)

    Ceriotti, Laura; Shibata, Takayuki; Folmer, Britta; Weiller, Bruce H.; Roberts, Matthew A.; De Rooij, Nico F.; Verpoorte, Elisabeth

    2002-01-01

    Due to the mounting evidence for altered lipoprotein and cholesterol-lipoprotein content in several disease states, there has been an increasing interest in analytical methods for lipoprotein profiling for diagnosis. The separation of low- and high-density lipoproteins (LDL and HDL, respectively)

  20. Association of lipase lipoprotein polymorphisms with high-density lipoprotein and triglycerides in elderly men

    OpenAIRE

    Araujo,Lara Miguel Quirino; Cendoroglo, Maysa Seabra [UNIFESP; Gigek, Carolina de Oliveira; Chen, Elizabeth Suchi; Smith, Maria de Arruda Cardoso [UNIFESP

    2010-01-01

    Lipoprotein lipase is essential for triglyceride hydrolysis. the polymorphisms S447X in exon 9 and HindIII in intron 8 have been associated with lower triglyceride levels and lower cardiovascular risk in adult men. We examined the association of these lipoprotein lipase polymorphisms with high-density lipoprotein (HDL) and triglyceride levels in elderly men. Blood samples were obtained from 87 elderly men, 48 of whom had cardiovascular disease and 39 (controls) had no history of cardiovascula...

  1. Computational models for analyzing lipoprotein profiles

    NARCIS (Netherlands)

    Graaf, A.A. de; Schalkwijk, D.B. van

    2011-01-01

    At present, several measurement technologies are available for generating highly detailed concentration-size profiles of lipoproteins, offering increased diagnostic potential. Computational models are useful in aiding the interpretation of these complex datasets and making the data more accessible f

  2. Genetics Home Reference: familial lipoprotein lipase deficiency

    Science.gov (United States)

    ... Rare Disorders (NORD) RareConnect GeneReviews (1 link) Familial Lipoprotein Lipase Deficiency ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (1 link) ...

  3. The Human Pathogen Streptococcus pyogenes Releases Lipoproteins as Lipoprotein-rich Membrane Vesicles.

    Science.gov (United States)

    Biagini, Massimiliano; Garibaldi, Manuela; Aprea, Susanna; Pezzicoli, Alfredo; Doro, Francesco; Becherelli, Marco; Taddei, Anna Rita; Tani, Chiara; Tavarini, Simona; Mora, Marirosa; Teti, Giuseppe; D'Oro, Ugo; Nuti, Sandra; Soriani, Marco; Margarit, Immaculada; Rappuoli, Rino; Grandi, Guido; Norais, Nathalie

    2015-08-01

    Bacterial lipoproteins are attractive vaccine candidates because they represent a major class of cell surface-exposed proteins in many bacteria and are considered as potential pathogen-associated molecular patterns sensed by Toll-like receptors with built-in adjuvanticity. Although Gram-negative lipoproteins have been extensively characterized, little is known about Gram-positive lipoproteins. We isolated from Streptococcus pyogenes a large amount of lipoproteins organized in vesicles. These vesicles were obtained by weakening the bacterial cell wall with a sublethal concentration of penicillin. Lipid and proteomic analysis of the vesicles revealed that they were enriched in phosphatidylglycerol and almost exclusively composed of lipoproteins. In association with lipoproteins, a few hypothetical proteins, penicillin-binding proteins, and several members of the ExPortal, a membrane microdomain responsible for the maturation of secreted proteins, were identified. The typical lipidic moiety was apparently not necessary for lipoprotein insertion in the vesicle bilayer because they were also recovered from the isogenic diacylglyceryl transferase deletion mutant. The vesicles were not able to activate specific Toll-like receptor 2, indicating that lipoproteins organized in these vesicular structures do not act as pathogen-associated molecular patterns. In light of these findings, we propose to name these new structures Lipoprotein-rich Membrane Vesicles. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Contribution of lipoproteins and lipoprotein processing to endocarditis virulence in Streptococcus sanguinis.

    Science.gov (United States)

    Das, Sankar; Kanamoto, Taisei; Ge, Xiuchun; Xu, Ping; Unoki, Takeshi; Munro, Cindy L; Kitten, Todd

    2009-07-01

    Streptococcus sanguinis is an important cause of infective endocarditis. Previous studies have identified lipoproteins as virulence determinants in other streptococcal species. Using a bioinformatic approach, we identified 52 putative lipoprotein genes in S. sanguinis strain SK36 as well as genes encoding the lipoprotein-processing enzymes prolipoprotein diacylglyceryl transferase (lgt) and signal peptidase II (lspA). We employed a directed signature-tagged mutagenesis approach to systematically disrupt these genes and screen each mutant for the loss of virulence in an animal model of endocarditis. All mutants were viable. In competitive index assays, mutation of a putative phosphate transporter reduced in vivo competitiveness by 14-fold but also reduced in vitro viability by more than 20-fold. Mutations in lgt, lspA, or an uncharacterized lipoprotein gene reduced competitiveness by two- to threefold in the animal model and in broth culture. Mutation of ssaB, encoding a putative metal transporter, produced a similar effect in culture but reduced in vivo competiveness by >1,000-fold. [(3)H]palmitate labeling and Western blot analysis confirmed that the lgt mutant failed to acylate lipoproteins, that the lspA mutant had a general defect in lipoprotein cleavage, and that SsaB was processed differently in both mutants. These results indicate that the loss of a single lipoprotein, SsaB, dramatically reduces endocarditis virulence, whereas the loss of most other lipoproteins or of normal lipoprotein processing has no more than a minor effect on virulence.

  5. Contribution of Lipoproteins and Lipoprotein Processing to Endocarditis Virulence in Streptococcus sanguinis▿ §

    Science.gov (United States)

    Das, Sankar; Kanamoto, Taisei; Ge, Xiuchun; Xu, Ping; Unoki, Takeshi; Munro, Cindy L.; Kitten, Todd

    2009-01-01

    Streptococcus sanguinis is an important cause of infective endocarditis. Previous studies have identified lipoproteins as virulence determinants in other streptococcal species. Using a bioinformatic approach, we identified 52 putative lipoprotein genes in S. sanguinis strain SK36 as well as genes encoding the lipoprotein-processing enzymes prolipoprotein diacylglyceryl transferase (lgt) and signal peptidase II (lspA). We employed a directed signature-tagged mutagenesis approach to systematically disrupt these genes and screen each mutant for the loss of virulence in an animal model of endocarditis. All mutants were viable. In competitive index assays, mutation of a putative phosphate transporter reduced in vivo competitiveness by 14-fold but also reduced in vitro viability by more than 20-fold. Mutations in lgt, lspA, or an uncharacterized lipoprotein gene reduced competitiveness by two- to threefold in the animal model and in broth culture. Mutation of ssaB, encoding a putative metal transporter, produced a similar effect in culture but reduced in vivo competiveness by >1,000-fold. [3H]palmitate labeling and Western blot analysis confirmed that the lgt mutant failed to acylate lipoproteins, that the lspA mutant had a general defect in lipoprotein cleavage, and that SsaB was processed differently in both mutants. These results indicate that the loss of a single lipoprotein, SsaB, dramatically reduces endocarditis virulence, whereas the loss of most other lipoproteins or of normal lipoprotein processing has no more than a minor effect on virulence. PMID:19395487

  6. Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling.

    Science.gov (United States)

    Brankatschk, Marko; Dunst, Sebastian; Nemetschke, Linda; Eaton, Suzanne

    2014-10-02

    The Insulin signaling pathway couples growth, development and lifespan to nutritional conditions. Here, we demonstrate a function for the Drosophila lipoprotein LTP in conveying information about dietary lipid composition to the brain to regulate Insulin signaling. When yeast lipids are present in the diet, free calcium levels rise in Blood Brain Barrier glial cells. This induces transport of LTP across the Blood Brain Barrier by two LDL receptor-related proteins: LRP1 and Megalin. LTP accumulates on specific neurons that connect to cells that produce Insulin-like peptides, and induces their release into the circulation. This increases systemic Insulin signaling and the rate of larval development on yeast-containing food compared with a plant-based food of similar nutritional content.

  7. Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease

    DEFF Research Database (Denmark)

    Wittrup, Hans H; Andersen, Rolf V; Tybjaerg-Hansen, Anne;

    2006-01-01

    Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD).......Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD)....

  8. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-01-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...... of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease....

  9. Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease

    DEFF Research Database (Denmark)

    Wittrup, Hans H; Andersen, Rolf V; Tybjaerg-Hansen, Anne

    2006-01-01

    Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD).......Genetic variants in lipoprotein lipase may affect triglycerides, high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD)....

  10. Chronic hepatitis C virus infection and lipoprotein metabolism.

    Science.gov (United States)

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

    2015-09-28

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

  11. Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells.

    Directory of Open Access Journals (Sweden)

    Roman Covarrubias

    Full Text Available Expression of molecules involved in lipid homeostasis such as the low density lipoprotein receptor (LDLr on antigen presenting cells (APCs has been shown to enhance invariant natural killer T (iNKT cell function. However, the contribution to iNKT cell activation by other lipoprotein receptors with shared structural and ligand binding properties to the LDLr has not been described. In this study, we investigated whether a structurally related receptor to the LDLr, known as LDL receptor-related protein (LRP, plays a role in iNKT cell activation. We found that, unlike the LDLr which is highly expressed on all immune cells, the LRP was preferentially expressed at high levels on F4/80+ macrophages (MΦ. We also show that CD169+ MΦs, known to present antigen to iNKT cells, exhibited increased expression of LRP compared to CD169- MΦs. To test the contribution of MΦ LRP to iNKT cell activation we used a mouse model of MΦ LRP conditional knockout (LRP-cKO. LRP-cKO MΦs pulsed with glycolipid alpha-galactosylceramide (αGC elicited normal IL-2 secretion by iNKT hybridoma and in vivo challenge of LRP-cKO mice led to normal IFN-γ, but blunted IL-4 response in both serum and intracellular expression by iNKT cells. Flow cytometric analyses show similar levels of MHC class-I like molecule CD1d on LRP-cKO MΦs and normal glycolipid uptake. Survey of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages and no homeostatic disruption as evidenced by the absence of programmed death-1 and Ly-49 surface receptors. Mixed bone marrow chimeras showed that the inability iNKT cells to make IL-4 is cell extrinsic and can be rescued in the presence of wild type APCs. Collectively, these data demonstrate that, although MΦ LRP may not be necessary for IFN-γ responses, it can contribute to iNKT cell activation by enhancing early IL-4 secretion.

  12. [Serum lipoprotein profile in newly recognized arterial hypertension. The role of atherogenic lipoproteins in the pathogenesis of disease].

    Science.gov (United States)

    Oravec, S; Dukát, A; Gavorník, P; Caprdna, M; Kucera, M

    2010-09-01

    New examination approaches in biochemical analysis of lipoproteins can identify and quantify atherogenic plasma lipoproteins, including small dense LDL and characterise a lipoprotein spectrum as a non-atherogenic lipoprotein profile phenotype A, respectively as an atherogenic lipoprotein profile phenotype B. Identification of a non-aterogenic hypercholesterolemia (48%), atherogenic hypertriglyceridemia (93%), atherogenic normolipemia (13%) in patients with arterial hypertension and an atherogenic normolipemia in control group of healthy subjects (7%), is an essential contribution of this new laboratory diagnostics.

  13. Lipoprotein profile, lipoprotein-associated phospholipase A2 and cardiovascular risk in hemodialysis patients.

    Science.gov (United States)

    Rolla, Roberta; De Mauri, Andreana; Valsesia, Ambra; Vidali, Matteo; Chiarinotti, Doriana; Bellomo, Giorgio

    2015-12-01

    Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients; the increased risk of cardiovascular disease is due to accelerated atherosclerosis, inflammation and impaired lipoprotein metabolism. We aimed to evaluate lipoprotein-associated phospholipase A2 (Lp-PLA2) and some pro-inflammatory aspects of the lipoprotein profile in dialyzed patients in order to evaluate the relationship with the accelerated atherosclerosis and vascular accidents. In 102 dialysis patients and 40 non-uremic controls, we investigated the lipoprotein plasma profile, high sensitivity C-reactive protein (CRP), ceruloplasmin and serum amyloid A protein (SAA), and followed patients for 1 year to analyze the risk of acute cardiovascular events. Total cholesterol, low-density lipoprotein and high-density lipoprotein plasma levels were significantly lower in uremic patients than controls, whereas CRP, SAA, ceruloplasmin, Lp-PLA2 and their ratio with apolipoprotein A1 were significantly higher. Patients with Lp-PLA2 levels >194 nmol/min/ml had more acute cardiovascular events than patients with lower values. Our results show that in dialysis subjects: (1) low-density lipoproteins show a more atherogenic phenotype than in the general population; (2) high-density lipoproteins are less anti-inflammatory; (3) Lp-PLA2 could potentially be used to evaluate cardiovascular risk.

  14. Revisiting the Gram-Negative Lipoprotein Paradigm

    Science.gov (United States)

    LoVullo, Eric D.; Wright, Lori F.; Isabella, Vincent; Huntley, Jason F.

    2015-01-01

    ABSTRACT The processing of lipoproteins (Lpps) in Gram-negative bacteria is generally considered an essential pathway. Mature lipoproteins in these bacteria are triacylated, with the final fatty acid addition performed by Lnt, an apolipoprotein N-acyltransferase. The mature lipoproteins are then sorted by the Lol system, with most Lpps inserted into the outer membrane (OM). We demonstrate here that the lnt gene is not essential to the Gram-negative pathogen Francisella tularensis subsp. tularensis strain Schu or to the live vaccine strain LVS. An LVS Δlnt mutant has a small-colony phenotype on sucrose medium and increased susceptibility to globomycin and rifampin. We provide data indicating that the OM lipoprotein Tul4A (LpnA) is diacylated but that it, and its paralog Tul4B (LpnB), still sort to the OM in the Δlnt mutant. We present a model in which the Lol sorting pathway of Francisella has a modified ABC transporter system that is capable of recognizing and sorting both triacylated and diacylated lipoproteins, and we show that this modified system is present in many other Gram-negative bacteria. We examined this model using Neisseria gonorrhoeae, which has the same Lol architecture as that of Francisella, and found that the lnt gene is not essential in this organism. This work suggests that Gram-negative bacteria fall into two groups, one in which full lipoprotein processing is essential and one in which the final acylation step is not essential, potentially due to the ability of the Lol sorting pathway in these bacteria to sort immature apolipoproteins to the OM. IMPORTANCE This paper describes the novel finding that the final stage in lipoprotein processing (normally considered an essential process) is not required by Francisella tularensis or Neisseria gonorrhoeae. The paper provides a potential reason for this and shows that it may be widespread in other Gram-negative bacteria. PMID:25755189

  15. Current situation of lipoprotein apheresis in Saxony.

    Science.gov (United States)

    Julius, U; Taseva, K; Fischer, S; Passauer, J; Bornstein, S R

    2013-01-01

    This paper summarizes the situation pertinent to treatment via lipoprotein apheresis in the federal state of Saxony, Germany in 2010. In total, 119 predominately male patients were treated in 10 centers; the majority of the patients was older than the mean age of the general population. Several risk factors were present, particularly a familial predisposition and hypertension. All patients had experienced cardiovascular events and the majority was taking statins. Patient data from the University Hospital Carl Gustav Carus in Dresden concurred with data derived from patients treated at nephrological practices. In the mean, patients attended the centers for about 6 years, the majority weekly. LDL cholesterol concentrations prior to apheresis were clearly higher than target levels; apheresis sessions decreased LDL cholesterol by 69%. Lipoprotein(a) levels could be measured in 75 patients and were effectively reduced by lipoprotein apheresis. In Saxony, 29 patients per 1 million inhabitants received lipoprotein apheresis, which is higher than the proportion of patients treated in Germany as a whole. The need for this extracorporeal treatment seems to be much greater than its current utilization. Among the patients only one homozygous patient with familial hypercholesterolemia was observed. Physicians should be actively informed about this therapeutic possibility to reduce the cardiovascular risk efficiently. The introduction of new drugs may alter the position of lipoprotein apheresis within the therapeutic spectrum.

  16. Increased transvascular lipoprotein transport in diabetes

    DEFF Research Database (Denmark)

    Jensen, Jan Skov; Feldt-Rasmussen, Bo; Borch-Johnsen, Knut

    2005-01-01

    CONTEXT: Diabetes is associated with a highly increased risk of atherosclerosis, especially if hypertension or albuminuria is present. OBJECTIVE: We hypothesized that the increased transvascular lipoprotein transport in diabetes may be further accelerated if hypertension or albuminuria is present......, possibly explaining increased intimal lipoprotein accumulation and thus atherosclerosis. DESIGN: The study was cross-sectional and was performed in 1999-2002. SETTING: The study took place in the referral center. PATIENTS: The patients included 60 with diabetes mellitus (27 with type 1 diabetes and 33...... with type 2 diabetes) and 42 healthy controls. All were randomly recruited. MAIN OUTCOME MEASURE: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL). Autologous 131I-LDL was reinjected iv, and the 1-h fractional escape rate was taken as an index...

  17. Immune response to lipoproteins in atherosclerosis.

    Science.gov (United States)

    Samson, Sonia; Mundkur, Lakshmi; Kakkar, Vijay V

    2012-01-01

    Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.

  18. Protein Interactions between Fe65, the LDL receptor-related protein and the amyloid precursor protein

    Science.gov (United States)

    Mulvihill, Melinda; Guttman, Miklos; Komives, Elizabeth A.

    2011-01-01

    The adapter protein, Fe65 has been proposed to be the link between the intracellular domains of the amyloid precursor protein, APP (AICD) and the LDL receptor-related protein (LRP-CT). Functional linkage between these two proteins has been established and mutations within LRP-CT affect the amount of Aβ produced from APP. Previous work showed that the AICD binds to the protein interaction domain 2 (PID2) of Fe65. Although the structure of PID1 was solved recently all attempts to demonstrate LRP-CT binding to this domain failed. We used biophysical experiments and binding studies to investigate the binding between these three proteins. Full-length Fe65 bound more weakly to AICD than did N-terminally truncated forms, however the intramolecular domain-domain interactions that had been proposed to inhibit binding could not be observed using amide H/D exchange. Surprisingly, when the LRP-CT is phosphorylated at Tyr4507, it bound to Fe65-PID1 despite the fact that this domain belongs to the Dab-like subclass of PIDs that is not supposed to be phosphorylation dependent. Mutation of a critical arginine abolished binding providing further proof of the phosphorylation-dependence. The Fe65-PID1 domain thus provides a link between the Dab-like class and the IRS-like class of PID domains and is the first Dab-like family member to show phosphorylation-dependent binding. PMID:21650223

  19. Identification of estrogen receptor-related receptor gamma as a direct transcriptional target of angiogenin.

    Directory of Open Access Journals (Sweden)

    Jian Ang

    Full Text Available Nuclear translocation of angiogenin (ANG is essential for the proliferation of its target cells. ANG promotes rRNA synthesis, while whether it regulates mRNA transcription remains unknown. Using the chromatin immunoprecipitation method, we have identified 12 ANG-binding sequences. One of these sequences lies in the estrogen receptor-related receptor gamma (ERRγ gene which we designated as ANG-Binding Sequence within ERRγ (ABSE. ABSE exhibited ANG-dependent repressor activity in the luciferase reporter system. Down-regulation of ANG increased ERRγ expression, and active gene marker level at the ABSE region. The expression levels of ERRγ targets genes, p21(WAF/CIP and p27(KIP1, and the occupation of ERRγ on their promoter regions were increased in ANG-deficient cells accordingly. Furthermore, knockdown of ERRγ promoted the proliferation rate in ANG-deficient breast cancer cells. Finally, immunohistochemistry staining showed negative correlation between ANG and ERRγ in breast cancer tissue. Altogether, our study provides evidence that nuclear ANG directly binds to the ABSE of ERRγ gene and inhibits ERRγ transcription to promote breast cancer cell proliferation.

  20. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-01-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance of such gene......To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...

  1. Lipoprotein apheresis for the treatment of elevated circulating levels of lipoprotein(a): a critical literature review

    Science.gov (United States)

    Franchini, Massimo; Capuzzo, Enrico; Liumbruno, Giancarlo M.

    2016-01-01

    Lipoprotein(a), which consists of a low-density lipoprotein (LDL) particle linked to an apolipoprotein(a) moiety, is currently considered an independent risk factor for cardiovascular disease due to its atherogenic (LDL-like) and prothrombotic (plasminogen-like) properties. The aim of this review is to provide an overview of the current and newer therapies for lowering increased lipoprotein(a) levels, focusing on lipoprotein apheresis. After a systematic literature search, we identified ten studies which, overall, documented that lipoprotein apheresis is effective in reducing increased lipoprotein(a) levels and cardiovascular events. PMID:26710351

  2. Analysis of individual lipoproteins and liposomes

    Energy Technology Data Exchange (ETDEWEB)

    Robbins, D.L.; Keller, R.A.; Nolan, J.P. [and others

    1997-08-01

    We describe the application of single molecule detection (SMD) technologies for the analysis of natural (serum lipoproteins) and synthetic (liposomes) transport systems. The need for advanced analytical procedures of these complex and important systems is presented with the specific enhancements afforded by SMD with flowing sample streams. In contrast to bulk measurements which yield only average values, measurement of individual species allows creation of population histograms from heterogeneous samples. The data are acquired in minutes and the analysis requires relatively small sample quantities. Preliminary data are presented from the analysis of low density lipoprotein, and multilamellar and unilamellar vesicles.

  3. Acute changes in lipoprotein subclasses during exercise.

    Science.gov (United States)

    Søndergaard, Esben; Poulsen, Marianne K; Jensen, Michael D; Nielsen, Søren

    2014-01-01

    Lipids are important substrates for oxidation in the basal fasting state and during exercise. Studies have demonstrated beneficial changes in lipoprotein subclass composition the day after an exercise bout. However, the acute effect of exercise on TG concentration and lipoprotein subclass composition remains unclear. Sixteen lean, healthy individuals (8 men and 8 women) were recruited (age 20-30 years, BMILipoprotein subclass composition was measured with (1)H NMR spectroscopy. During exercise, LDL and HDL particle concentration increased significantly (plipoprotein subclass composition. These changes are similar to the effects of exercise training. © 2013.

  4. The usefulness of total cholesterol and high density lipoprotein ...

    African Journals Online (AJOL)

    The usefulness of total cholesterol and high density lipoprotein - cholesterol ratio in ... cholesterol and/or highdensity lipoprotein cholesterol/total cholesterol ratios in the interpretation of lipid profile result in clinical practice. ... Article Metrics.

  5. Lipoprotein profiling methodology based on determination of apolipoprotein concentration.

    Science.gov (United States)

    Takeda, Hiroaki; Izumi, Yoshihiro; Tomita, Atsumi; Koike, Tomonari; Shiomi, Masashi; Fukusaki, Eiichiro; Matsuda, Fumio; Bamba, Takeshi

    2017-01-01

    Abnormal lipid metabolism results in the alteration of lipid compositions in lipoproteins; therefore an accurate and quantitative analytical approach is required for the detailed structural characterization of lipoproteins. However, the specific lipid composition of each lipoprotein particle is poorly understood. Lipid composition of very-low-density lipoprotein and low-density lipoprotein particles derived from myocardial infarction-prone rabbits was determined by normalization of lipidomics data using apoB-100 levels. The ratio of lipid levels between very-low-density lipoprotein and low-density lipoprotein particles was different according to not only lipid classes, but also phosphatidylethanolamine subclasses by applying our developed methodology to myocardial infarction-prone rabbits. Our novel analytical approach represents to be a potentially useful tool to obtain particle-specific lipid components of lipoproteins.

  6. Evaluation of Homocysteine, Lipoprotein(a) and Endothelin as ...

    African Journals Online (AJOL)

    Evaluation of Homocysteine, Lipoprotein(a) and Endothelin as diagnostic markers of Coronary Artery Disease in Indian population. ... The objective of this study was to assess the role of endothelin, lipoprotein(a), ... Article Metrics.

  7. Correlation between serum lipoproteins and abdominal fat pad in ...

    African Journals Online (AJOL)

    Correlation between serum lipoproteins and abdominal fat pad in broiler chickens. ... The high density lipoprotein (HDL) concentration in birds fed fish oil diet was higher than other treatments, but the serum low density ... Article Metrics.

  8. Serum Lipids and Lipoproteins Levels and Selected Trace Metals In ...

    African Journals Online (AJOL)

    Serum Lipids and Lipoproteins Levels and Selected Trace Metals In Newly ... This study aim to determine the serum levels of trace metals and correlate same with serum levels of lipoproteins (an established marker of HBP) in ... Article Metrics.

  9. Effects of dietary turmeric supplementation on plasma lipoproteins ...

    African Journals Online (AJOL)

    Effects of dietary turmeric supplementation on plasma lipoproteins, meat quality and fatty acid composition in broilers. ... dietary supplementation of turmeric rhizome powder (TRP) on plasma lipoprotein concentrations, and the ... Article Metrics.

  10. Human Low Density Lipoprotein as a Vehicle of Atherosclerosis ...

    African Journals Online (AJOL)

    Human Low Density Lipoprotein as a Vehicle of Atherosclerosis. ... Low-density lipoproteins have been sufficiently established as an important precursor of atherosclerosis. The actual mechanism is still ... Article Metrics. Metrics Loading .

  11. Evaluation of plasma lipids and lipoproteins in nigerians suffering ...

    African Journals Online (AJOL)

    Evaluation of plasma lipids and lipoproteins in nigerians suffering from depressive illness. ... Very little is known about the lipid and lipoprotein status in Nigerian adults suffering from depression. One hundred subjects ... Article Metrics.

  12. Apolipoprotein (A) Isoform Distribution and Plasma Lipoprotein (a ...

    African Journals Online (AJOL)

    Apolipoprotein (A) Isoform Distribution and Plasma Lipoprotein (a) Levels In Nigerian Subjects With and Without Coronary Heart Disease. ... Plasma lipoprotein (a) Concentrations and apo(a) isoforms were determined in 101 ... Article Metrics.

  13. Interference of phenol during quantification of a bacterial lipoprotein ...

    African Journals Online (AJOL)

    Interference of phenol during quantification of a bacterial lipoprotein. ... bacterial Braun liporotein (BLP) from E. coli (a Toll-2 receptor ligand) is purified via phenol extraction on the basis of selective extraction of the lipoprotein. ... Article Metrics.

  14. Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family

    DEFF Research Database (Denmark)

    Ambjørn, Malene; Asmussen, Johanne W; Lindstam, Mats;

    2007-01-01

    Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT...... and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar...... granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite...

  15. Lipoprotein lipase isoelectric point isoforms in humans

    DEFF Research Database (Denmark)

    Badia-Villanueva, M.; Carulla, P.; Carrascal, M.

    2014-01-01

    Lipoprotein lipase (LPL) hydrolyzes circulating triacylglycerols (TAG) into free fatty acids and glycerol. It is present in almost all tissues and its tissue-specific regulation directs the flow of circulating TAG in the body. We demonstrated in a previous study that, in rat heart and post-hepari...

  16. Unfavorable apoAI-containing lipoproteins profile in Tunisian obese ...

    African Journals Online (AJOL)

    hope&shola

    be more sensitive to obesity effect than traditional lipid and lipoprotein parameters. The nature of .... The glucose assay was immediate, while other parameters were quantified ..... Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter ... regulator of very low density lipoprotein metabolism and insulin.

  17. Metabolism of high density lipoproteins in liver cancer

    Institute of Scientific and Technical Information of China (English)

    Jing-Ting Jiang; Ning Xu; Chang-Ping Wu

    2007-01-01

    Liver plays a vital role in the production and catabolism of plasma lipoproteins. It depends on the integrity of cellular function of liver, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs these processes are impaired and high-density lipoproteins are changed.

  18. Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4.

    Science.gov (United States)

    Nilsson, Stefan K; Anderson, Fredrick; Ericsson, Madelene; Larsson, Mikael; Makoveichuk, Elena; Lookene, Aivar; Heeren, Joerg; Olivecrona, Gunilla

    2012-10-01

    Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. A Computational Model for the Analysis of Lipoprotein Distributions in the Mouse: Translating FPLC Profiles to Lipoprotein Metabolism

    Science.gov (United States)

    Sips, Fianne L. P.; Tiemann, Christian A.; Oosterveer, Maaike H.; Groen, Albert K.; Hilbers, Peter A. J.; van Riel, Natal A. W.

    2014-01-01

    Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions, which complicates the identification of changes in metabolism. In this study we aim to develop a method which quantitatively relates murine lipoprotein size, composition and concentration to the molecular mechanisms underlying lipoprotein metabolism. We introduce a computational framework which incorporates a novel kinetic model of murine lipoprotein metabolism. The model is applied to compute a distribution of plasma lipoproteins, which is then related to experimental lipoprotein profiles through the generation of an in silico lipoprotein profile. The model was first applied to profiles obtained from wild-type C57Bl/6J mice. The results provided insight into the interplay of lipoprotein production, remodelling and catabolism. Moreover, the concentration and metabolism of unmeasured lipoprotein components could be determined. The model was validated through the prediction of lipoprotein profiles of several transgenic mouse models commonly used in cardiovascular research. Finally, the framework was employed for longitudinal analysis of the profiles of C57Bl/6J mice following a pharmaceutical intervention with a liver X receptor (LXR) agonist. The multifaceted regulatory response to the administration of the compound is incompletely understood. The results explain the characteristic changes of the observed lipoprotein profile in terms of the underlying metabolic perturbation and resultant modifications of lipid fluxes in the body. The Murine Lipoprotein Profiler (MuLiP) presented here is thus a valuable tool to assess the metabolic origin of altered murine lipoprotein profiles and can be applied in preclinical research performed in mice for analysis of lipid fluxes and

  20. A computational model for the analysis of lipoprotein distributions in the mouse: translating FPLC profiles to lipoprotein metabolism.

    Science.gov (United States)

    Sips, Fianne L P; Tiemann, Christian A; Oosterveer, Maaike H; Groen, Albert K; Hilbers, Peter A J; van Riel, Natal A W

    2014-05-01

    Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions, which complicates the identification of changes in metabolism. In this study we aim to develop a method which quantitatively relates murine lipoprotein size, composition and concentration to the molecular mechanisms underlying lipoprotein metabolism. We introduce a computational framework which incorporates a novel kinetic model of murine lipoprotein metabolism. The model is applied to compute a distribution of plasma lipoproteins, which is then related to experimental lipoprotein profiles through the generation of an in silico lipoprotein profile. The model was first applied to profiles obtained from wild-type C57Bl/6J mice. The results provided insight into the interplay of lipoprotein production, remodelling and catabolism. Moreover, the concentration and metabolism of unmeasured lipoprotein components could be determined. The model was validated through the prediction of lipoprotein profiles of several transgenic mouse models commonly used in cardiovascular research. Finally, the framework was employed for longitudinal analysis of the profiles of C57Bl/6J mice following a pharmaceutical intervention with a liver X receptor (LXR) agonist. The multifaceted regulatory response to the administration of the compound is incompletely understood. The results explain the characteristic changes of the observed lipoprotein profile in terms of the underlying metabolic perturbation and resultant modifications of lipid fluxes in the body. The Murine Lipoprotein Profiler (MuLiP) presented here is thus a valuable tool to assess the metabolic origin of altered murine lipoprotein profiles and can be applied in preclinical research performed in mice for analysis of lipid fluxes and

  1. Secretion of biologically active interferon-gamma inducible protein-10 (IP-10 by Lactococcus lactis

    Directory of Open Access Journals (Sweden)

    Saucedo-Cardenas Odila

    2008-07-01

    Full Text Available Abstract Background Chemokines are a large group of chemotactic cytokines that regulate and direct migration of leukocytes, activate inflammatory responses, and are involved in many other functions including regulation of tumor development. Interferon-gamma inducible-protein-10 (IP-10 is a member of the C-X-C subfamily of the chemokine family of cytokines. IP-10 specifically chemoattracts activated T lymphocytes, monocytes, and NK cells. IP-10 has been described also as a modulator of other antitumor cytokines. These properties make IP-10 a novel therapeutic molecule for the treatment of chronic and infectious diseases. Currently there are no suitable live biological systems to produce and secrete IP-10. Lactococcus lactis has been well-characterized over the years as a safe microorganism to produce heterologous proteins and to be used as a safe, live vaccine to deliver antigens and cytokines of interest. Here we report a recombinant strain of L. lactis genetically modified to produce and secrete biologically active IP-10. Results The IP-10 coding region was isolated from human cDNA and cloned into an L. lactis expression plasmid under the regulation of the pNis promoter. By fusion to the usp45 secretion signal, IP-10 was addressed out of the cell. Western blot analysis demonstrated that recombinant strains of L. lactis secrete IP-10 into the culture medium. Neither degradation nor incomplete forms of IP-10 were detected in the cell or supernatant fractions of L. lactis. In addition, we demonstrated that the NICE (nisin-controlled gene expression system was able to express IP-10 "de novo" even two hours after nisin removal. This human IP-10 protein secreted by L. lactis was biological active as demonstrated by Chemotaxis assay over human CD3+T lymphocytes. Conclusion Expression and secretion of mature IP-10 was efficiently achieved by L. lactis forming an effective system to produce IP-10. This recombinant IP-10 is biologically active as

  2. Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase

    NARCIS (Netherlands)

    Man, F.H.A.F. de; Beer, F. de; Laarse, A. van der; Smelt, A.H.M.; Leuven, J.A.G.; Havekes, L.M.

    1998-01-01

    Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the luminal surface of endothelium. It is the key enzyme involved in the hydrolysis of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the lipoproteins are considered to interact with vessel wall HSPG. Apo

  3. Boc SPPS of two hydrophobic peptides using a ''solubilising tail'' strategy : Dodecaalanine and chemotactic protein 10(42-55)

    NARCIS (Netherlands)

    Englebretsen, DR; Alewood, PF

    1996-01-01

    The solid phase syntheses of the hydrophobic peptides dodecaalanine and chemotactic protein-10(42-55) were achieved using a ''solubilising tail'' strategy. Peptide constructs of the form H-hydrophobic peptide-glycolamide ester-(Gly-Arg)(4)-Gly-OH were synthesised by Boc SPPS. The peptide-constructs

  4. Boc SPPS of two hydrophobic peptides using a ''solubilising tail'' strategy : Dodecaalanine and chemotactic protein 10(42-55)

    NARCIS (Netherlands)

    Englebretsen, DR; Alewood, PF

    1996-01-01

    The solid phase syntheses of the hydrophobic peptides dodecaalanine and chemotactic protein-10(42-55) were achieved using a ''solubilising tail'' strategy. Peptide constructs of the form H-hydrophobic peptide-glycolamide ester-(Gly-Arg)(4)-Gly-OH were synthesised by Boc SPPS. The peptide-constructs

  5. Dissection of LolB function--lipoprotein binding, membrane targeting and incorporation of lipoproteins into lipid bilayers.

    Science.gov (United States)

    Tsukahara, Jun; Mukaiyama, Keita; Okuda, Suguru; Narita, Shin-ichiro; Tokuda, Hajime

    2009-08-01

    Escherichia coli cells express at least 90 species of lipoprotein. LolB is one of the essential outer membrane lipoproteins, being involved in the last step of lipoprotein sorting. It accepts lipoproteins from a periplasmic molecular chaperone, LolA, and mediates the outer membrane anchoring of lipoproteins through a largely unknown mechanism. It has been shown previously that a LolB derivative, mLolB, lacking an N-terminal acyl chain, can bind lipoproteins. We examined how the lack of an N-terminal anchor affects the outer membrane anchoring of lipoproteins. Surprisingly, mLolB compensates for LolB function and supports E. coli growth, indicating that the N-terminal anchor is not essential for its function. Indeed, mLolB correctly localizes lipoproteins to either the inner or outer membrane depending on the sorting signal at the steady state. Furthermore, periplasmic mLolB enables the dissection of LolB function, namely lipoprotein binding, membrane targeting and lipoprotein anchoring. It mediates the transfer of lipoproteins from LolA to the outer membrane, but also the inner membrane and liposomes, indicating that mLolB exhibits no membrane preference and targets to phospholipids. Consequently, an outer membrane-specific lipoprotein is transiently mislocalized to the inner membrane when cells express only mLolB. LolB anchored to the outer membrane does not cause such mislocalization and is more active than mLolB. Phosphatidylethanolamine has been found to stimulate the mLolB-dependent membrane anchoring of lipoproteins. Taken together, these results indicate that lipoprotein binding, membrane targeting and membrane incorporation of lipoproteins are intrinsic functions of LolB.

  6. Binding of anthracycline derivatives to human serum lipoproteins.

    Science.gov (United States)

    Chassany, O; Urien, S; Claudepierre, P; Bastian, G; Tillement, J P

    1994-01-01

    The binding of eight anthracycline analogues (including mitoxantrone) to isolated serum lipoproteins (high, low and very low density lipoproteins) was studied in order to elucidate some determinants of their interaction with lipidic structures. Serum lipoproteins were isolated by ultracentrifugation. Drug binding experiments were run by ultrafiltration at 37 degrees C and pH 7.4. Anthracycline concentrations (total and free) were determined by HPLC with fluorometric detection. All the ligands were significantly bound to the three lipoprotein classes, and for each ligand the binding increased as the lipidic fraction of lipoprotein increased. From doxorubicin to iododoxorubicin, there was a tenfold increase in lipoprotein binding (doxorubicin < mitoxantrone < epirubicin < daunorubicin < pirarubicin < aclarubicin < zorubicin < iododoxorubicin). For all the ligands studied, the extent of lipoprotein binding appears to be related to chemical determinants of lipophilicity.

  7. Analyzing the molecular mechanism of lipoprotein localization in Brucella

    Science.gov (United States)

    Goolab, Shivani; Roth, Robyn L.; van Heerden, Henriette; Crampton, Michael C.

    2015-01-01

    Bacterial lipoproteins possess diverse structure and functionality, ranging from bacterial physiology to pathogenic processes. As such many lipoproteins, originating from Brucella are exploited as potential vaccines to countermeasure brucellosis infection in the host. These membrane proteins are translocated from the cytoplasm to the cell membrane where they are anchored peripherally by a multifaceted targeting mechanism. Although much research has focused on the identification and classification of Brucella lipoproteins and their potential use as vaccine candidates for the treatment of Brucellosis, the underlying route for the translocation of these lipoproteins to the outer surface of the Brucella (and other pathogens) outer membrane (OM) remains mostly unknown. This is partly due to the complexity of the organism and evasive tactics used to escape the host immune system, the variation in biological structure and activity of lipoproteins, combined with the complex nature of the translocation machinery. The biosynthetic pathway of Brucella lipoproteins involves a distinct secretion system aiding translocation from the cytoplasm, where they are modified by lipidation, sorted by the lipoprotein localization machinery pathway and thereafter equipped for export to the OM. Surface localized lipoproteins in Brucella may employ a lipoprotein flippase or the β-barrel assembly complex for translocation. This review provides an overview of the characterized Brucella OM proteins that form part of the OM, including a handful of other characterized bacterial lipoproteins and their mechanisms of translocation. Lipoprotein localization pathways in gram negative bacteria will be used as a model to identify gaps in Brucella lipoprotein localization and infer a potential pathway. Of particular interest are the dual topology lipoproteins identified in Escherichia coli and Haemophilus influenza. The localization and topology of these lipoproteins from other gram negative bacteria

  8. Identification and characterization of estrogen receptor-related receptor alpha and gamma in human glioma and astrocytoma cells

    OpenAIRE

    Gandhari, Mukesh K; Frazier, Chester R.; Hartenstein, Julia S; Cloix, Jean-Francois; Bernier, Michel; Wainer, Irving W.

    2009-01-01

    The purpose of this study was to examine expression and function of estrogen receptor-related receptors (ERRs) in human glioma and astrocytoma cell lines. These estrogen receptor-negative cell lines expressed ERRα and ERRγ proteins to varying degree in a cell context dependent manner, with U87MG glioma cells expressing both orphan nuclear receptors. Cell proliferation assays were performed in the presence of ERR isoform-specific agonists and antagonists, and the calculated EC50 and IC50 value...

  9. Sortilins: new players in lipoprotein metabolism

    DEFF Research Database (Denmark)

    Willnow, Thomas; Kjølby, Mads Fuglsang; Nykjær, Anders

    2011-01-01

    PURPOSE OF REVIEW: Sortilins are sorting receptors that direct proteins through secretory and endocytic pathways of the cell. Previously, these receptors have been shown to play important roles in regulating protein transport in neurons and to control neuronal viability and death in many diseases...... of the nervous system. Recent data, including genome-wide association studies, now suggest equally important functions for sortilins in control of systemic lipoprotein metabolism and risk of cardiovascular disease. This review discusses the evidence implicating two members of this gene family, sortilin and SORLA...... on the importance of sorting receptors in control of cellular and systemic lipoprotein metabolism and how altered trafficking pathways may represent a major risk factor for dyslipidemia and atherosclerosis in the human population....

  10. Mycoplasma lipoproteins and Toll-like receptors

    Institute of Scientific and Technical Information of China (English)

    Ling-ling ZUO; Yi-mou WU; Xiao-xing YOU

    2009-01-01

    Mycoplasmas, the smallest free-living, self-replicating bacteria with diameters of 200 to 800 nm, have been reported to be associated with human diseases. It is well known that the mycoplasma lipoprotein/peptide is able to modulate the host immune system, whose N-terminal structure is an important factor in inducing immunity and distinguishing Toll-like receptors (TLRs). However, there is still no clear elucidation about the pathogenic mechanism of mycoplasma lipoprotein/peptide and the signaling pathway. Some researchers have focused on understanding the structures of these proteins and the relationships between their structure and biological function. This review provides an update on the research in this field.

  11. Lipoprotein lipase deficiency with visceral xanthomas

    Energy Technology Data Exchange (ETDEWEB)

    Servaes, Sabah; Bellah, Richard [Department of Radiology, Philadelphia, PA (United States); Verma, Ritu [Department of Gastroenterology, Philadelphia, PA (United States); Pawel, Bruce [Department of Pathology, Philadelphia, PA (United States)

    2010-08-15

    Lipoprotein lipase deficiency (LLD) is a rare metabolic disorder that typically presents with skin xanthomas and pancreatitis in childhood. We report a case of LLD in an infant who presented with jaundice caused by a pancreatic head mass. Abdominal imaging also incidentally revealed hyperechoic renal masses caused by renal xanthomas. This appearance of the multiple abdominal masses makes this a unique infantile presentation of LLD. (orig.)

  12. Lipoprotein secretion: It takes two to TANGO.

    Science.gov (United States)

    Pfeffer, Suzanne R

    2016-05-09

    An unsolved mystery in cell biology is how unusually large secretory cargoes are exported from the endoplasmic reticulum. In this issue, Santos et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201603072) report the function of a Mia2/cTAGE5 transcript fusion, named TALI, in the endoplasmic reticulum export of chylomicrons and very low-density lipoproteins, but not collagen XII.

  13. Immune Response to Lipoproteins in Atherosclerosis

    OpenAIRE

    Sonia Samson; Lakshmi Mundkur; Kakkar, Vijay V

    2012-01-01

    Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation re...

  14. [Analysis of lipoprotein metabolism in alcoholics].

    Science.gov (United States)

    Mizukami, Yuki; Okazaki, Mitsuyo; Usui, Shinichi; Hosaki, Seijin; Maruyama, Katsuya; Hosokawa, Yu

    2008-04-01

    High density lipoprotein (HDL) is increased by exercise and drinking and is well known as a negative risk factor of coronary heart disease. We analyzed serum lipids of alcoholics from the view points of biochemical examination, remnant like particle (RLP) and particle size of lipoprotein for the purpose of estimated effect of serum lipids, especially HDL quality in alcoholics. Serum levels of total cholesterol, free glycerol, RLP-C and RLP-TG were significantly decreased after hospitalization. The condition of RLP-C/RLP-TG on admission revealed cholesterol-rich composition. In case of HDL-C, the longer period from last drinking to hospitalization affected its decrease. From analytical study of particle size of lipoprotein, quantities of HDL-C in very large size and large size were significantly decreased after hospitalization which means that HDL composition at hospitalization is cholesterol-rich. So, it is speculated that increased serum level of HDL in alcoholics may be caused by expanded cholesterol ester and its quality may be different from that of healthy people. In this meaning, the study of arteriosclerosis in alcoholics will be necessary in relation to high level of serum HDL-C.

  15. Immune Response to Lipoproteins in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sonia Samson

    2012-01-01

    Full Text Available Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.

  16. Abnormal high density lipoproteins in cerebrotendinous xanthomatosis

    Energy Technology Data Exchange (ETDEWEB)

    Shore, V. (Lawrence Livermore Lab., CA); Salen, G.; Cheng, F.W.; Forte, T.; Shefer, S.; Tint, G.S.

    1981-11-01

    The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The adnormalities in lipoprotein distribution profiles and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.

  17. Chromatofocusing of human high density lipoproteins and isolation of lipoproteins A and A-I.

    Science.gov (United States)

    Nestruck, A C; Niedmann, P D; Wieland, H; Seidel, D

    1983-08-29

    Using chromatofocusing, a column chromatography method with an internally generated pH gradient and focusing effects, human plasma high density lipoproteins (HDL) were fractionated into six subclasses within an interval of less than 1 pH unit (pH 5.1-4.2). All fractions floated in the ultracentrifuge at density = 1.21 g X ml-1, retained a typical HDL electron micrographic morphology and as a single band, alpha-migration on agarose electrophoresis. Compositional analysis of the subclasses revealed an inverse relationship between cholesterol ester and cholesterol on a molar basis. Distinct differences in the distribution of the apolipoproteins between the fractions were found. Two of the subclasses contained only apolipoprotein A-I and were therefore considered to be two forms of the lipid-combined form of apolipoprotein A-I, i.e., lipoprotein A-I. One subclass contained only apolipoproteins A-I + A-II and was, therefore, lipoprotein A. One subclass contained apolipoproteins A-I + A-II + D, and the two remaining contained additionally apolipoproteins C and E. Lipoprotein A-I was also demonstrated after immunoabsorption of apolipoprotein A-II-containing lipoproteins from whole serum. It is suggested that this method, which allows the fractionation of HDL into subclasses with distinct differences in apolipoprotein composition, offers new avenues for the study of the structural and metabolic heterogeneity of HDL.

  18. Characteristics of Lipoprotein Peak x Eluted from a Column with the Eluent of High-magnesium Ion Concentration in Lipoprotein Analysis Using the Cation-exchange Chromatography

    OpenAIRE

    Yuji Hirowatari; Hiroshi Yoshida; Yutaka Ogura; Hidekastu Yanai; Hideo Kurosawa; Norio Tada

    2005-01-01

    The new lipoprotein analysis method using a cation-exchange chromatography, which contains a sulfopropyl-ligand column and two magnesium ion-containing eluents was previously reported. This method can separate serum lipoproteins on the column gel with a magnesium ion concentration gradient and high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and an unspecified lipoprotein peak are eluted in order from the column. We have now characterize...

  19. Lipoprotein-induced phenoloxidase-activity in tarantula hemocyanin.

    Science.gov (United States)

    Schenk, Sven; Schmidt, Juliane; Hoeger, Ulrich; Decker, Heinz

    2015-08-01

    Phenoloxidases play vital roles in invertebrate innate immune reactions, wound closure and sclerotization processes in arthropods. In chelicerates, where phenoloxidases are lacking, phenoloxidase-activity can be induced in the oxygen carrier hemocyanin in vitro by proteolytic cleavage, incubation with the artificial inducer SDS, or lipids. The role of protein-protein interaction has up to now received little attention. This is remarkable, as lipoproteins - complexes of proteins and lipids - are present at high concentrations in arthropod hemolymph. We characterized the three lipoproteins present in tarantula hemolymph, two high-density lipoproteins and one very high-density lipoprotein, and show that the two high-density lipoproteins have distinct structures: the more abundant high-density lipoprotein is an ellipsoid particle with axes of ~22.5 nm and ~16.8 nm, respectively. The second high-density lipoprotein, present only in trace amount, is a large discoidal lipoprotein with a diameter of ~38.4 nm and an on-edge thickness of ~7.1 nm. We further demonstrate that the interaction between lipoproteins and hemocyanin induces phenoloxidase activity in hemocyanin, and propose that this activation is due to protein-protein interaction rather than protein-lipid interaction, as neither lipid micelles nor lipid monomers were found to be activating. Activation was strongest in the presence of high-density lipoproteins; very high-density lipoproteins were found to be non-activating. This is the first time that the ability of lipoproteins to induce phenoloxidase activity of hemocyanin has been demonstrated, thus adding novel aspects to the function of lipoproteins apart from their known role in nutrient supply. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling

    National Research Council Canada - National Science Library

    Riwanto, Meliana; Rohrer, Lucia; Roschitzki, Bernd; Besler, Christian; Mocharla, Pavani; Mueller, Maja; Perisa, Damir; Heinrich, Kathrin; Altwegg, Lukas; von Eckardstein, Arnold; Lüscher, Thomas F; Landmesser, Ulf

    2013-01-01

    ...). High-density lipoprotein from healthy subjects (HDL(Healthy)) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein...

  1. Human placenta secretes apolipoprotein B-100-containing lipoproteins

    DEFF Research Database (Denmark)

    Munk-Madsen, Eva; Lindegaard, Marie Louise Skakkebæk; Andersen, Claus B;

    2004-01-01

    early during pregnancy in the placenta. To examine whether the human placenta produces lipoproteins, we examined apoB and microsomal triglyceride transfer protein (MTP) mRNA expression in placental biopsies. ApoB and MTP are mandatory for assembly and secretion of apoB-containing lipoproteins. Both...... genes were expressed in placenta and microsomal extracts from human placenta contained triglyceride transfer activity, indicating expression of bioactive MTP. To detect lipoprotein secretion, biopsies from term placentas were placed in medium with [(35)S]methionine and [(35)S]cysteine for 3-24 h. Upon...... lipoproteins secreted from placental tissue showed spherical particles with a diameter of 47 +/- 10 nm. These results demonstrate that human placenta expresses both apoB and MTP and consequently synthesize and secrete apoB-100-containing lipoproteins. Placental lipoprotein formation constitutes a novel pathway...

  2. Increased transvascular low density lipoprotein transport in insulin dependent diabetes

    DEFF Research Database (Denmark)

    Kornerup, Karen; Nordestgaard, Børge Grønne; Feldt-Rasmussen, Bo

    2003-01-01

    BACKGROUND: The increased risk of atherosclerosis associated with diabetes cannot be explained by conventional cardiovascular risk factors alone. We hypothesized that transvascular lipoprotein transport may be increased in patients with diabetes, possibly explaining increased intimal lipoprotein ...... be increased in patients with type 1 diabetes. This suggests that lipoprotein flux into the arterial wall is increased in people with type 1 diabetes, possibly explaining accelerated development of atherosclerosis....

  3. Fish plasma lipoproteins--comparative observations in serranides and sparides.

    Science.gov (United States)

    Santulli, A; Cusenza, L; Modica, A; Curatolo, A; D'Amelio, V

    1991-01-01

    1. Diet, time from last feeding, temperature, season and sexual stage are some of the factors influencing the lipoprotein pattern. 2. Keeping these factors constant species-specific differences observed among lipoprotein patterns of Sparus aurata, Puntazzo puntazzo, Diplodus sargus, Diplodus vulgaris and Dicentrarchus labrax are discussed. 3. Feeding habits and therefore lipid absorption and the rate of lipoprotein maturation process are the factors determining the observed differences.

  4. Computational lipidology: predicting lipoprotein density profiles in human blood plasma.

    Directory of Open Access Journals (Sweden)

    Katrin Hübner

    2008-05-01

    Full Text Available Monitoring cholesterol levels is strongly recommended to identify patients at risk for myocardial infarction. However, clinical markers beyond "bad" and "good" cholesterol are needed to precisely predict individual lipid disorders. Our work contributes to this aim by bringing together experiment and theory. We developed a novel computer-based model of the human plasma lipoprotein metabolism in order to simulate the blood lipid levels in high resolution. Instead of focusing on a few conventionally used predefined lipoprotein density classes (LDL, HDL, we consider the entire protein and lipid composition spectrum of individual lipoprotein complexes. Subsequently, their distribution over density (which equals the lipoprotein profile is calculated. As our main results, we (i successfully reproduced clinically measured lipoprotein profiles of healthy subjects; (ii assigned lipoproteins to narrow density classes, named high-resolution density sub-fractions (hrDS, revealing heterogeneous lipoprotein distributions within the major lipoprotein classes; and (iii present model-based predictions of changes in the lipoprotein distribution elicited by disorders in underlying molecular processes. In its present state, the model offers a platform for many future applications aimed at understanding the reasons for inter-individual variability, identifying new sub-fractions of potential clinical relevance and a patient-oriented diagnosis of the potential molecular causes for individual dyslipidemia.

  5. Outer membrane lipoprotein biogenesis: Lol is not the end.

    Science.gov (United States)

    Konovalova, Anna; Silhavy, Thomas J

    2015-10-05

    Bacterial lipoproteins are lipid-anchored proteins that contain acyl groups covalently attached to the N-terminal cysteine residue of the mature protein. Lipoproteins are synthesized in precursor form with an N-terminal signal sequence (SS) that targets translocation across the cytoplasmic or inner membrane (IM). Lipid modification and SS processing take place at the periplasmic face of the IM. Outer membrane (OM) lipoproteins take the localization of lipoproteins (Lol) export pathway, which ends with the insertion of the N-terminal lipid moiety into the inner leaflet of the OM. For many lipoproteins, the biogenesis pathway ends here. We provide examples of lipoproteins that adopt complex topologies in the OM that include transmembrane and surface-exposed domains. Biogenesis of such lipoproteins requires additional steps beyond the Lol pathway. In at least one case, lipoprotein sequences reach the cell surface by being threaded through the lumen of a beta-barrel protein in an assembly reaction that requires the heteropentomeric Bam complex. The inability to predict surface exposure reinforces the importance of experimental verification of lipoprotein topology and we will discuss some of the methods used to study OM protein topology.

  6. 21 CFR 866.5580 - Alpha-1-lipoprotein immuno-logical test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Alpha-1-lipoprotein immuno-logical test system....5580 Alpha-1-lipoprotein immuno-logical test system. (a) Identification. An alpha-1-lipoprotein... the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of alpha-1...

  7. 21 CFR 866.5600 - Low-density lipoprotein immunological test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Low-density lipoprotein immunological test system....5600 Low-density lipoprotein immunological test system. (a) Identification. A low-density lipoprotein... the low-density lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in...

  8. Apolipoprotein B-100 containing lipoprotein metabolism in subjects with lipoprotein lipase gene mutations (106/120)

    Science.gov (United States)

    Ooi, Esther M M; Russell, Betsy S; Olson, Eric; Sun, Sam Z; Diffenderfer, Margaret R; Lichtenstein, Alice H; Keilson, Leonard; Barrett, P Hugh R; Schaefer, Ernst J; Sprecher, Dennis L

    2012-01-01

    Objective We investigated the impact of lipoprotein lipase (LPL) gene mutations on apolipoprotein (apo) B-100 metabolism. Methods and Results We studied 3 subjects with familial LPL deficiency (FLD), 14 subjects heterozygous for the LPL gene mutations, Gly188Glu, Trp64Stop and Ile194Thr, and 10 control subjects. Very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL)-apoB-100 kinetics were determined in the fed state using stable isotope methods and compartmental modeling. Compared with controls, FLD had markedly elevated plasma triglycerides and lower VLDL-apoB-100 fractional catabolic rate (FCR), IDL-apoB-100 FCR, VLDL-to-IDL conversion and VLDL-apoB-100 production rate (PR) (ptriglyceride, VLDL- and IDL-apoB-100 concentrations, and lower VLDL- and IDL-apoB-100 FCR (ptriglycerides were not different but IDL-apoB-100 concentration and PR, and VLDL-to-IDL conversion were lower in Trp64Stop compared with controls (ptriglycerides. The changes in plasma triglycerides and apoB-100 kinetics are attributable to the effects of the LPL genotype. PMID:22095987

  9. Lipoprotein glomerulopathy treated with LDL-apheresis (Heparin-induced Extracorporeal Lipoprotein Precipitation system: a case report

    Directory of Open Access Journals (Sweden)

    Rivasi Paolo

    2009-12-01

    Full Text Available Abstract Introduction Lipoprotein glomerulopathy is a glomerulonephritis which was described for the first time by Saito in 1989 and is currently acknowledged as a separate nosological entity. It is histologically characterized by a marked dilatation of the glomerular capillaries and the presence of lipoprotein thrombi in the glomerular lumens. The dyslipidemic profile is similar to that of type III dyslipoproteinemia with Apolipoprotein E values that are often high; proteinuria and renal dysfunction are present. Proteinuria often does not respond to steroid and cytostatic treatments. The phenotypic expression of lipoprotein glomerulopathy is most probably correlated to a genetic alteration of the lipoprotein metabolism (mutation of the Apolipoprotein E coding gene. In literature, lipoprotein glomerulopathies have mainly been reported in Japanese and Chinese subjects, except for three cases in the Caucasian race, reported in France and the USA. Case presentation We describe the case of a 60-year-old female, Caucasian patient suffering from lipoprotein glomerulopathy, carrier of a new mutation on the Apolipoprotein E gene (Apolipoprotein EMODENA, and treated successfully with low density lipoprotein-apheresis with the Heparin induced extracorporeal lipoprotein precipitation system. After a first phase of therapeutic protocol with statins, the patient was admitted for nephrotic syndrome, renal failure and hypertension. Since conventional treatment alone was not able to control dyslipidemia, aphaeretic treatment with heparin-induced Extracorporeal Lipoprotein Precipitation - apheresis (HELP-apheresis was started to maintain angiotensin converting enzyme inhibitor therapy for the treatment of hypertension. Treatment with HELP-apheresis led to a complete remission of the proteinuria in a very short time (four months, as well as control of hypercholesterolemia and renal function recovery. Conclusion According to this case of lipoprotein glomerulopathy

  10. Changes in lipoprotein kinetics associated with type 2 diabetes affect the distribution of lipopolysaccharides among lipoproteins.

    Science.gov (United States)

    Vergès, Bruno; Duvillard, Laurence; Lagrost, Laurent; Vachoux, Christelle; Garret, Céline; Bouyer, Karine; Courtney, Michael; Pomié, Céline; Burcelin, Rémy

    2014-07-01

    Lipopolysaccharides (LPSs) are inflammatory components of the outer membrane of Gram-negative bacteria and, in plasma, are mostly associated with lipoproteins. This association is thought to promote their catabolism while reducing their proinflammatory effects. Our aim was to determine the impact of lipoprotein kinetics on plasma LPS distribution and how it may affect patients with type 2 diabetes mellitus (T2DM). We performed a kinetic study in 30 individuals (16 T2DM patients, 14 controls) and analyzed the impact of changes in lipoprotein kinetics on LPS distribution among lipoproteins. Plasma LPS levels in T2DM patients were not different from those in controls, but LPS distribution in the two groups was different. Patients with T2DM had higher LPS-very low-density lipoprotein (VLDL; 31% ± 7% vs 22% ± 11%, P = .002), LPS-high-density lipoprotein (HDL; 29% ± 9% vs 19% ± 10%, P = .015), free (nonlipoprotein bound) LPS (10% ± 4% vs 7% ± 4%, P = .043) and lower LPS-low-density lipoprotein (LDL; 30% ± 13% vs 52% ± 16%, P = .001). In multivariable analysis, VLDL-LPS was associated with HDL-LPS (P < .0001); LDL-LPS was associated with VLDL-LPS (P = .004), and VLDL apolipoprotein (apo) B100 catabolism (P = .002); HDL-LPS was associated with free LPS (P < .0001) and VLDL-LPS (P = .033); free LPS was associated with HDL-LPS (P < .0001). In a patient featuring a dramatic decrease in VLDL catabolism due to apoA-V mutation, LDL-LPS was severely decreased (0.044 EU/mL vs 0.788 EU/mL in controls). The difference between T2DM patients and controls for LDL-LPS fraction was no longer significant after controlling for VLDL apoB100 total fractional catabolic rate. Our data suggest that in humans, free LPS transfers first to HDL and then to VLDL, whereas the LPS-bound LDL fraction is mainly derived from VLDL catabolism; the latter may hence represent a LPS catabolic pathway. T2DM patients show lower LDL-LPS secondary to reduced VLDL catabolism, which may represent an

  11. Lipoprotein Receptors Redundantly Participate in Entry of Hepatitis C Virus.

    Directory of Open Access Journals (Sweden)

    Satomi Yamamoto

    2016-05-01

    Full Text Available Scavenger receptor class B type 1 (SR-B1 and low-density lipoprotein receptor (LDLR are known to be involved in entry of hepatitis C virus (HCV, but their precise roles and their interplay are not fully understood. In this study, deficiency of both SR-B1 and LDLR in Huh7 cells was shown to impair the entry of HCV more strongly than deficiency of either SR-B1 or LDLR alone. In addition, exogenous expression of not only SR-B1 and LDLR but also very low-density lipoprotein receptor (VLDLR rescued HCV entry in the SR-B1 and LDLR double-knockout cells, suggesting that VLDLR has similar roles in HCV entry. VLDLR is a lipoprotein receptor, but the level of its hepatic expression was lower than those of SR-B1 and LDLR. Moreover, expression of mutant lipoprotein receptors incapable of binding to or uptake of lipid resulted in no or slight enhancement of HCV entry in the double-knockout cells, suggesting that binding and/or uptake activities of lipid by lipoprotein receptors are essential for HCV entry. In addition, rescue of infectivity in the double-knockout cells by the expression of the lipoprotein receptors was not observed following infection with pseudotype particles bearing HCV envelope proteins produced in non-hepatic cells, suggesting that lipoproteins associated with HCV particles participate in the entry through their interaction with lipoprotein receptors. Buoyant density gradient analysis revealed that HCV utilizes these lipoprotein receptors in a manner dependent on the lipoproteins associated with HCV particles. Collectively, these results suggest that lipoprotein receptors redundantly participate in the entry of HCV.

  12. Lipoprotein Receptors Redundantly Participate in Entry of Hepatitis C Virus.

    Science.gov (United States)

    Yamamoto, Satomi; Fukuhara, Takasuke; Ono, Chikako; Uemura, Kentaro; Kawachi, Yukako; Shiokawa, Mai; Mori, Hiroyuki; Wada, Masami; Shima, Ryoichi; Okamoto, Toru; Hiraga, Nobuhiko; Suzuki, Ryosuke; Chayama, Kazuaki; Wakita, Takaji; Matsuura, Yoshiharu

    2016-05-01

    Scavenger receptor class B type 1 (SR-B1) and low-density lipoprotein receptor (LDLR) are known to be involved in entry of hepatitis C virus (HCV), but their precise roles and their interplay are not fully understood. In this study, deficiency of both SR-B1 and LDLR in Huh7 cells was shown to impair the entry of HCV more strongly than deficiency of either SR-B1 or LDLR alone. In addition, exogenous expression of not only SR-B1 and LDLR but also very low-density lipoprotein receptor (VLDLR) rescued HCV entry in the SR-B1 and LDLR double-knockout cells, suggesting that VLDLR has similar roles in HCV entry. VLDLR is a lipoprotein receptor, but the level of its hepatic expression was lower than those of SR-B1 and LDLR. Moreover, expression of mutant lipoprotein receptors incapable of binding to or uptake of lipid resulted in no or slight enhancement of HCV entry in the double-knockout cells, suggesting that binding and/or uptake activities of lipid by lipoprotein receptors are essential for HCV entry. In addition, rescue of infectivity in the double-knockout cells by the expression of the lipoprotein receptors was not observed following infection with pseudotype particles bearing HCV envelope proteins produced in non-hepatic cells, suggesting that lipoproteins associated with HCV particles participate in the entry through their interaction with lipoprotein receptors. Buoyant density gradient analysis revealed that HCV utilizes these lipoprotein receptors in a manner dependent on the lipoproteins associated with HCV particles. Collectively, these results suggest that lipoprotein receptors redundantly participate in the entry of HCV.

  13. Lipoproteins, cholesterol homeostasis and cardiac health

    Directory of Open Access Journals (Sweden)

    Tyler F. Daniels, Karen M. Killinger, Jennifer J. Michal, Raymond W. Wright Jr., Zhihua Jiang

    2009-01-01

    Full Text Available Cholesterol is an essential substance involved in many functions, such as maintaining cell membranes, manufacturing vitamin D on surface of the skin, producing hormones, and possibly helping cell connections in the brain. When cholesterol levels rise in the blood, they can, however, have dangerous consequences. In particular, cholesterol has generated considerable notoriety for its causative role in atherosclerosis, the leading cause of death in developed countries around the world. Homeostasis of cholesterol is centered on the metabolism of lipoproteins, which mediate transport of the lipid to and from tissues. As a synopsis of the major events and proteins that manage lipoprotein homeostasis, this review contributes to the substantial attention that has recently been directed to this area. Despite intense scrutiny, the majority of phenotypic variation in total cholesterol and related traits eludes explanation by current genetic knowledge. This is somewhat disappointing considering heritability estimates have established these traits as highly genetic. Thus, the continued search for candidate genes, mutations, and mechanisms is vital to our understanding of heart disease at the molecular level. Furthermore, as marker development continues to predict risk of vascular illness, this knowledge has the potential to revolutionize treatment of this leading human disease.

  14. SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a)

    DEFF Research Database (Denmark)

    Yang, Xiaoping; Sethi, Amar A; Yanek, Lisa R

    2016-01-01

    BACKGROUND: SR-B1 (scavenger receptor class B type 1), encoded by the gene SCARB1, is a lipoprotein receptor that binds both high-density lipoprotein (HDL) and low-density lipoprotein. We reported that SR-B1 is also a receptor for lipoprotein (a) (Lp(a)), mediating cellular uptake of Lp(a) in vitro...

  15. Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.

    Science.gov (United States)

    Mahley, R W; Palaoğlu, K E; Atak, Z; Dawson-Pepin, J; Langlois, A M; Cheung, V; Onat, H; Fulks, P; Mahley, L L; Vakar, F

    1995-04-01

    We examined the plasma lipids, lipoproteins, and selected apolipoproteins in approximately 9,000 men and women from six different regions of Turkey with markedly different diets, ranging from an Aegean coast diet high in olive oil (plasma cholesteryl ester fatty acids enriched in monounsaturated fatty acids) to an inland Anatolian diet high in meat and dairy products (plasma cholesteryl esters enriched in saturated fatty acids). The rural population consuming an olive oil-rich diet had the lowest plasma cholesterol levels (men, 149 mg/dl; women, 150 mg/dl). The urban populations of Istanbul and Adana had higher plasma cholesterol levels (men, 202 and 184 mg/dl, respectively; women, 181 and 190 mg/dl, respectively). Affluent men had the highest cholesterol levels (207 mg/dl). The low density lipoprotein (LDL) cholesterol levels tended to parallel the total cholesterol levels (highest for Istanbul men at 136 mg/dl and lowest for Aegean coast men and women at approximately 100 mg/dl). Strikingly, the Turkish people were found to have very low levels of high density lipoprotein (HDL) cholesterol (HDL-C) (mean values for all six regions: men, 34-38 mg/dl; women, 37-45 mg/dl) and total cholesterol/HDL-C ratios that were high (mean values for all six regions: men, 4.5-5.5; women, 3.9-5.0). The low HDL-C levels appear to be caused, at least in part, by a genetic factor. Triglyceride levels also tended to be high in Turkish men (approximately 120-150 mg/dl) and women (approximately 90-110 mg/dl). Thus, even though the total plasma cholesterol levels are not excessively elevated in comparison to those in other populations, the presence of low HDL-C or low HDL-C coupled with mildly elevated triglyceride levels may represent a significant risk factor for heart disease in the Turkish population. Affluence and higher education were associated with higher cholesterol levels. Lack of physical activity, smoking, and alcohol consumption also tended to be associated with a

  16. Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection

    DEFF Research Database (Denmark)

    Petrucci, Roberta; Abu Amer, Nabil; Gurgel, Ricardo Queiroz;

    2008-01-01

    BACKGROUND: Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays....... Other biomarkers such as interferon-gamma-induced-protein 10 (IP-10) may have potential for the diagnosis of latent TB infections. OBJECTIVES: To describe IP-10 concentrations and their association to TST and INF-gamma responses in children recently exposed to adults with smear-positive TB in Brazil...

  17. Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

    Science.gov (United States)

    Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute...

  18. Hindiii and S447x polymorphisms of lipoprotein lipase gene and ...

    African Journals Online (AJOL)

    Hindiii and S447x polymorphisms of lipoprotein lipase gene and their relationship to coronary artery disease. ... Lipoprotein lipase is a key enzyme in lipoprotein metabolism and its gene is a major candidate gene for coronary ... Article Metrics.

  19. TRIIODOTHYRONINE RAPIDLY LOWERS PLASMA-LIPOPROTEIN (A) IN HYPOTHYROID SUBJECTS

    NARCIS (Netherlands)

    DULLAART, RPF; VANDOORMAAL, JJ; HOOGENBERG, K; SLUITER, WJ

    1995-01-01

    Background: Increases in plasma low-density-lipoprotein (LDL) cholesterol and apolipoprotein B (apo-B) are well known in primary hypothyroidism, but it is uncertain whether thyroid dysfunction is associated with elevated levels of the atherogenic lipoprotein (a) (Lp(a)). Methods: The effect of short

  20. A Phospholipidomic Analysis of All Defined Human Plasma Lipoproteins

    NARCIS (Netherlands)

    Dashti, Monireh; Kulik, Willem; Hoek, Frans; Veerman, Enno C.; Peppelenbosch, Maikel P.; Rezaee, Farhad

    2011-01-01

    Since plasma lipoproteins contain both protein and phospholipid components, either may be involved in processes such as atherosclerosis. In this study the identification of plasma lipoprotein-associated phospholipids, which is essential for understanding these processes at the molecular level, are

  1. A phospholipidomic analysis of all defined human plasma lipoproteins

    NARCIS (Netherlands)

    Dashti, M.; Kulik, W.; Hoek, F.; Veerman, E.C.; Peppelenbosch, M.P.; Rezaee, F.

    2011-01-01

    Since plasma lipoproteins contain both protein and phospholipid components, either may be involved in processes such as atherosclerosis. In this study the identification of plasma lipoprotein-associated phospholipids, which is essential for understanding these processes at the molecular level, are

  2. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction

    DEFF Research Database (Denmark)

    Kamstrup, Pia R; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2013-01-01

    The study tested whether extreme lipoprotein(a) levels and/or corresponding LPA risk genotypes improve myocardial infarction (MI) and coronary heart disease (CHD) risk prediction beyond conventional risk factors.......The study tested whether extreme lipoprotein(a) levels and/or corresponding LPA risk genotypes improve myocardial infarction (MI) and coronary heart disease (CHD) risk prediction beyond conventional risk factors....

  3. Mendelian Disorders of High-Density Lipoprotein Metabolism

    NARCIS (Netherlands)

    Oldoni, Federico; Sinke, Richard J.; Kuivenhoven, Jan Albert

    2014-01-01

    High-density lipoproteins (HDLs) are a highly heterogeneous and dynamic group of the smallest and densest lipoproteins present in the circulation. This review provides the current molecular insight into HDL metabolism led by articles describing mutations in genes that have a large affect on HDL chol

  4. A clustering analysis of lipoprotein diameters in the metabolic syndrome

    Science.gov (United States)

    The presence of smaller low-density lipoproteins (LDL) has been associated with atherosclerosis risk, and the insulin resistance (IR) underlying the metabolic syndrome (MetS). In addition, some research has supported the association of very low-, low- and high-density lipoprotein (VLDL HDL) particle...

  5. Serum lipoproteins attenuate macrophage activation and Toll-Like Receptor stimulation by bacterial lipoproteins

    Directory of Open Access Journals (Sweden)

    James Richard W

    2010-09-01

    Full Text Available Abstract Background Chlamydia trachomatis was previously shown to express a lipoprotein, the macrophage infectivity potentiator (Mip, exposed at the bacterial surface, and able to stimulate human primary monocytes/macrophages through Toll Like Receptor (TLR2/TLR1/TLR6, and CD14. In PMA-differentiated THP-1 cells the proinflammatory activity of Mip was significantly higher in the absence than in the presence of serum. The present study aims to investigate the ability of different serum factors to attenuate Mip proinflammatory activity in PMA-differentiated THP-1 cells and in primary human differentiated macrophages. The study was also extend to another lipoprotein, the Borrelia burgdorferi outer surface protein (OspA. The proinflammatory activity was studied through Tumor Necrosis Factor alpha (TNF-α and Interleukin (IL-8 release. Finally, TLR1/2 human embryonic kidney-293 (HEK-293 transfected cells were used to test the ability of the serum factors to inhibit Mip and OspA proinflammatory activity. Results In the absence of any serum and in the presence of 10% delipidated FBS, production of Mip-induced TNF-α and IL-8 in PMA-differentiated THP-1 cells were similar whereas they were significantly decreased in the presence of 10% FBS suggesting an inhibiting role of lipids present in FBS. In the presence of 10% human serum, the concentrations of TNF-α and IL-8 were 2 to 5 times lower than in the presence of 10% FBS suggesting the presence of more potent inhibitor(s in human serum than in FBS. Similar results were obtained in primary human differentiated macrophages. Different lipid components of human serum were then tested (total lipoproteins, HDL, LDL, VLDL, triglyceride emulsion, apolipoprotein (apoA-I, B, E2, and E3. The most efficient inhibitors were LDL, VLDL, and apoB that reduced the mean concentration of TNF-α release in Mip-induced macrophages to 24, 20, and 2%, respectively (p Conclusions These results demonstrated the ability of

  6. Prediction of lipoprotein signal peptides in Gram-negative bacteria

    DEFF Research Database (Denmark)

    Juncker, Agnieszka; Willenbrock, Hanni; Von Heijne, G.

    2003-01-01

    A method to predict lipoprotein signal peptides in Gram-negative Eubacteria, LipoP, has been developed. The hidden Markov model (HMM) was able to distinguish between lipoproteins (SPaseII-cleaved proteins), SPaseI-cleaved proteins, cytoplasmic proteins, and transmembrane proteins. This predictor...... was able to predict 96.8% of the lipoproteins correctly with only 0.3% false positives in a set of SPaseI-cleaved, cytoplasmic, and transmembrane proteins. The results obtained were significantly better than those of previously developed methods. Even though Gram-positive lipoprotein signal peptides differ...... from Gram-negatives, the HMM was able to identify 92.9% of the lipoproteins included in a Gram-positive test set. A genome search was carried out for 12 Gram-negative genomes and one Gram-positive genome. The results for Escherichia coli K12 were compared with new experimental data, and the predictions...

  7. Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.

    Science.gov (United States)

    Millán, Jesús; Pintó, Xavier; Muñoz, Anna; Zúñiga, Manuel; Rubiés-Prat, Joan; Pallardo, Luis Felipe; Masana, Luis; Mangas, Alipio; Hernández-Mijares, Antonio; González-Santos, Pedro; Ascaso, Juan F; Pedro-Botet, Juan

    2009-01-01

    Low-density lipoprotein (LDL) cholesterol concentration has been the prime index of cardiovascular disease risk and the main target for therapy. However, several lipoprotein ratios or "atherogenic indices" have been defined in an attempt to optimize the predictive capacity of the lipid profile. In this review, we summarize their pathophysiological aspects, and highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy. Total/high-density lipoprotein (HDL) cholesterol and LDL/HDL cholesterol ratios are risk indicators with greater predictive value than isolated parameters used independently, particularly LDL. Future recommendations regarding the diagnosis and treatment of dyslipidemia, including instruments for calculating cardiovascular risk or action guidelines, should include the lipoprotein ratios with greater predictive power which, in view of the evidence-based results, are none other than those which include HDL cholesterol.

  8. Modulation of low-density lipoprotein-induced inhibition of intercellular communication by antioxidants and high-density lipoproteins

    NARCIS (Netherlands)

    Zwijsen, R M; de Haan, L. H. J.; Kuivenhoven, J A; Nusselder, I C

    1991-01-01

    In order to study the capacity of antioxidants and high-density lipoproteins (HDL) to modulate the effects of low-density lipoprotein (LDL) on intercellular communication, arterial smooth muscle cells and a dye transfer method were used. LDL, in contrast to HDL, inhibited the communication between a

  9. Modulation of low-density lipoprotein-induced inhibition of intercellular communication by antioxidants and high-density lipoproteins

    NARCIS (Netherlands)

    Zwijsen, R M; de Haan, L. H. J.; Kuivenhoven, J A; Nusselder, I C

    In order to study the capacity of antioxidants and high-density lipoproteins (HDL) to modulate the effects of low-density lipoprotein (LDL) on intercellular communication, arterial smooth muscle cells and a dye transfer method were used. LDL, in contrast to HDL, inhibited the communication between

  10. Softness of atherogenic lipoproteins: a comparison of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) using elastic incoherent neutron scattering (EINS).

    Science.gov (United States)

    Mikl, Christian; Peters, Judith; Trapp, Marcus; Kornmueller, Karin; Schneider, Wolfgang J; Prassl, Ruth

    2011-08-31

    Apolipoprotein B100 (apoB100)-containing plasma lipoproteins (LDL and VLDL) supply tissues and cells with cholesterol and fat. During lipolytic conversion from VLDL to LDL the size and chemical composition of the particles change, but the apoB100 molecule remains bound to the lipids and regulates the receptor mediated uptake. The molecular physical parameters which control lipoprotein remodeling and enable particle stabilization by apoB100 are largely unknown. Here, we have compared the molecular dynamics and elasticities of VLDL and LDL derived by elastic neutron scattering temperature scans. We have determined thermal motions, dynamical transitions, and molecular fluctuations, which reflect the temperature-dependent motional coupling between lipid and protein. Our results revealed that lipoprotein particles are extremely soft and flexible. We found substantial differences in the molecular resiliences of lipoproteins, especially at higher temperatures. These discrepancies not only can be explained in terms of lipid composition and mobility but also suggest that apoB100 displays different dynamics dependent on the lipoprotein it is bound to. Hence, we suppose that the inherent conformational flexibility of apoB100 permits particle stabilization upon lipid exchange, whereas the dynamic coupling between protein and lipids might be a key determinant for lipoprotein conversion and atherogenicity.

  11. Nanotechnology for Synthetic High Density Lipoproteins

    Science.gov (United States)

    Luthi, Andrea J.; Patel, Pinal C.; Ko, Caroline H.; Mutharasan, R. Kannan; Mirkin, Chad A.; Thaxton, C. Shad

    2014-01-01

    Atherosclerosis is the disease mechanism responsible for coronary heart disease (CHD), the leading cause of death worldwide. One strategy to combat atherosclerosis is to increase the amount of circulating high density lipoproteins (HDL), which transport cholesterol from peripheral tissues to the liver for excretion. The process, known as reverse cholesterol transport, is thought to be one of the main reasons for the significant inverse correlation observed between HDL blood levels and the development of CHD. This article highlights the most common strategies for treating atherosclerosis using HDL. We further detail potential treatment opportunities that utilize nanotechnology to increase the amount of HDL in circulation. The synthesis of biomimetic HDL nanostructures that replicate the chemical and physical properties of natural HDL provides novel materials for investigating the structure-function relationships of HDL and for potential new therapeutics to combat CHD. PMID:21087901

  12. Interfacial Tension and Surface Pressure of High Density Lipoprotein, Low Density Lipoprotein, and Related Lipid Droplets

    DEFF Research Database (Denmark)

    Ollila, O. H. S.; Lamberg, A.; Lehtivaara, M.

    2012-01-01

    Lipid droplets play a central role in energy storage and metabolism on a cellular scale. Their core is comprised of hydrophobic lipids covered by a surface region consisting of amphiphilic lipids and proteins. For example, high and low density lipoproteins (HDL and LDL, respectively) are essentia...... of interfacial tension becomes significant for particles with a radius of similar to 5 nm, when the area per molecule in the surface region is...

  13. Transcriptomic Analysis of THP-1 Macrophages Exposed to Lipoprotein Hydrolysis Products Generated by Lipoprotein Lipase.

    Science.gov (United States)

    Thyagarajan, Narmadaa; Marshall, Jenika D; Pickett, Arthur T; Schumacher, Clemens; Yang, Yanbo; Christian, Sherri L; Brown, Robert J

    2017-03-01

    Macrophage lipoprotein lipase (LPL) induces lipid accumulation and promotes atherosclerosis. However, the effects of lipoprotein hydrolysis products generated by LPL on macrophage-derived foam cell formation are not clearly understood. Thus, we analyzed the transcriptomic response to hydrolysis products via microarray analyses on RNA isolated from human THP-1 macrophages incubated with total lipoprotein hydrolysis products generated by LPL. The expression of 183 transcripts was significantly upregulated and 133 transcripts were significantly downregulated. Bioinformatics analyses revealed that there was a significant over-representation of genes involved in cell cycling, stress response, type I interferon signaling, cellular metal ion homeostasis, sterol metabolism, and nuclease activity. Interestingly, transcripts for 63 small nucleolar RNA were significantly upregulated. We verified the microarray data by quantitative real-time PCR and found that the expression of SNORA56, as well as the expression of genes associated with the cell cycle (PCNA and DKC1 variant 3), stress response (ATF3), type I interferon signaling (IFITM1), and lipid metabolism (CD36 and PLIN2) were significantly affected by LPL hydrolysis products. To determine if the free fatty acid (FFA) component of total lipoprotein hydrolysis products is sufficient to alter the expression of these genes, THP-1 macrophages were also incubated with the total FFA or individual classes of the FFA component. The gene regulation by the FFA component did not mimic that of the hydrolysis products, suggesting that the regulation of gene expression in THP-1 macrophages depends on the specific combination and concentration of lipid species present in the hydrolysis products, and not solely on FFA.

  14. Leukocyte activation by triglyceride-rich lipoproteins.

    Science.gov (United States)

    Alipour, Arash; van Oostrom, Antonie J H H M; Izraeljan, Alisa; Verseyden, Caroline; Collins, Jennifer M; Frayn, Keith N; Plokker, Thijs W M; Elte, Jan Willem F; Castro Cabezas, Manuel

    2008-04-01

    Postprandial lipemia has been linked to atherosclerosis and inflammation. Because leukocyte activation is obligatory for atherogenesis, leukocyte activation by triglyceride-rich lipoproteins (TRLs) was investigated. The expression of CD11b and CD66b after incubation with glucose and native and artificial TRLs (NTRL and ATRL) in vivo and in vitro was evaluated by flowcytometry. Oral fat loading tests showed an increased expression of CD11b on monocytes and neutrophils and CD66b on neutrophils. In 11 volunteers, postprandial leukocytes became enriched with meal-derived fatty acids ([1-(13)C]16:0) suggesting uptake of exogenous fat. ApoB binding on leukocytes measured by flowcytometry in 65 subjects was highest on neutrophils and monocytes suggesting adherence of apoB-containing lipoproteins. Physiological concentrations of TRLs showed 62% increased neutrophil CD11b and a dose-dependent increased monocyte CD11b up to 84% in vitro. Incubations with lipid emulsions in the hypertriglyceridemic range showed a 5-fold increased monocyte CD11b expression, which was higher than the positive control (fMLP), and a dose-dependent 2- to 3-fold increased neutrophil CD11b and CD66b. The oxidative scavenger DMTU decreased the neutrophil CD66b expression by 36%. Acute hypertriglyceridemia is a leukocyte activator most likely by direct interaction between TRLs and leukocytes and uptake of fatty acids. TG-mediated leukocyte activation is an alternative proinflammatory and proatherogenic mechanism of hypertriglyceridemia in part associated to the generation of oxidative stress.

  15. Specificity of Lipoprotein Chaperones for the Characteristic Lipidated Structural Motifs of their Cognate Lipoproteins.

    Science.gov (United States)

    Mejuch, Tom; van Hattum, Hilde; Triola, Gemma; Jaiswal, Mamta; Waldmann, Herbert

    2015-11-01

    Lipoprotein-binding chaperones mediate intracellular transport of lipidated proteins and determine their proper localisation and functioning. Understanding of the exact structural parameters that determine recognition and transport by different chaperones is of major interest. We have synthesised several lipid-modified peptides, representative of different lipoprotein classes, and have investigated their binding to the relevant chaperones PDEδ, UNC119a, UNC119b, and galectins-1 and -3. Our results demonstrate that PDEδ recognises S-isoprenylated C-terminal peptidic structures but not N-myristoylated peptides. In contrast, UNC119 proteins bind only mono-N-myristoylated, but do not recognise doubly lipidated and S-isoprenylated peptides at the C terminus. For galectins-1 and -3, neither binding to N-acylated, nor to C-terminally prenylated peptides could be determined. These results shed light on the specificity of the chaperone-mediated cellular lipoprotein transport systems. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Identification and characterization of estrogen receptor-related receptor alpha and gamma in human glioma and astrocytoma cells.

    Science.gov (United States)

    Gandhari, Mukesh K; Frazier, Chester R; Hartenstein, Julia S; Cloix, Jean-Francois; Bernier, Michel; Wainer, Irving W

    2010-02-05

    The purpose of this study was to examine expression and function of estrogen receptor-related receptors (ERRs) in human glioma and astrocytoma cell lines. These estrogen receptor-negative cell lines expressed ERRalpha and ERRgamma proteins to varying degree in a cell context dependent manner, with U87MG glioma cells expressing both orphan nuclear receptors. Cell proliferation assays were performed in the presence of ERR isoform-specific agonists and antagonists, and the calculated EC(50) and IC(50) values were consistent with previous reported values determined in other types of cancer cell lines. Induction of luciferase expression under the control of ERR isoform-specific promoters was also observed in these cells. These results indicate that ERRalpha and ERRgamma are differentially expressed in these tumor cell lines and likely contribute to agonist-dependent ERR transcriptional activity.

  17. An efficient depyrogenation method for recombinant bacterial outer membrane lipoproteins.

    Science.gov (United States)

    Basto, Afonso P; Morais, Joana; Marcelino, Eduardo; Leitão, Alexandre; Santos, Dulce M

    2014-06-01

    Bacterial outer membrane lipoproteins are anchored in the outer membrane lipid layer in close association with lipopolysaccharides (LPS) and with other hydrophobic membrane proteins, making their purification technically challenging. We have previously shown that a thorough delipidation of outer membrane preparations from the Escherichia coli expression host is an important step to eliminate contaminant proteins when purifying recombinant antigens expressed in fusion with the Pseudomonas aeruginosa OprI lipoprotein. Here we report the cloning and expression of three antigens in fusion with OprI (ovalbumin, eGFP and BbPDI) and our efforts to deal with the variable LPS contamination levels observed in different batches of purified lipoproteins. The use of polymyxin B columns or endotoxin removal polycationic magnetic beads for depyrogenation of purified lipoproteins resulted in high protein losses and the use of Triton X-114 or sodium deoxycholate during the course of affinity chromatography showed to be ineffective to reduce LPS contamination. Instead, performing a hot phenol/water LPS extraction from outer membrane preparations prior to metal affinity chromatography allowed the purification of the recombinant fusion lipoproteins with LPS contents below 0.02EU/μg of protein. The purified recombinant lipoproteins retain their capacity to stimulate bone marrow-derived dendritic cells allowing for the study of their immunomodulatory properties through TLR2/1. This is a simple and easy to scale up method that can also be considered for the purification of other outer membrane lipoproteins.

  18. The Acylation State of Surface Lipoproteins of Mollicute Acholeplasma laidlawii*

    Science.gov (United States)

    Serebryakova, Marina V.; Demina, Irina A.; Galyamina, Maria A.; Kondratov, Ilya G.; Ladygina, Valentina G.; Govorun, Vadim M.

    2011-01-01

    Acylation of the N-terminal Cys residue is an essential, ubiquitous, and uniquely bacterial posttranslational modification that allows anchoring of proteins to the lipid membrane. In Gram-negative bacteria, acylation proceeds through three sequential steps requiring lipoprotein diacylglyceryltransferase, lipoprotein signal peptidase, and finally lipoprotein N-acyltransferase. The apparent lack of genes coding for recognizable homologs of lipoprotein N-acyltransferase in Gram-positive bacteria and Mollicutes suggests that the final step of the protein acylation process may be absent in these organisms. In this work, we monitored the acylation state of eight major lipoproteins of the mollicute Acholeplasma laidlawii using a combination of standard two-dimensional gel electrophoresis protein separation, blotting to nitrocellulose membranes, and MALDI-MS identification of modified N-terminal tryptic peptides. We show that for each A. laidlawii lipoprotein studied a third fatty acid in an amide linkage on the N-terminal Cys residue is present, whereas diacylated species were not detected. The result thus proves that A. laidlawii encodes a lipoprotein N-acyltransferase activity. We hypothesize that N-acyltransferases encoded by genes non-homologous to N-acyltransferases of Gram-negative bacteria are also present in other mollicutes and Gram-positive bacteria. PMID:21540185

  19. Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise

    Directory of Open Access Journals (Sweden)

    Harrison Michael

    2012-07-01

    Full Text Available Abstract Background Many of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS, it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects. Methods Using a randomized cross-over design, very low density lipoprotein (VLDL responses were evaluated in eight men on the morning after i an inactive control trial (CON, ii exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF, and iii after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL. Results The intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70–120 nm (large particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43–55 nm (medium particle range. VLDL-TG in smaller particles (29–43 nm was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state. Conclusions These findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in

  20. Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise

    LENUS (Irish Health Repository)

    Harrison, Michael

    2012-06-06

    AbstractBackgroundMany of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS), it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects.MethodsUsing a randomized cross-over design, very low density lipoprotein (VLDL) responses were evaluated in eight men on the morning after i) an inactive control trial (CON), ii) exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF), and iii) after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL).ResultsThe intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG) determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70–120 nm (large) particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43–55 nm (medium) particle range. VLDL-TG in smaller particles (29–43 nm) was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL) activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state.ConclusionsThese findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in LPL activity.

  1. The influence of lipoprotein(a) on fibrinolytic activity

    OpenAIRE

    Rahajuningsih D. Setiabudy; Marzuki Suryaatmadja; Fifi Henrika

    2004-01-01

    Lipoprotein(a) is a plasma lipoprotein whose structure and composition are similar with low density lipoprotein (LDL) with an addition of apo(a) that is bound to apo B100. The structure of apo(a) is similar with plasminogen, a proenzym in fibrinolytic system. Due to this similarity, it is assumed that Lp(a) can inhibit plasminogen activity and decreases fibrinolytic activity. The purpose of this study is to prove that addition of Lp(a) to normal plasma can inhibit fibrinolytic activity. Four ...

  2. Hepatitis C virus relies on lipoproteins for its life cycle.

    Science.gov (United States)

    Grassi, Germana; Di Caprio, Giorgia; Fimia, Gian Maria; Ippolito, Giuseppe; Tripodi, Marco; Alonzi, Tonino

    2016-02-14

    Hepatitis C virus (HCV) infects over 150 million people worldwide. In most cases, HCV infection becomes chronic causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. Viral persistence and pathogenesis are due to the ability of HCV to deregulate specific host processes, mainly lipid metabolism and innate immunity. In particular, HCV exploits the lipoprotein machineries for almost all steps of its life cycle. The aim of this review is to summarize current knowledge concerning the interplay between HCV and lipoprotein metabolism. We discuss the role played by members of lipoproteins in HCV entry, replication and virion production.

  3. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk.

    Science.gov (United States)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-04-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease. Evidence for concordance or discordance with cardiovascular disease risk has come from Mendelian randomization studies, whereas indirect evidence also has emerged from genome-wide and candidate gene association studies. The major limitations of studies of genetic variation and concordance or discordance with cardiovascular disease are pleiotropic effects of the variants studied, and/or lack of sufficient statistical power of the majority of studies to firmly demonstrate a positive association, or even more difficult, to exclude an association. New and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), and triglyceride-rich lipoproteins are concordant with both the magnitude and direction of the expected risk of cardiovascular disease, whereas this is unclear for HDL cholesterol. The data are compatible with cardiovascular disease causality for the three former lipoprotein classes, but not for HDL cholesterol.

  4. 21 CFR 866.5590 - Lipoprotein X immunolog-ical test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Lipoprotein X immunolog-ical test system. 866.5590... Lipoprotein X immunolog-ical test system. (a) Identification. A lipoprotein X immunological test system is a device that consists of the reagents used to measure by immunochemical techniques lipoprotein X (a high...

  5. Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins.

    Science.gov (United States)

    Beltz, W F; Kesäniemi, Y A; Howard, B V; Grundy, S M

    1985-01-01

    To quantify more precisely the metabolism of apolipoprotein B (apo B) in human beings, an integrated model was developed for the analysis of the isotope kinetics of apo B in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL). The experimental basis for model development was a series of 30 triple-isotope studies in which patients received autologous 131I-VLDL, 125I-IDL, and [3H]glycerol as a precursor of VLDL triglycerides. The currently proposed model contains the following components: (a) a VLDL delipidation cascade that has a variable number of subcompartments, (b) a slowly catabolized pool of VLDL, (c) an IDL compartment consisting of two closely connected subcompartments, one of which is outside the immediate circulation, and (d) a two-compartment subsystem for LDL. Because mass data indicate that not all VLDL were converted to LDL, the model allows for irreversible removal of apo B from VLDL (or IDL) subsystems. It accounts for apparent "direct" input of LDL by postulating an early, rapidly metabolized compartment of VLDL that is converted directly to IDL. The model appears to be consistent with specific activity curves from the current triple-isotope studies and with present concepts of lipoprotein physiology; it also can be used to quantify pathways of lipoprotein apo B transport in normal and abnormal states. PMID:4031063

  6. Distribution of perfluorooctanesulfonate and perfluorooctanoate into human plasma lipoprotein fractions

    NARCIS (Netherlands)

    Butenhoff, J.L.; Pieterman, E.; Ehresman, D.J.; Gorman, G.S.; Olsen, G.W.; Chang, S.C.; Princen, H.M.

    2012-01-01

    Some cross-sectional epidemiological studies have reported positive associations of serum concentrations of non-high density lipoprotein cholesterol with serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA). However, the strength of the reported associations is inconsistent for

  7. Mycoplasmal lipoprotein p37 binds human protein HER2.

    Science.gov (United States)

    Wu, Jun; Wu, Lijuan; Fang, Cheng; Nie, Rong; Wang, Jiamou; Wang, Xuan; Liu, Wenbin

    2016-11-01

    Mycoplasmas are a group of microbes that can cause human diseases. The mycoplasmal lipoprotein p37 promotes cancer metastasis, at least in part, by interacting with EGFR. In this study, we show that the p37 lipoprotein binds another member of the EGFR family, HER2, through the HER2 extracellular domain. The binding of p37-HER2 promotes phosphorylation of HER2 and activates the downstream signaling molecule Erk1/2. Because the HER2 signaling pathway contributes to breast tumor metastasis, our results imply that the mycoplasmal lipoprotein p37 may also be involved in breast cancer metastasis. This study contributes to our understanding of mycoplasmal lipoprotein p37 function and its potential involvement in tumorigenesis. Copyright © 2016. Published by Elsevier GmbH.

  8. [Basic mechanisms: structure, function and metabolism of plasma lipoproteins].

    Science.gov (United States)

    Errico, Teresa L; Chen, Xiangyu; Martin Campos, Jesús M; Julve, Josep; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

    2013-01-01

    The aim of this work is to present basic information on the lipoprotein physiology. The protein fraction of lipoproteins consists of several apolipoproteins and enzymes whose functions are lipid transport and metabolism. Classification of lipoproteins is based on their density. Chylomicrons, VLDL, IDL, LDL and HDL can be isolated by ultracentrifugation. Both chylomicrons- and VLDL-triglycerides are transported from the intestine and liver, respectively, to the peripheral tissues. The metabolism of VLDL originates IDL and LDL. LDL is the main transporter of cholesterol to extrahepatic tissues. HDL mobilizes cholesterol from peripheral tissues to the liver where it is secreted to bile as free cholesterol or bile salts, a process termed reverse cholesterol transport. Lipoprotein metabolism can be regulated by nuclear receptors that regulate the expression of genes involved in triglyceride and apolipoprotein metabolism. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

  9. Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study.

    Science.gov (United States)

    Rao, Fangwen; Schork, Andrew J; Maihofer, Adam X; Nievergelt, Caroline M; Marcovina, Santica M; Miller, Elizabeth R; Witztum, Joseph L; O'Connor, Daniel T; Tsimikas, Sotirios

    2015-07-01

    To determine whether biomarkers of oxidized lipoproteins are genetically determined. Lipoprotein(a) (Lp[a]) is a heritable risk factor and carrier of oxidized phospholipids (OxPL). We measured oxidized phospholipids on apolipoprotein B-containing lipoproteins (OxPL-apoB), Lp(a), IgG, and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes in 386 monozygotic and dizygotic twins to estimate trait heritability (h(2)) and determine specific genetic effects among traits. A genome-wide linkage study followed by genetic association was performed. The h(2) (scale: 0-1) for Lp(a) was 0.91±0.01 and for OxPL-apoB 0.87±0.02, which were higher than physiological, inflammatory, or lipid traits. h(2) of IgM malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes were 0.69±0.04, 0.67±0.05, and 0.80±0.03, respectively, and for IgG malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes 0.62±0.05, 0.52±0.06, and 0.53±0.06, respectively. There was an inverse correlation between the major apo(a) isoform and OxPL-apoB (R=-0.49; Plipoprotein and copper oxidized low-density lipoprotein, and apoB-immune complexes. Sib-pair genetic linkage of the Lp(a) trait revealed that single nucleotide polymorphism rs10455872 was significantly associated with OxPL-apoB after adjusting for Lp(a). OxPL-apoB and other biomarkers of oxidized lipoproteins are highly heritable cardiovascular risk factors that suggest novel genetic origins of atherothrombosis. © 2015 American Heart Association, Inc.

  10. Optimized Negative-Staining Electron Microscopy for Lipoprotein Studies

    Science.gov (United States)

    Zhang, Lei; Tong, Huimin; Garewal, Mark; Ren, Gang

    2012-01-01

    Background Negative-staining (NS), a rapid, simple and conventional technique of electron microscopy (EM), has been commonly used to initially study the morphology and structure of proteins for half a century. Certain NS protocols however can cause artifacts, especially for structurally flexible or lipid-related proteins, such as lipoproteins. Lipoproteins were often observed in the form of rouleau as lipoprotein particles appeared to be stacked together by conventional NS protocols. The flexible components of lipoproteins, i.e. lipids and amphipathic apolipoproteins, resulted in the lipoprotein structure being sensitive to the NS sample preparation parameters, such as operational procedures, salt concentrations, and the staining reagents. Scope of review The most popular NS protocols that have been used to examine lipoprotein morphology and structure were reviewed. Major conclusions The comparisons show that an optimized NS (OpNS) protocol can eliminate the rouleau artifacts of lipoproteins, and that the lipoproteins are similar in size and shape as statistically measured from two EM methods, OpNS and cryo-electron microscopy (cryo-EM). OpNS is a high-throughput, high-contrast and high-resolution (near 1 nm, but rarely better than 1 nm) method which has been used to discover the mechanics of a small protein, 53 kDa cholesterol ester transfer protein (CETP), and the structure of an individual particle of a single protein by individual-particle electron tomography (IPET), i.e. a 14 Å-resolution IgG antibody three-dimensional map. General significance It is suggested that OpNS can be used as a general protocol to study the structure of proteins, especially highly dynamic proteins with equilibrium-fluctuating structures. PMID:23032862

  11. Lipoprotein(a) as a cardiovascular risk factor: current status

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Chapman, M John; Ray, Kausik

    2010-01-01

    The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.......The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies....

  12. Nanobiotechnology applications of reconstituted high density lipoprotein.

    Science.gov (United States)

    Ryan, Robert O

    2010-12-01

    High-density lipoprotein (HDL) plays a fundamental role in the Reverse Cholesterol Transport pathway. Prior to maturation, nascent HDL exist as disk-shaped phospholipid bilayers whose perimeter is stabilized by amphipathic apolipoproteins. Methods have been developed to generate reconstituted (rHDL) in vitro and these particles have been used in a variety of novel ways. To differentiate between physiological HDL particles and non-natural rHDL that have been engineered to possess additional components/functions, the term nanodisk (ND) is used. In this review, various applications of ND technology are described, such as their use as miniature membranes for solubilization and characterization of integral membrane proteins in a native like conformation. In other work, ND harboring hydrophobic biomolecules/drugs have been generated and used as transport/delivery vehicles. In vitro and in vivo studies show that drug loaded ND are stable and possess potent biological activity. A third application of ND is their use as a platform for incorporation of amphiphilic chelators of contrast agents, such as gadolinium, used in magnetic resonance imaging. Thus, it is demonstrated that the basic building block of plasma HDL can be repurposed for alternate functions.

  13. Neisserial surface lipoproteins: structure, function and biogenesis.

    Science.gov (United States)

    Hooda, Yogesh; Shin, Hyejin E; Bateman, Thomas J; Moraes, Trevor F

    2017-03-01

    The surface of many Gram-negative bacteria contains lipidated protein molecules referred to as surface lipoproteins or SLPs. SLPs play critical roles in host immune evasion, nutrient acquisition and regulation of the bacterial stress response. The focus of this review is on the SLPs present in Neisseria, a genus of bacteria that colonise the mucosal surfaces of animals. Neisseria contains two pathogens of medical interest, namely Neisseria meningitidis and N. gonorrhoeae. Several SLPs have been identified in Neisseria and their study has elucidated key strategies used by these pathogens to survive inside the human body. Herein, we focus on the identification, structure and function of SLPs that have been identified in Neisseria. We also survey the translocation pathways used by these SLPs to reach the cell surface. Specifically, we elaborate on the strategies used by neisserial SLPs to translocate across the outer membrane with an emphasis on Slam, a novel outer membrane protein that has been implicated in SLP biogenesis. Taken together, the study of SLPs in Neisseria illustrates the widespread roles played by this family of proteins in Gram-negative bacteria. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. High-density lipoprotein cholesterol: How High

    Directory of Open Access Journals (Sweden)

    G Rajagopal

    2012-01-01

    Full Text Available The high-density lipoprotein cholesterol (HDL-C is considered anti-atherogenic good cholesterol. It is involved in reverse transport of lipids. Epidemiological studies have found inverse relationship of HDL-C and coronary heart disease (CHD risk. When grouped according to HDL-C, subjects having HDL-C more than 60 mg/dL had lesser risk of CHD than those having HDL-C of 40-60 mg/dL, who in turn had lesser risk than those who had HDL-C less than 40 mg/dL. No upper limit for beneficial effect of HDL-C on CHD risk has been identified. The goals of treating patients with low HDL-C have not been firmly established. Though many drugs are known to improve HDL-C concentration, statins are proven to improve CHD risk and mortality. Cholesteryl ester transfer protein (CETP is involved in metabolism of HDL-C and its inhibitors are actively being screened for clinical utility. However, final answer is still awaited on CETP-inhibitors.

  15. Lipoprotein(a in Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Michele Malaguarnera

    2013-01-01

    Full Text Available Lipoprotein(a (Lp(a is an LDL-like molecule consisting of an apolipoprotein B-100 (apo(B-100 particle attached by a disulphide bridge to apo(a. Many observations have pointed out that Lp(a levels may be a risk factor for cardiovascular diseases. Lp(a inhibits the activation of transforming growth factor (TGF and contributes to the growth of arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells and the migration of smooth muscle cells to endothelial cells. Moreover Lp(a inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of fibrin-dependent tissue-type plasminogen activator. Lp(a may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques. Elevated serum Lp(a is an independent predictor of coronary artery disease and myocardial infarction. Furthermore, Lp(a levels should be a marker of restenosis after percutaneous transluminal coronary angioplasty, saphenous vein bypass graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation. Finally, the possibility that Lp(a may be a risk factor for ischemic stroke has been assessed in several studies. Recent findings suggest that Lp(a-lowering therapy might be beneficial in patients with high Lp(a levels. A future therapeutic approach could include apheresis in high-risk patients in order to reduce major coronary events.

  16. The use of transgenic animals to study lipoprotein metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Rubin, E.M.; Plump, A.S.

    1993-12-01

    The application of transgenic technology to lipoprotein metabolism and atherosclerosis was first reported in 1988. Today, a large percentage of the genes involved in lipoprotein metabolism have been overexpressed in mice, and a substantial number of these same genes have been disrupted by homologous recombination in embryonic stem (ES) cells. The utility of animal models of lipoprotein metabolism and atherosclerosis is far-reaching given the complex nature of these systems. There are at least 17 known genes directly involved in lipoprotein metabolism and likely dozens more may be involved. This massive network of interacting factors has necessitated the development of in vivo systems which can be subject to genetic manipulation. The power of overexpression is obvious: elucidating function in a relatively controlled genetic environment in which the whole system is present and operational. The not-so-obvious problem with transgenics is ``background,`` or for purposes of the current discussion, the mouse`s own lipoprotein system. With the advent of gene knockout, we have been given the ability to overcome ``background.`` By recreating the genetic complement of the mouse we can alter a system in essentially any manner desired. As unique tools, and in combination with one another, the overexpression of foreign genes and the targeted disruption or alteration of endogenous genes has already and will continue to offer a wealth of information on the biology of lipoprotein metabolism and its effect on atherosclerosis susceptibility.

  17. Mechanisms and signiifcance of lipoprotein(a) in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jing-Ting Jiang; Chang-Ping Wu; Ning Xu; Xue-Guang Zhang

    2009-01-01

    BACKGROUND: The liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. It has been demonstrated that plasma lipid proifles are changed in liver cancer. DATA SOURCES: A MEDLINE database search was performed to identify relevant articles using the keywords "hepatocellular carcinoma" and "lipoprotein(a)". The search was conducted and research articles were reviewed from 1960 to 2008. RESULTS: Production and homeostasis of lipids, apo-lipoproteins and lipoproteins depend on the integrity of hepatocellular functions, which ensures normal lipid and lipoprotein metabolismin vivo. When hepatocellular injury or liver cancer occurs these processes can be impaired. It has been suggested that plasma levels of apolipoprotein(a) (apo(a)) and/or lipoprotein(a) (Lp(a)) may be considered as sensitive markers of hepatic impairment. CONCLUSIONS: Plasma levels of apo(a) and Lp(a) display signiifcant correlations with hepatic status. Most studies demonstrated that the plasma levels of apo(a) and Lp(a) can be considered as an additional clinical index of liver function.

  18. Modulation of lipoprotein receptor functions by intracellular adaptor proteins.

    Science.gov (United States)

    Stolt, Peggy C; Bock, Hans H

    2006-10-01

    Members of the low density lipoprotein (LDL) receptor gene family are critically involved in a wide range of physiological processes including lipid and vitamin homeostasis, cellular migration, neurodevelopment, and synaptic plasticity, to name a few. Lipoprotein receptors exert these diverse biological functions by acting as cellular uptake receptors or by inducing intracellular signaling cascades. It was discovered that a short sequence in the intracellular region of all lipoprotein receptors, Asn-Pro-X-Tyr (NPXY) is important for mediating either endocytosis or signal transduction events, and that this motif serves as a binding site for phosphotyrosine-binding (PTB) domain containing scaffold proteins. These molecular adaptors connect the transmembrane receptors with the endocytosis machinery and regulate cellular trafficking, or function as assembly sites for dynamic multi-protein signaling complexes. Whereas the LDL receptor represents the archetype of an endocytic lipoprotein receptor, the structurally closely related apolipoprotein E receptor 2 (apoER2) and very low density lipoprotein (VLDL) receptor activate a kinase-dependent intracellular signaling cascade after binding to the neuronal signaling molecule Reelin. This review focuses on two related PTB domain containing adaptor proteins that mediate these divergent lipoprotein receptor responses, ARH (autosomal recessive hypercholesterolemia protein) and Dab1 (disabled-1), and discusses the structural and molecular basis of this different behaviour.

  19. Transvascular lipoprotein transport in patients with chronic renal disease

    DEFF Research Database (Denmark)

    Jensen, Trine Krogsgaard; Nordestgaard, Børge Grønne; Feldt-Rasmussen, Bo

    2004-01-01

    BACKGROUND: While increased plasma cholesterol is a well-established cardiovascular risk factor in the general population, this is not so among patients with chronic renal disease. We hypothesized that the transvascular lipoprotein transport, in addition to the lipoprotein concentration in plasma......: Transvascular LDL transport may be increased in diabetic patients with chronic renal disease, suggesting that lipoprotein flux into the arterial wall is increased. A similar mechanism does not operate in nondiabetic patients with chronic renal disease.......BACKGROUND: While increased plasma cholesterol is a well-established cardiovascular risk factor in the general population, this is not so among patients with chronic renal disease. We hypothesized that the transvascular lipoprotein transport, in addition to the lipoprotein concentration in plasma......, determines the degree of atherosclerosis among patients with chronic renal disease. METHODS: We used an in vivo method for measurement of transvascular transport of low-density lipoprotein (LDL) in 21 patients with chronic renal disease and in 42 healthy control patients. Autologous 131-iodinated LDL...

  20. Dissecting the proteome of lipoproteins: New biomarkers for cardiovascular diseases?

    Directory of Open Access Journals (Sweden)

    Anne von Zychlinski

    2015-06-01

    Full Text Available Proteomics has proven to be a powerful tool for the characterization of lipoproteins and has provided important insights into the biochemistry and pathophysiology of various lipoprotein classes. It has significantly contributed to the way we now see lipoproteins as complex particles not only involved in lipid transport and exchange, but also in processes such as immune response, inflammation and wound healing. Ongoing proteomics research is focussing on the identification of new candidate markers for cardiovascular disease, the leading cause of death worldwide. The ratio between good cholesterol (high density lipoprotein and bad cholesterol (low density lipoprotein is routinely used to estimate an individual’s risk for developing premature coronary heart disease. While statin therapy has proven effects in reducing cardiovascular events, other therapies such as resins, fibrates and niacin have failed to substantially reduce cardiovascular risk. Thus new targets and candidate biomarkers for risk assessment and for the development of alternative drugs and treatments of disease are needed. Here we review the recent findings in lipoprotein proteomics with the main emphasis on studies that differentially displayed various states of diseases and on new targeted, high throughput strategies with the capability to translate discovery findings into the clinical context of large cohort analyzes.

  1. Mycobacterium tuberculosis 19-kDa lipoprotein promotes neutrophil activation.

    Science.gov (United States)

    Neufert, C; Pai, R K; Noss, E H; Berger, M; Boom, W H; Harding, C V

    2001-08-01

    Certain microbial substances, e.g., LPS, can activate neutrophils or prime them to enhance their response to other activating agents, e.g., fMLP. We investigated the role of the Mycobacterium tuberculosis (MTB) 19-kDa lipoprotein in activation of human neutrophils. MTB 19-kDa lipoprotein initiated phenotypic changes characteristic of neutrophil activation, including down-regulation of CD62 ligand (L-selectin) and up-regulation of CD35 (CR1) and CD11b/CD18 (CR3, Mac-1). In addition, exposure of neutrophils to MTB 19-kDa lipoprotein enhanced the subsequent oxidative burst in response to fMLP as assessed by oxidation of dihydrorhodamine 123 (determined by flow cytometry). LPS also produced these effects with similar kinetics, but an oligodeoxynucleotide containing a CpG motif failed to induce any priming or activation response. Although the effects of LPS required the presence of serum, neutrophil activation by MTB 19-kDa lipoprotein occurred independently of serum factors, suggesting the involvement of different receptors and signaling mechanisms for LPS and MTB 19-kDa lipoprotein. Thus, MTB 19-kDa lipoprotein serves as a pathogen-associated molecular pattern that promotes neutrophil priming and activation.

  2. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Gram, Jeppe; Høegh-Andersen, Pernille;

    2005-01-01

    Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts...

  3. SAA is Found on ApoB-Containing Lipoproteins in Obese Diabetic Humans

    OpenAIRE

    Jahangiri, Anisa; Wilson, Patricia G.; Hou, Tianfei; Brown, Aparna; King, Victoria L.; Tannock, Lisa R.

    2013-01-01

    In murine models of obesity/diabetes there is an increase in plasma SAA levels along with redistribution of SAA from high density lipoprotein (HDL) to apo-B containing lipoprotein particles, namely low density lipoprotein (LDL) and very low density lipoprotein (VLDL). The goal of this study was to determine if obesity is associated with similar SAA lipoprotein redistribution in humans. Three groups of obese individuals were recruited from a weight loss clinic: healthy obese (n=14), metabolic ...

  4. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches

    National Research Council Canada - National Science Library

    deGoma, Emil M; deGoma, Rolando L; Rader, Daniel J

    2008-01-01

    A number of therapeutic strategies targeting high-density lipoprotein (HDL) cholesterol and reverse cholesterol transport are being developed to halt the progression of atherosclerosis or even induce regression...

  5. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M.; Brown, Robert J., E-mail: rbrown@mun.ca

    2014-09-05

    Highlights: • Lipoprotein hydrolysis products were produced by lipoprotein lipase. • Hydrolysis products lowers expression of macrophage cholesterol transporters. • Hydrolysis products reduces expression of select nuclear receptors. • Fatty acid products lowers cholesterol transporters and select nuclear receptors. • Fatty acid products reduces cholesterol efflux from macrophages. - Abstract: Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

  6. Pistachio intake increases high density lipoprotein levels and inhibits low-density lipoprotein oxidation in rats.

    Science.gov (United States)

    Aksoy, Nur; Aksoy, Mehmet; Bagci, Cahit; Gergerlioglu, H Serdar; Celik, Hakim; Herken, Emine; Yaman, Abdullah; Tarakcioglu, Mehmet; Soydinc, Serdar; Sari, Ibrahim; Davutoglu, Vedat

    2007-05-01

    There is increasing evidence that nuts have protective effects against coronary artery disease by improving lipid profile and inhibiting lipid oxidation. However, data about pistachio nuts are limited, and to our knowledge, there is no study investigating the effects of pistachio intake on lipid oxidation and serum antioxidant levels. This study, therefore, sought to determine the effects of pistachio intake on serum lipids and determine whether consumption of pistachio would alter serum antioxidant levels. Rats were randomly divided into three groups (n=12 for each): control group fed basic diet for 10 weeks and treated groups fed basic diet plus pistachio which constituted 20% and 40% of daily caloric intake, respectively. Consumption of pistachio as 20% of daily caloric intake increased high-density lipoprotein (HDL) levels and decreased total cholesterol (TC)/HDL ratio, compared with those not taking pistachio. However, TC, low-density lipoprotein (LDL) cholesterol and triglyceride levels were unaffected by pistachio consumption. Consumption of pistachio as 20% of daily caloric intake increased serum paraoxonase activity by 35% and arylesterase activity by 60%, which are known to inhibit LDL cholesterol oxidation, compared with the control group. However, increased antioxidant activity was blunted when pistachio intake was increased to 40% of daily caloric intake. In conclusion, the present results show that consumption of pistachio as 20% of daily caloric intake leads to significant improvement in HDL and TC/HDL ratio and inhibits LDL cholesterol oxidation. These results suggest that pistachio may be beneficial for both prevention and treatment of coronary artery disease.

  7. Single immunoglobulin interleukin-1 receptor-related molecule impairs host defense during pneumonia and sepsis caused by Streptococcus pneumoniae.

    Science.gov (United States)

    Blok, Dana C; van Lieshout, Miriam H P; Hoogendijk, Arie J; Florquin, Sandrine; de Boer, Onno J; Garlanda, Cecilia; Mantovani, Alberto; van't Veer, Cornelis; de Vos, Alex F; van der Poll, Tom

    2014-01-01

    Streptococcus pneumoniae is a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis. Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniae and euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/- mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/- mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/- mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/- alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae.

  8. Smooth muscle LDL receptor-related protein-1 deletion induces aortic insufficiency and promotes vascular cardiomyopathy in mice.

    Directory of Open Access Journals (Sweden)

    Joshua E Basford

    Full Text Available Valvular disease is common in patients with Marfan syndrome and can lead to cardiomyopathy. However, some patients develop cardiomyopathy in the absence of hemodynamically significant valve dysfunction, suggesting alternative mechanisms of disease progression. Disruption of LDL receptor-related protein-1 (Lrp1 in smooth muscle cells has been shown to cause vascular pathologies similar to Marfan syndrome, with activation of smooth muscle cells, vascular dysfunction and aortic aneurysms. This study used echocardiography and blood pressure monitoring in mouse models to determine whether inactivation of Lrp1 in vascular smooth muscle leads to cardiomyopathy, and if so, whether the mechanism is a consequence of valvular disease. Hemodynamic changes during treatment with captopril were also assessed. Dilation of aortic roots was observed in young Lrp1-knockout mice and progressed as they aged, whereas no significant aortic dilation was detected in wild type littermates. Diastolic blood pressure was lower and pulse pressure higher in Lrp1-knockout mice, which was normalized by treatment with captopril. Aortic dilation was followed by development of aortic insufficiency and subsequent dilated cardiomyopathy due to valvular disease. Thus, smooth muscle cell Lrp1 deficiency results in aortic dilation and insufficiency that causes secondary cardiomyopathy that can be improved by captopril. These findings provide novel insights into mechanisms of cardiomyopathy associated with vascular activation and offer a new model of valvular cardiomyopathy.

  9. Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor α (RORα.

    Directory of Open Access Journals (Sweden)

    Christine Crumbley

    Full Text Available The retinoic acid receptor-related orphan receptor α (RORα is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORα display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORα response element (RORE in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression.

  10. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection.

    Science.gov (United States)

    Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio; Carreño, Vicente

    2016-02-01

    Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P hepatitis C. © 2015 Wiley Periodicals, Inc.

  11. The Tat protein of human immunodeficiency virus-1 enhances hepatitis C virus replication through interferon gamma-inducible protein-10

    Directory of Open Access Journals (Sweden)

    Qu Jing

    2012-04-01

    Full Text Available Abstract Background Co-infection with human immunodeficiency virus-1 (HIV-1 and hepatitis C virus (HCV is associated with faster progression of liver disease and an increase in HCV persistence. However, the mechanism by which HIV-1 accelerates the progression of HCV liver disease remains unknown. Results HIV-1/HCV co-infection is associated with increased expression of interferon gamma-induced protein-10 (IP-10 mRNA in peripheral blood mononuclear cells (PBMCs. HCV RNA levels were higher in PBMCs of patients with HIV-1/HCV co-infection than in patients with HCV mono-infection. HIV-1 Tat and IP-10 activated HCV replication in a time-dependent manner, and HIV-1 Tat induced IP-10 production. In addition, the effect of HIV-1 Tat on HCV replication was blocked by anti-IP-10 monoclonal antibody, demonstrating that the effect of HIV-1 Tat on HCV replication depends on IP-10. Taken together, these results suggest that HIV-1 Tat protein activates HCV replication by upregulating IP-10 production. Conclusions HIV-1/HCV co-infection is associated with increased expression of IP-10 mRNA and replication of HCV RNA. Furthermore, both HIV-1 Tat and IP-10 activate HCV replication. HIV-1 Tat activates HCV replication by upregulating IP-10 production. These results expand our understanding of HIV-1 in HCV replication and the mechanism involved in the regulation of HCV replication mediated by HIV-1 during co-infection.

  12. Antitumor efficacy of combination of interferon-gamma-inducible protein 10 gene with gemcitabine, a study in murine model

    Directory of Open Access Journals (Sweden)

    Zhang Zhixuan

    2008-11-01

    Full Text Available Abstract Background Interferon-γ-inducible protein 10 (IP-10 is a potent inhibitor of tumor angiogenesis. It has been reported that the antiangiogenic therapy combined with chemotherapy has synergistic effects. Methods To elucidate the mechanisms of IP-10 gene combined with a chemotherapy agent, we intramuscularly injected pBLAST-IP-10 expression plasmid combined with gemcitabine into tumor-bearing mice. Results The proliferation of endothelial cells was effectively inhibited by IP-10 combined with gemcitabine in vitro. Treatment with pBLAST-IP-10 twice a week for 4 weeks combined with gemcitabine 10 mg/kg (once a week resulted in sustained high level of IP-10 protein in serum, inhibition of tumor growth and prolongation of the survival of tumor-bearing mice. Compared with administration of IP-10 plasmid or gemcitabine alone, the angiogenesis in tumors were apparently inhibited, and the numbers of apoptotic cells and lymphocytes in tumor increased in the combination therapy group. Conclusion Our data indicate that the gene therapy of antiangiogenesis by intramuscular delivery of plasmid DNA encoding IP-10 combined with gemcitabine has synergistic effects on tomor by inhibiting the proliferation of endothelail cells, inducing the apoptosis of tumor cells, and recruiting lymphocytes to tumor in murine models. The present findings provided evidence of antitumor effects of genetherapy combined with chemotherapy.

  13. Cholesterol efflux from THP-1 macrophages is impaired by the fatty acid component from lipoprotein hydrolysis by lipoprotein lipase.

    Science.gov (United States)

    Yang, Yanbo; Thyagarajan, Narmadaa; Coady, Breanne M; Brown, Robert J

    2014-09-05

    Lipoprotein lipase (LPL) is an extracellular lipase that primarily hydrolyzes triglycerides within circulating lipoproteins. Macrophage LPL contributes to atherogenesis, but the mechanisms behind it are poorly understood. We hypothesized that the products of lipoprotein hydrolysis generated by LPL promote atherogenesis by inhibiting the cholesterol efflux ability by macrophages. To test this hypothesis, we treated human THP-1 macrophages with total lipoproteins that were hydrolyzed by LPL and we found significantly reduced transcript levels for the cholesterol transporters ATP binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor BI. These decreases were likely due to significant reductions for the nuclear receptors liver-X-receptor-α, peroxisome proliferator activated receptor (PPAR)-α, and PPAR-γ. We prepared a mixture of free fatty acids (FFA) that represented the ratios of FFA species within lipoprotein hydrolysis products, and we found that the FFA mixture also significantly reduced cholesterol transporters and nuclear receptors. Finally, we tested the efflux of cholesterol from THP-1 macrophages to apolipoprotein A-I, and we found that the treatment of THP-1 macrophages with the FFA mixture significantly attenuated cholesterol efflux. Overall, these data show that the FFA component of lipoprotein hydrolysis products generated by LPL may promote atherogenesis by inhibiting cholesterol efflux, which partially explains the pro-atherogenic role of macrophage LPL.

  14. Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism

    NARCIS (Netherlands)

    Dashty Rahmatabady, Monireh; Motazacker, Mohammad M.; Levels, Johannes; de Vries, Marcel; Mahmoudi, Morteza; Peppelenbosch, Maikel; Rezaee, Farhad

    2014-01-01

    Apart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis fr

  15. Aminoacylation of the N-terminal cysteine is essential for Lol-dependent release of lipoproteins from membranes but does not depend on lipoprotein sorting signals.

    Science.gov (United States)

    Fukuda, Ayumu; Matsuyama, Shin-Ichi; Hara, Takashi; Nakayama, Jiro; Nagasawa, Hiromichi; Tokuda, Hajime

    2002-11-08

    Lipoproteins are present in a wide variety of bacteria and are anchored to membranes through lipids attached to the N-terminal cysteine. The Lol system of Escherichia coli mediates the membrane-specific localization of lipoproteins. Aspartate at position 2 functions as a Lol avoidance signal and causes the retention of lipoproteins in the inner membrane, whereas lipoproteins having residues other than aspartate at position 2 are released from the inner membrane and localized to the outer membrane by the Lol system. Phospholipid:apolipoprotein transacylase, Lnt, catalyzes the last step of lipoprotein modification, converting apolipoprotein into mature lipoprotein. To reveal the importance of this aminoacylation for the Lol-dependent membrane localization, apolipoproteins were prepared by inhibiting lipoprotein maturation. Lnt was also purified and used to convert apolipoprotein into mature lipoprotein in vitro. The release of these lipoproteins was examined in proteoliposomes. We show here that the aminoacylation is essential for the Lol-dependent release of lipoproteins from membranes. Furthermore, lipoproteins with aspartate at position 2 were found to be aminoacylated both in vivo and in vitro, indicating that the lipoprotein-sorting signal does not affect lipid modification.

  16. Lipoprotein-Related and Apolipoprotein-Mediated Delivery Systems for Drug Targeting and Imaging

    Science.gov (United States)

    Almer, Gunter; Mangge, Harald; Zimmer, Andreas; Prassl, Ruth

    2015-01-01

    The integration of lipoprotein-related or apolipoprotein-targeted nanoparticles as pharmaceutical carriers opens new therapeutic and diagnostic avenues in nanomedicine. The concept is to exploit the intrinsic characteristics of lipoprotein particles as being the natural transporter of apolar lipids and fat in human circulation. Discrete lipoprotein assemblies and lipoprotein-based biomimetics offer a versatile nanoparticle platform that can be manipulated and tuned for specific medical applications. This article reviews the possibilities for constructing drug loaded, reconstituted or artificial lipoprotein particles. The advantages and limitations of lipoprotein-based delivery systems are critically evaluated and potential future challenges, especially concerning targeting specificity, concepts for lipoprotein rerouting and design of innovative lipoprotein mimetic particles using apolipoprotein sequences as targeting moieties are discussed. Finally, the review highlights potential medical applications for lipoprotein-based nanoparticle systems in the fields of cardiovascular research, cancer therapy, gene delivery and brain targeting focusing on representative examples from literature. PMID:26180001

  17. Moderate Exercise Increases Affinity of Large Very Low-Density Lipoproteins for Hydrolysis by Lipoprotein Lipase.

    Science.gov (United States)

    Ghafouri, Khloud; Cooney, Josephine; Bedford, Dorothy K; Wilson, John; Caslake, Muriel J; Gill, Jason M R

    2015-06-01

    Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations, but the mechanisms responsible are unclear. The objective was to determine the effects of exercise on affinity of chylomicrons, large very low-density lipoproteins (VLDL1), and smaller VLDL (VLDL2) for lipoprotein lipase (LPL)-mediated TG hydrolysis. This was designed as a within-participant crossover study. The setting was a university metabolic investigation unit. Participants were 10 overweight/obese men. Participants undertook two oral fat tolerance tests, separated by 7-14 days, in which they had blood taken while fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (exercise trial [EX]); no exercise was performed before the control trial (CON). We measured circulating TG-rich lipoprotein concentrations and affinity of chylomicrons, VLDL1, and VLDL2 for LPL-mediated TG hydrolysis. Exercise significantly reduced fasting VLDL1-TG concentration (CON, 0.49 [0.33-0.72] mmol.L(-1); EX, 0.36 [0.22-0.59] mmol.L(-1); geometric means [95% confidence interval]; P = .04). Time-averaged postprandial chylomicron-TG (CON, 0.55 ± 0.10 mmol.L(-1); EX, 0.39 ± 0.08 mmol.L(-1); mean ± SEM; P = .03) and VLDL1-TG (CON, 0.85 ± 0.13 mmol.L(-1); EX, 0.66 ± 0.10 mmol.L(-1); P = .01) concentrations were both lower in EX than CON. Affinity of VLDL1 for LPL-mediated TG hydrolysis increased by 2.2 (1.3-3.7)-fold [geometric mean (95% confidence interval)] (P = .02) in the fasted state and 2.6 (1.8-2.6)-fold (P = .001) postprandially. Affinity of chylomicrons and VLDL2 was not significantly different between trials. Exercise increases affinity of VLDL1 for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to the TG-lowering effect of exercise.

  18. Achieving secondary prevention low-density lipoprotein particle concentration goals using lipoprotein cholesterol-based data.

    Directory of Open Access Journals (Sweden)

    Simon C Mathews

    Full Text Available BACKGROUND: Epidemiologic studies suggest that LDL particle concentration (LDL-P may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C ≥ 40; TG<150; and TG/HDL-C<3. METHODS: We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients. RESULTS: TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F = 84.1, p<10(-6. The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150 was also effective (F = 42.8, p<10(-5. However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150 was also effective but yielded higher LDL-P than the very high risk composite (F = 42.0, p<10(-5 with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F = 15.8, p = 0.0001 and F = 9.7, p = 0.002 respectively. LDL density phenotype neared significance (F = 2.85, p = 0.094 and the HDL-C cutpoint of 40 mg/dL did not discriminate (F = 0.53, p = 0.47 alone or add discriminatory power to ATP-III targets. CONCLUSIONS: A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical

  19. Cloning of a cDNA encoding a putative human very low density lipoprotein/Apolipoprotein E receptor and assignment of the gene to chromosome 9pter-p23[sup 6

    Energy Technology Data Exchange (ETDEWEB)

    Gafvels, M.E.; Strauss, J.F. III (Univ. of Pennyslvania, Philadelphia, PA (United States)); Caird, M.; Patterson, D. (Eleanor Roosevelt Institute, Denver, CO (United States)); Britt, D.; Jackson, C.L. (Brown Univ., Providence, RI (United States))

    1993-11-01

    The authors report the cloning of a 3656-bp cDNA encoding a putative human very low density lipoprotein (VLDL)/apolipoprotein E (ApoE) receptor. The gene encoding this protein was mapped to chromosome 9pter-p23. Northern analysis of human RNA identified cognate mRNAs of 6.0 and 3.8 kb with most abundant expression in heart and skeletal muscle, followed by kidney, placenta, pancreas, and brain. The pattern of expression generally paralleled that of lipoprotein lipase mRNA but differed from that of the low density lipoprotein (LDL) receptor and the low density lipoprotein receptor-related protein/[alpha][sub 2]-macroglobulin receptor (LRP), which are members of the same gene family. VLDL/ApoE receptor message was not detected in liver, whereas mRNAs for both LDL receptor and LRP were found in hepatic tissue. In mouse 3T3-L1 cells, VLDL/ApoE receptor mRNA was induced during the transformation of the cells into adipocytes. Expression was also detected in human choriocarcinoma cells, suggesting that at least part of the expression observed in placenta may be in trophoblasts, cells which would be exposed to maternal blood. Expression in brain may be related to high levels of ApoE expression in that organ, an observation of potential relevance to the recently hypothesized role for ApoE in late onset Alzheimer disease. The results suggest that the putative VLDL/ApoE receptor could play a role in the uptake of triglyceride-rich lipoprotein particles by specific organs including striated and cardiac muscle and adipose tissue and in the transport of maternal lipids across the placenta. The findings presented here, together with recent observations from other laboratories, bring up the possibility that a single gene, the VLDL/ApoE receptor, may play a role in the pathogenesis of certain forms of atherosclerosis, Alzheimer disease, and obesity.

  20. Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10.

    Science.gov (United States)

    Susan-Resiga, Delia; Essalmani, Rachid; Hamelin, Josée; Asselin, Marie-Claude; Benjannet, Suzanne; Chamberland, Ann; Day, Robert; Szumska, Dorota; Constam, Daniel; Bhattacharya, Shoumo; Prat, Annik; Seidah, Nabil G

    2011-07-01

    Bone morphogenetic protein 10 (BMP10) is a member of the TGF-β superfamily and plays a critical role in heart development. In the postnatal heart, BMP10 is restricted to the right atrium. The inactive pro-BMP10 (∼60 kDa) is processed into active BMP10 (∼14 kDa) by an unknown protease. Proteolytic cleavage occurs at the RIRR(316)↓ site (human), suggesting the involvement of proprotein convertase(s) (PCs). In vitro digestion of a 12-mer peptide encompassing the predicted cleavage site with furin, PACE4, PC5/6, and PC7, showed that furin cleaves the best, whereas PC7 is inactive on this peptide. Ex vivo studies in COS-1 cells, a cell line lacking PC5/6, revealed efficient processing of pro-BMP10 by endogenous PCs other than PC5/6. The lack of processing of overexpressed pro-BMP10 in the furin- and PACE4-deficient cell line, CHO-FD11, and in furin-deficient LoVo cells, was restored by stable (CHO-FD11/Fur cells) or transient (LoVo cells) expression of furin. Use of cell-permeable and cell surface inhibitors suggested that endogenous PCs process pro-BMP10 mostly intracellularly, but also at the cell surface. Ex vivo experiments in mouse primary hepatocytes (wild type, PC5/6 knock-out, and furin knock-out) corroborated the above findings that pro-BMP10 is a substrate for endogenous furin. Western blot analyses of heart right atria extracts from wild type and PACE4 knock-out adult mice showed no significant difference in the processing of pro-BMP10, implying no in vivo role of PACE4. Overall, our in vitro, ex vivo, and in vivo data suggest that furin is the major convertase responsible for the generation of BMP10.

  1. Furin Is the Major Processing Enzyme of the Cardiac-specific Growth Factor Bone Morphogenetic Protein 10*

    Science.gov (United States)

    Susan-Resiga, Delia; Essalmani, Rachid; Hamelin, Josée; Asselin, Marie-Claude; Benjannet, Suzanne; Chamberland, Ann; Day, Robert; Szumska, Dorota; Constam, Daniel; Bhattacharya, Shoumo; Prat, Annik; Seidah, Nabil G.

    2011-01-01

    Bone morphogenetic protein 10 (BMP10) is a member of the TGF-β superfamily and plays a critical role in heart development. In the postnatal heart, BMP10 is restricted to the right atrium. The inactive pro-BMP10 (∼60 kDa) is processed into active BMP10 (∼14 kDa) by an unknown protease. Proteolytic cleavage occurs at the RIRR316↓ site (human), suggesting the involvement of proprotein convertase(s) (PCs). In vitro digestion of a 12-mer peptide encompassing the predicted cleavage site with furin, PACE4, PC5/6, and PC7, showed that furin cleaves the best, whereas PC7 is inactive on this peptide. Ex vivo studies in COS-1 cells, a cell line lacking PC5/6, revealed efficient processing of pro-BMP10 by endogenous PCs other than PC5/6. The lack of processing of overexpressed pro-BMP10 in the furin- and PACE4-deficient cell line, CHO-FD11, and in furin-deficient LoVo cells, was restored by stable (CHO-FD11/Fur cells) or transient (LoVo cells) expression of furin. Use of cell-permeable and cell surface inhibitors suggested that endogenous PCs process pro-BMP10 mostly intracellularly, but also at the cell surface. Ex vivo experiments in mouse primary hepatocytes (wild type, PC5/6 knock-out, and furin knock-out) corroborated the above findings that pro-BMP10 is a substrate for endogenous furin. Western blot analyses of heart right atria extracts from wild type and PACE4 knock-out adult mice showed no significant difference in the processing of pro-BMP10, implying no in vivo role of PACE4. Overall, our in vitro, ex vivo, and in vivo data suggest that furin is the major convertase responsible for the generation of BMP10. PMID:21550985

  2. New and emerging regulators of intestinal lipoprotein secretion.

    Science.gov (United States)

    Xiao, Changting; Dash, Satya; Morgantini, Cecilia; Lewis, Gary F

    2014-04-01

    Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of

  3. Capillary isotachophoresis study of lipoprotein network sensitive to apolipoprotein E phenotype. 1. ApoE distribution between lipoproteins.

    Science.gov (United States)

    Dergunov, Alexander D; Ponthieux, Anne; Mel'kin, Maxim V; Lambert, Daniel; Visvikis-Siest, Sophie; Siest, Gerard

    2009-05-01

    Sixteen patients differing widely in plasma triglyceride content were divided into three groups by their apolipoprotein E (apoE) phenotype-E33 homozygotes, E23, and E34 heterozygotes. The plasma lipid and apoE distribution between individual lipoproteins was followed by capillary isotachophoresis (CITP) of plasma samples pre-stained with lipid fluorescent probe NBD-C6-ceramide and by fluorescein-labeled apoE, respectively. Among 12 peaks visualized by ceramide staining, an individual peak with very low density lipoproteins (VLDL) was identified. The VLDL cholesterol and apoE content determined by CITP directly in whole plasma were significantly related to their content as determined by conventional analysis with isolated VLDL. The ceramide distribution among lipoprotein pools was insensitive to apoE phenotype (49-53 : 7-11 : 39-43% for HDL, VLDL, and IDL/LDL, respectively) while the preferential binding of apoE to VLDL was observed in E34 patients compared to E33 (62 : 19 : 20 vs. 70 : 9 : 22%). In a study of apoE/F displacement from lipoproteins at plasma titration by apoC-III in vitro, apoE was found to bind more tightly to VLDL from E34 compared to E33 patients as evidenced by both the increased non-displaceable apoE pool, the increased VLDL sorbtion capacity for apoE, and the decreased displacement parameter in a "container" model of lipoprotein binding. Two different types of apoE package in a whole lipoprotein profile were observed. ApoE structure in a particular lipoprotein may underlie the phenotype-sensitive apoE distribution and apoC-III interference in hypertriglyceridemia.

  4. Hydrolysis of guinea pig nascent very low density lipoproteins catalyzed by lipoprotein lipase: activation by hjman apolipoprotein C-II.

    Science.gov (United States)

    Fitzharris, T J; Quinn, D M; Goh, E H; Johnson, J D; Kashyap, M L; Srivastava, L S; Jackson, R L; Harmony, J A

    1981-08-01

    Very low density lipoproteins isolated from guinea pig liver perfusate (VLDLp) lack the equivalent of human apolipoprotein C-II (apoC-II), the activator of lipoprotein lipase (LpL). These lipoproteins are therefore ideal substrates with which to investigate the mechanism by which apoC-II activates the enzyme. VLDLp binds apoC-II, and apoC-II associated with VLDLp markedly increases the rate of lipoprotein lipase-catalyzed hydrolysis of VLDLp-triglycerides. The activator potency of apoC-II is independent of the method of enrichment of VLDLp with apoC-II: delipidated human apoC-II and apoC-II transferred from human high density lipoproteins activate lipoprotein lipase to equal extents. ApoC-II causes pH-dependent changes in both apparent Km and VmaX of LpL-catalyzed hydrolysis of VLDLp-triglycerides. At pH l7.4--7.5, the major effects of apoC-II is to decrease the apparent Km by 3.3--4.0 fold. The apparent Vmax is increased 1.3-fold. At pH 6.5 and 8.5, the decrease of apparent Km is less marked, 1.6-fold and 1.4-fold, respectively. At pH 6.5, apoC-II increases the apparent Vmax ty 1.3-fold, while at pH 8.5 the primary effect of apoC-II is a 1.6-fold increase of apparent Vmax. Based on a simple kinetic model, the data suggest that apoC-II favors direct interaction between enzyme and triglyceride within the lipoprotein particle, as well as subsequent catalytic turnover.

  5. Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis.

    Science.gov (United States)

    Hoeke, Geerte; Kooijman, Sander; Boon, Mariëtte R; Rensen, Patrick C N; Berbée, Jimmy F P

    2016-01-08

    Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading cause of morbidity and mortality in Western society, and new therapeutic strategies are highly warranted. Brown adipose tissue (BAT) is metabolically active in human adults. Although positron emission tomography-computed tomography using a glucose tracer is the golden standard to visualize and quantify the volume and activity of BAT, it has become clear that activated BAT combusts fatty acids rather than glucose. Here, we review the role of brown and beige adipocytes in lipoprotein metabolism and atherosclerosis, with evidence derived from both animal and human studies. On the basis of mainly data from animal models, we propose a model in which activated brown adipocytes use their intracellular triglyceride stores to generate fatty acids for combustion. BAT rapidly replenishes these stores by internalizing primarily lipoprotein triglyceride-derived fatty acids, generated by lipoprotein lipase-mediated hydrolysis of triglycerides, rather than by holoparticle uptake. As a consequence, BAT activation leads to the generation of lipoprotein remnants that are subsequently cleared via the liver provided that an intact apoE-low-density lipoprotein receptor pathway is present. Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Initial studies suggest that BAT activation in humans may also reduce triglyceride and cholesterol levels, but potential antiatherogenic effects should be assessed in future studies. © 2016 American Heart Association, Inc.

  6. Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins

    Science.gov (United States)

    Yang, Peng; Subbaiah, Papasani V.

    2015-01-01

    Hepatic lipase (HL) is an important enzyme in the clearance of triacylglycerol (TAG) from the circulation, and has been proposed to have pro-atherogenic as well as anti-atherogenic properties. It hydrolyzes both phospholipids and TAG of lipoproteins, and its activity is negatively correlated with HDL levels. Although it is known that HL acts preferentially on HDL lipids, the basis for this specificity is not known, since it does not require any specific apoprotein for activity. In this study, we tested the hypothesis that sphingomyelin (SM), whose concentration is much higher in VLDL and LDL compared to HDL, is an inhibitor of HL, and that this could explain the lipoprotein specificity of the enzyme. The results presented show that the depletion of SM from normal lipoproteins activated the HL roughly in proportion to their SM content. SM depletion stimulated the hydrolysis of both phosphatidylcholine (PC) and TAG, although the PC hydrolysis was stimulated more. In the native lipoproteins, HL showed specificity for PC species containing polyunsaturated fatty acids at sn-2 position, and produced more unsaturated lyso PC species. The enzyme also showed preferential hydrolysis of certain TAG species over others. SM depletion affected the specificity of the enzyme towards PC and TAG species modestly. These results show that SM is a physiological inhibitor of HL activity in lipoproteins and that the specificity of the enzyme towards HDL is at least partly due to its low SM content. PMID:26193433

  7. Low density lipoproteins mediated nanoplatforms for cancer targeting

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Anupriya; Jain, Keerti; Kesharwani, Prashant, E-mail: prashant_pharmacy04@rediffmail.com; Jain, Narendra K., E-mail: jnarendr@yahoo.co.in [Dr. H. S. Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

    2013-09-15

    Chemotherapy is a foremost remedial approach for the treatment of localized and metastasized tumors. In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. One such difference may be that of increased receptor-mediated cellular uptake of low density lipoproteins (LDLs) by cancer cells. Lipoproteins in general and specifically LDL are ideal candidates for loading and delivering cancer therapeutic and diagnostic agents due to their biocompatibility. By mimicking the endogenous shape and structure of lipoproteins, the reconstituted lipoproteins can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. In this account, we review the field of low density inspired nanoparticles in relation to the delivery of cancer imaging and therapeutic agents. LDL has instinctive cancer targeting potential and has been used to incorporate various lipophillic molecules to transport them to tumors. Nature's method of rerouting LDL provides a strategy to extend the cancer targeting potential of lipoproteins far off its constricted purview. In this review, we have discussed the various aspects of LDL including its role in cancer imaging and chemotherapy in retrospect and prospect and current efforts aimed to further improve the delivery efficacy of LDL-drug complexes with reduced chances of drug resistance leading to optimal drug delivery. This review provides a strong support for the concept of using LDL as a drug carrier.

  8. Lipoproteins tethered dendrimeric nanoconstructs for effective targeting to cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Anupriya; Jain, Keerti, E-mail: keertijain02@gmail.com; Mehra, Neelesh Kumar, E-mail: neelesh81mph@gmail.com; Jain, N. K., E-mail: dr.jnarendr@gmail.com [Dr. H. S. Gour University, Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences (India)

    2013-10-15

    In the present investigation, poly (propylene imine) dendrimers up to fifth generation (PPI G5.0) were synthesized using ethylene diamine and acrylonitrile. Lipoproteins (high-density lipoprotein; HDL and low-density lipoprotein; LDL) were isolated from human plasma by discontinuous density gradient ultracentrifugation, characterized and tethered to G5.0 PPI dendrimers to construct LDL- and HDL-conjugated dendrimeric nanoconstructs for tumor-specific delivery of docetaxel. Developed formulations showed sustained release characteristics in in vitro drug release and in vivo pharmacokinetic studies. The cancer targeting potential of lipoprotein coupled dendrimers was investigated by ex vivo cytotoxicity and cell uptake studies using human hepatocellular carcinoma cell lines (HepG2 cells) and biodistribution studies in albino rats of Sprague-Dawley strain. Lipoprotein anchored dendrimeric nanoconstructs showed significant uptake by cancer cells as well as higher biodistribution of docetaxel to liver and spleen. It is concluded that these precisely synthesized engineered dendrimeric nanoconstructs could serve as promising drug carrier for fighting with the fatal disease, i.e., cancer, attributed to their defined targeting and therapeutic potential.

  9. Lipoproteins tethered dendrimeric nanoconstructs for effective targeting to cancer cells

    Science.gov (United States)

    Jain, Anupriya; Jain, Keerti; Mehra, Neelesh Kumar; Jain, N. K.

    2013-10-01

    In the present investigation, poly (propylene imine) dendrimers up to fifth generation (PPI G5.0) were synthesized using ethylene diamine and acrylonitrile. Lipoproteins (high-density lipoprotein; HDL and low-density lipoprotein; LDL) were isolated from human plasma by discontinuous density gradient ultracentrifugation, characterized and tethered to G5.0 PPI dendrimers to construct LDL- and HDL-conjugated dendrimeric nanoconstructs for tumor-specific delivery of docetaxel. Developed formulations showed sustained release characteristics in in vitro drug release and in vivo pharmacokinetic studies. The cancer targeting potential of lipoprotein coupled dendrimers was investigated by ex vivo cytotoxicity and cell uptake studies using human hepatocellular carcinoma cell lines (HepG2 cells) and biodistribution studies in albino rats of Sprague-Dawley strain. Lipoprotein anchored dendrimeric nanoconstructs showed significant uptake by cancer cells as well as higher biodistribution of docetaxel to liver and spleen. It is concluded that these precisely synthesized engineered dendrimeric nanoconstructs could serve as promising drug carrier for fighting with the fatal disease, i.e., cancer, attributed to their defined targeting and therapeutic potential.

  10. High Density Lipoprotein Metabolism in Man

    Science.gov (United States)

    Blum, Conrad B.; Levy, Robert I.; Eisenberg, Shlomo; Hall, Marshall; Goebel, Robert H.; Berman, Mones

    1977-01-01

    The turnover of 125I-high density lipoprotein (HDL) was examined in a total of 14 studies in eight normal volunteers in an attempt to determine the metabolic relationship between apolipoproteins A-I (apoA-I) and A-II (apoA-II) of HDL and to define further some of the determinants of HDL metabolism. All subjects were first studied under conditions of an isocaloric balanced diet (40% fat, 40% carbohydrate). Four were then studied with an 80% carbohydrate diet, and two were studied while receiving nicotinic acid (1 g three times daily) and ingesting the same isocaloric balanced diet. The decay of autologous 125I-HDL and the appearance of urinary radioactivity were followed for at least 2 wk in each study. ApoA-I and apoA-II were isolated by Sephadex G-200 chromatography from serial plasma samples in each study. The specific activities of these peptides were then measured directly. It was found that the decay of specific activity of apoA-I and apoA-II were parallel to one another in all studies. The mean half-life of the terminal portion of decay was 5.8 days during the studies with a balanced diet. Mathematical modeling of the decay of plasma radioactivity and appearance of urinary radioactivity was most consistent with a two-compartment model. One compartment is within the plasma and exchanges with a nonplasma component. Catabolism occurs from both of these compartments. With a balanced isocaloric diet, the mean synthetic rate for HDL protein was 8.51 mg/kg per day. HDL synthesis was not altered by the high carbohydrate diet and was only slightly decreased by nicotinic acid treatment. These perturbations had effects on HDL catabolic pathways that were reciprocal in many respects. With an 80% carbohydrate diet, the rate of catabolism from the plasma compartment rose by a mean of 39.1%; with nicotinic acid treatment, it fell by 42.2%. Changes in the rate of catabolism from the second compartment were generally opposite those in the rate of catabolism from the plasma

  11. Effect of oral mesoglycan on plasma lipoprotein concentration and on lipoprotein lipase activity in primary hyperlipoproteinemia.

    Science.gov (United States)

    Postiglione, A; De Simone, B; Rubba, P; Lamenza, F; Montefusco, S; Mastranzo, P

    1984-01-01

    Mesoglycan extracted from calf aorta was orally administered (96 mg/day) to 15 patients with primary hyperlipoproteinemia: 4 type IIA, 4 type IIB, 6 type IV and one type V. In the seven hypertriglyceridemic patients the drug after two months of treatment reduced total and VLDL-triglyceride from 701 mg/dl to 423 mg/dl (p less than 0.025) and from 562 mg/dl to 377 mg/dl (p less than 0.025) respectively and increased lipoprotein lipase activity from 19.7 mumol/l/min to 27.8 mumol/l/min (p less than 0.05). No change was observed in the group with type IIA-IIB hyperlipoproteinemia.

  12. Lipoprotein Metabolism, Dyslipidemia and Nonalcoholic Fatty Liver Disease

    Science.gov (United States)

    Cohen, David E.; Fisher, Edward A.

    2014-01-01

    Cardiovascular disease represents the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). NAFLD patients exhibit an atherogenic dyslipidemia that is characterized by an increased plasma concentration of triglycerides, reduced concentration of high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) particles that are smaller and more dense than normal. The pathogenesis of NAFLD-associated atherogenic dyslipidemia is multifaceted, but many aspects are attributable to manifestations of insulin resistance. Here we review the structure, function and metabolism of lipoproteins, which are macromolecular particles of lipids and proteins that transport otherwise insoluble triglyceride and cholesterol molecules within the plasma. We provide a current explanation of the metabolic perturbations that are observed in the setting of insulin resistance. An improved understanding of the pathophysiology of atherogenic dyslipidemia would be expected to guide therapies aimed at reducing morbidity and mortality in NAFLD patients. PMID:24222095

  13. Lipoprotein-associated phospholipase A2 distribution among lipoproteins differs in type 1 diabetes.

    Science.gov (United States)

    Jarvie, Jennifer L; Wang, Hong; Kinney, Gregory L; Snell-Bergeon, Janet; Hokanson, John E; Eckel, Robert H

    2016-01-01

    LpPLA2 mass and activity have been variably related to cardiovascular disease risk, and the distribution of LpPLA2 in patients with type 1 diabetes (T1D), wherein cardiovascular disease risk is high despite normal or higher levels of high-density lipoprotein (HDL) cholesterol, is unknown. To determine whether there are differences in the distribution of LpPLA2 mass and activity across lipoproteins and their association with coronary artery calcium (CAC) in patients with T1D. Men with T1D (n = 19) not on statins, with and without CAC progression, and men without diabetes matched for HDL cholesterol (n = 25) had lipoproteins separated by fast protein liquid chromatography. Both LpPLA2 mass and activity were found within low-density lipoprotein (LDL) and HDL pools with more LpPLA2 mass being associated with HDL (54% vs 44%; P-value diabetes. However, no difference in LpPLA2 activity or mass between lipoprotein subfractions was observed between all groups, and there was no relationship between LpPLA2 activity or mass and its distribution and CAC score progression in healthy or T1D men. LpPLA2 is found in both LDL and HDL and is distributed differently in men with T1D without any relationship to CAC score progression. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  14. Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia.

    Science.gov (United States)

    Hooper, Amanda J; Heeks, Liesl; Robertson, Ken; Champain, Danie; Hua, Jianmin; Song, Swithin; Parhofer, Klaus G; Barrett, P Hugh R; van Bockxmeer, Frank M; Burnett, John R

    2015-11-01

    Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apoB). The objective was to examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceride-rich lipoprotein (TRL) and fasting lipoprotein metabolism. Plasma incremental area under the curve apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. The postprandial incremental area under the curve (0-10 h) in FHBL subjects (n = 3) was lower for large TRL-triglyceride (-77%; P < .0001), small TRL-cholesterol (-83%; P < .001), small TRL-triglyceride (-88%; P < .001), and for plasma triglyceride (-70%; P < .01) and apoB (-63%; P < .0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (-91%; P < .05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n = 2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P < .01). The VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P = .07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, whereas the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

  15. Influence of liver cancer on lipid and lipoprotein metabolism

    Directory of Open Access Journals (Sweden)

    Nilsson-Ehle Peter

    2006-03-01

    Full Text Available Abstract Liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma (HCC is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. This has been attributed to the high incidence of hepatitis B infection. Hepatitis B proteins, such as the hepatitis B X protein (HBx that is large hepatitis B surface protein could regulate transcription of many candidate genes for liver carcinogenesis. It has known that patients who suffered from acute hepatitis B could have lipid disorders such as decreased plasma level of high-density lipoproteins (HDL. Furthermore, aberrations of lipid metabolism are often seen in the chronic hepatitis B infection. Plasma lipid profiles could be changed under HCC. In majority of the reports in HCC, plasma levels of triglycerides (TG, cholesterol, free fatty acids (FFA, HDL, low-density lipoproteins (LDL, lipoprotein (a (Lp(a, apolipoprotein AI (apoAI and apoB were slight to significantly decreased, however, in some cases plasma levels of TG and Lp(a might be increased. It has been suggested that analysis of plasma levels of lipids, lipoproteins and apolipoproteins in the patients suffered from HCC reflects on the hepatic cellular impairment status. Studies revealed that alterations seen in the plasma levels of lipids, lipoproteins and apolipoproteins reflecting patients' pathologic conditions. Decreased serum levels of cholesterol and apoAI may indicate a poor prognosis. Human leukaemic cells and certain tumor tissues have a higher receptor-mediated uptake of HDL and LDL than the corresponding normal cells or tissues. LDL and HDL have therefore been proposed as a carrier for the water-insoluble anti-cancer agents.

  16. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G

    2016-01-01

    Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need.......1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate...

  17. Improving lipoprotein profiles by liver-directed gene transfer of low density lipoprotein receptor gene in hypercholesterolaemia mice

    Indian Academy of Sciences (India)

    HAILONG OU; QINGHAI ZHANG; JIA ZENG

    2016-06-01

    The defect of low density lipoprotein receptor disturbs cholesterol metabolism and causes familial hypercholesterolaemia(FH). In this study, we directly delivered exogenousLdlrgene into the liver of FH model mice (Ldlr − / −) by lentiviral genetransfer system. The results showed that theLdlrgene controlled by hepatocyte-specific human thyroxine-binding globulin(TBG) promoter successfully and exclusively expressed in livers. We found that, although, the content of high density lipopro-tein in serum was not significantly affected by theLdlrgene expression, the serum low density lipoprotein level was reducedby 46%, associated with a 30% and 28% decrease in triglyceride and total cholesterol, respectively, compared to uninjectedLdlr − / −mice. Moreover, the TBG directed expression ofLdlrsignificantly decreased the lipid accumulation in liver andreduced plaque burden in aorta (32%). Our results indicated that the hepatocyte-specific expression ofLdlrgene strikinglylowered serum lipid levels and resulted in amelioration of hypercholesterolaemia.

  18. Interaction between retinoid acid receptor-related orphan receptor alpha (RORA and neuropeptide S receptor 1 (NPSR1 in asthma.

    Directory of Open Access Journals (Sweden)

    Nathalie Acevedo

    Full Text Available Retinoid acid receptor-related Orphan Receptor Alpha (RORA was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs in the vicinity of the asthma-associated SNP (rs11071559 and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1, has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children and the European cross-sectional PARSIFAL study (1120 children. Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36-2.93, p = 0.0003 in BAMSE; and 1.61, 1.18-2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively, and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.

  19. Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection

    DEFF Research Database (Denmark)

    Stylianou, E; Aukrust, P; Bendtzen, K;

    2000-01-01

    Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infec...

  20. Early secretory antigenic target protein-6/culture filtrate protein-10 fusion protein-specific Th1 and Th2 response and its diagnostic value in tuberculous pleural effusion

    Institute of Scientific and Technical Information of China (English)

    戈启萍

    2013-01-01

    Objective To detect the Th1 and Th2 cell percentage in pleural effusion mononuclear cells (PEMCs) stimulated by early secretory antigenic target protein-6 (ESAT-6) /culture filtrate protein-10 (CFP-10) fusion protein (E/C) with flow cytometry (FCM) ,and to explore the local antigen specific Th1 and Th2 response and

  1. Evaluation of gamma interferon (IFN-gamma)-induced protein 10 (IP-10) responses for detection of cattle infected with Mycobacterium bovis: comparisons to IFN-gamma responses

    Science.gov (United States)

    Gamma interferon (IFN-gamma)-induced protein 10 (IP-10) has recently shown promise as a diagnostic biomarker of Mycobacterium tuberculosis infection of humans. The aim of the current study was to compare IP-10 and IFN-gamma responses upon Mycobacterium bovis infection in cattle using archived sample...

  2. Interferon-gamma inducible protein 10 as a biomarker for active tuberculosis and latent tuberculosis infection in children: A case-control study

    DEFF Research Database (Denmark)

    Alsleben, Neele; Ruhwald, Morten; Rüssmann, Holger;

    2012-01-01

    Background: Interferon-gamma (IFN-γ) release assays (IGRAs) are suboptimally sensitive to diagnose tuberculosis (TB) and latent TB infection (LTBI) in young children. In this study we compared Mycobacterium tuberculosis antigen-stimulated IFN-γ inducible protein 10 (IP-10) responses in children w...

  3. Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

    National Research Council Canada - National Science Library

    Chasman, Daniel I; Pare, Guillaume; Zee, Robert Y.L; Parker, Alex N; Cook, Nancy R; Buring, Julie E; Kwiatkowski, David J; Rose, Lynda M; Smith, Joshua D; Williams, Paul T; Rieder, Mark J; Rotter, Jerome I; Nickerson, Deborah A; Krauss, Ronald M; Miletich, Joseph P; Ridker, Paul M

    2008-01-01

    Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White...

  4. DMPD: Low density lipoprotein oxidation and its pathobiological significance. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 9261091 Low density lipoprotein oxidation and its pathobiological significance. Ste...in oxidation and its pathobiological significance. PubmedID 9261091 Title Low density lipoprotein oxidation ...and its pathobiological significance. Authors Steinberg D. Publication J Biol Che

  5. Lipoprotein Lipase mRNA expression in different tissues of farm ...

    African Journals Online (AJOL)

    Lipoprotein Lipase mRNA expression in different tissues of farm animals. ... Lipoprotein lipase (LPL) controls triacylglycerol partitioning between adipose tissues and muscles, so it is important enzyme for ... Article Metrics. Metrics Loading .

  6. The effect of interaction between Lipoprotein Lipase and ApoVLDL-II ...

    African Journals Online (AJOL)

    The effect of interaction between Lipoprotein Lipase and ApoVLDL-II genes on fat and serum biochemical levels. ... Single nucleotide polymorphism (SNP) in apoVLDL-II and lipoprotein lipase genes was screened by ... Article Metrics.

  7. Quantification of lipoprotein profiles by nuclear magnetic resonance spectroscopy and multivariate data analysis

    DEFF Research Database (Denmark)

    Aru, Violetta; Lam, Chloie; Khakimov, Bekzod

    2017-01-01

    Lipoproteins and their subfraction profiles have been associated to diverse diseases including Cardio Vascular Disease (CVD). There is thus a great demand for measuring and quantifying the lipoprotein profile in an efficient and accurate manner. Nuclear Magnetic Resonance (NMR) spectroscopy...

  8. Circulating lipoproteins are a crucial component of host defense against invasive Salmonella typhimurium infection.

    NARCIS (Netherlands)

    Netea, M.G.; Joosten, L.A.B.; Keuter, M.; Wagener, F.A.D.T.G.; Stalenhoef, A.F.H.; Meer, J.W.M. van der; Kullberg, B.J.

    2009-01-01

    BACKGROUND: Circulating lipoproteins improve the outcome of severe Gram-negative infections through neutralizing lipopolysaccharides (LPS), thus inhibiting the release of proinflammatory cytokines. METHODS/PRINCIPAL FINDINGS: Low density lipoprotein receptor deficient (LDLR-/-) mice, with a 7-fold i

  9. Apolipoprotein B-containing lipoprotein particle assembly: Lipid capacity of the nascent lipoprotein particle

    Energy Technology Data Exchange (ETDEWEB)

    Manchekar, Medha; Forte, Trudy M.; Datta, Geeta; Richardson, Paul E.; Segrest, Jere P.; Dashti, Nassrin

    2003-12-01

    We previously proposed that the N-terminal 1000 residue {beta}{alpha}{sub 1} domain of apolipoprotein B (apoB) forms a bulk lipid pocket homologous to that of lamprey lipovitellin (LV). In support of this ''lipid pocket'' hypothesis, apoB:1000 (residues 1-1000) was shown to be secreted by a stable transformant of McA-RH7777 cells as a monodisperse particle with HDL{sub 3} density and Stokes diameter of 112 {angstrom}. In contrast, apoB:931 (residues 1-931), missing only 69 residues of the sequence homologous to LV, was secreted as a particle considerably more dense than HDL with Stokes diameter of 110 {angstrom}. The purpose of the present study was to determine the stoichiometry of the lipid component of the apoB:931 and apoB:1000 particles. This was accomplished by metabolic labeling of cells with either [{sup 14}C]oleic acid or [{sup 3}H]glycerol followed by immunoprecipitation (IP) or nondenaturing gradient gel electrophoresis (NDGGE) of secreted lipoproteins and by immunoaffinity chromatography of secreted unlabeled lipoproteins. The [{sup 3}H]-labeled apoB:1000-containing particles, isolated by NDGGE, contained 50 phospholipids (PL) and 11 triacylglycerols (TAG) molecules per particle. In contrast, apoB:931-containing particles contained only a few molecules of PL and were devoid of TAG. The unlabeled apoB:1000-containing particles isolated by immunoaffinity chromatography and analyzed for lipid mass, contained 56 PL, 8 TAG, and 7 cholesteryl ester molecules per particle. The surface:core lipid ratio of apoB:1000-containing particles was approximately 4:1 and was not affected by incubation of cells with oleate. Although small amounts of microsomal triglyceride transfer protein (MTP) were associated with apoB:1000-containing particles, it never approached a 1:1 molar ratio of MTP to apoB. These results support a model in which: (1) the first 1000 amino acid residues of apoB are competent to complete the ''lipid pocket

  10. Circulating Oxidized Low-Density Lipoproteins and Antibodies against Oxidized Low-Density Lipoproteins as Potential Biomarkers of Colorectal Cancer

    OpenAIRE

    2015-01-01

    Introduction. The aim of the study was evaluation of the diagnostic utility of serum oxidized low-density lipoproteins (oxLDL), antibodies against oxLDLs (o-LAB), and CEA as risk markers of colorectal cancer (CRC). Material and Methods. The serum levels of study factors were measured in 73 patients with CRC and in 35 healthy controls who were gender- and BMI-matched to the study group. Concentrations of oxLDL, o-LAB, and CEA were detected in ELISA tests. Serum lipids, lipoproteins, and gl...

  11. Lipoprotein lipase release from BFC-1 beta adipocytes. Effects of triglyceride-rich lipoproteins and lipolysis products.

    Science.gov (United States)

    Sasaki, A; Goldberg, I J

    1992-07-25

    Lipoprotein lipase (LPL), synthesized by adipocytes and myocytes, must be transported to the luminal endothelial cell surface where it then interacts with circulating lipoproteins. The first step in this extracellular LPL transport pathway is LPL release from the surface of LPL-synthesizing cells. Because hydrolysis of triglyceride (TG)-rich lipoproteins releases LPL from the apical surface of endothelial cells, we hypothesized that the same substances dissociate LPL from adipocytes. 125I-LPL was bound to the surface of brown adipocytes (BFC-1 beta). LPL binding to the adipocyte surface was greater than to endothelial cell surfaces. Using low concentrations of heparin, more LPL was released from endothelial cells than BFC-1 beta, suggesting that the affinity of LPL binding to the adipocytes was greater than LPL affinity for endothelial cells. Greater than 3-fold more LPL was released from the cell surface when very low density lipoproteins (VLDL) were added to culture medium containing 3% bovine serum albumin. LPL remaining on the cell surface decreased with VLDL addition. Endogenously produced LPL activity was also released from the cells by VLDL. Low and high density lipoproteins did not release 125I-LPL or LPL activity from the adipocytes. To assess whether lipolysis was necessary for LPL release, BFC-1 beta were incubated with TG-rich lipoproteins from a patient with apoCII deficiency. The apoCII-deficient lipoproteins did not release LPL unless an exogenous source of apoCII was added. Apolipoproteins E and Cs and high molar ratios of oleic acid:bovine serum albumin did not release surface-associated LPL. Lysolecithin (25 and 100 microM), but not lecithin, monoglycerides, or diglycerides, released adipocyte surface LPL. Because lysolecithin also released LPL during a 4 degrees C incubation, cellular metabolic functions are not required for LPL dissociation from the cells. Lysolecithin also inhibited LPL binding to endothelial cells; however, this effect was

  12. One precursor, three apolipoproteins: the relationship between two crustacean lipoproteins, the large discoidal lipoprotein and the high density lipoprotein/β-glucan binding protein.

    Science.gov (United States)

    Stieb, Stefanie; Roth, Ziv; Dal Magro, Christina; Fischer, Sabine; Butz, Eric; Sagi, Amir; Khalaila, Isam; Lieb, Bernhard; Schenk, Sven; Hoeger, Ulrich

    2014-12-01

    The novel discoidal lipoprotein (dLp) recently detected in the crayfish, differs from other crustacean lipoproteins in its large size, apoprotein composition and high lipid binding capacity, We identified the dLp sequence by transcriptome analyses of the hepatopancreas and mass spectrometry. Further de novo assembly of the NGS data followed by BLAST searches using the sequence of the high density lipoprotein/1-glucan binding protein (HDL-BGBP) of Astacus leptodactylus as query revealed a putative precursor molecule with an open reading frame of 14.7 kb and a deduced primary structure of 4889 amino acids. The presence of an N-terminal lipid bind- ing domain and a DUF 1943 domain suggests the relationship with the large lipid transfer proteins. Two-putative dibasic furin cleavage sites were identified bordering the sequence of the HDL-BGBP. When subjected to mass spectroscopic analyses, tryptic peptides of the large apoprotein of dLp matched the N-terminal part of the precursor, while the peptides obtained for its small apoprotein matched the C-terminal part. Repeating the analysis in the prawn Macrobrachium rosenbergii revealed a similar protein with identical domain architecture suggesting that our findings do not represent an isolated instance. Our results indicate that the above three apolipoproteins (i.e HDL-BGBP and both the large and the small subunit of dLp) are translated as a large precursor. Cleavage at the furin type sites releases two subunits forming a heterodimeric dLP particle, while the remaining part forms an HDL-BGBP whose relationship with other lipoproteins as well as specific functions are yet to be elucidated.

  13. Peri and Postparturient Concentrations of Lipid Lipoprotein Insulin and Glucose in Normal Dairy Cows

    OpenAIRE

    BAŞOĞLU, Abdullah; SEVİNÇ, Mutlu; OK, Mahmut

    1998-01-01

    In order to provide uniqe insight into the metabolic disturbences seen after calving cholesterol, triglycerid, high density lipoprotein, low density lipoprotein, very low density lipoprotein, glucose and insulin levels in serum were studied before calving (group I), in aerly (group II) and late (group III) lactation in 24 normal cows. Serum lipoproteins were separeted into various density classes by repeated ultracentrifugation. The results indicate that there was a rise in glucose, trygl...

  14. Associations between airway hyperresponsiveness, obesity, and lipoproteins in a longitudinal cohort

    DEFF Research Database (Denmark)

    Rasmussen, Finn; Hancox, Robert; Nair, Parameswaran;

    2013-01-01

    . The present study investigated the association between airway hyperresponsiveness (AHR) to methacholine and body mass index (BMI) and plasma lipoproteins [low-density lipoprotein (LDL), high-density lipoprotein (HDL) and total cholesterol]. Methods Associations between AHR, BMI and plasma lipoproteins were...... assessed in a population-based cohort at ages 14 and 20 years. Results In unadjusted analyses, higher LDL cholesterol levels at age 14 were associated with AHR at age 20 in both sexes (P...

  15. Human placenta secretes apolipoprotein B-100-containing lipoproteins

    DEFF Research Database (Denmark)

    Munk-Madsen, Eva; Lindegaard, Marie Louise Skakkebæk; Andersen, Claus B

    2004-01-01

    Supply of lipids from the mother is essential for fetal growth and development. In mice, disruption of yolk sac cell secretion of apolipoprotein (apo) B-containing lipoproteins results in embryonic lethality. In humans, the yolk sac is vestigial. Nutritional functions are instead established very...... of lipid transfer from the mother to the developing fetus....

  16. Intravenous Glucose Acutely Stimulates Intestinal Lipoprotein Secretion in Healthy Humans.

    Science.gov (United States)

    Xiao, Changting; Dash, Satya; Morgantini, Cecilia; Lewis, Gary F

    2016-07-01

    Increased production of intestinal triglyceride-rich lipoproteins (TRLs) contributes to dyslipidemia and increased risk of atherosclerotic cardiovascular disease in insulin resistance and type 2 diabetes. We have previously demonstrated that enteral glucose enhances lipid-stimulated intestinal lipoprotein particle secretion. Here, we assessed whether glucose delivered systemically by intravenous infusion also enhances intestinal lipoprotein particle secretion in humans. On 2 occasions, 4 to 6 weeks apart and in random order, 10 healthy men received a constant 15-hour intravenous infusion of either 20% glucose to induce hyperglycemia or normal saline as control. Production of TRL-apolipoprotein B48 (apoB48, primary outcomes) and apoB100 (secondary outcomes) was assessed during hourly liquid-mixed macronutrient formula ingestion with stable isotope enrichment and multicompartmental modeling, under pancreatic clamp conditions to limit perturbations in pancreatic hormones (insulin and glucagon) and growth hormone. Compared with saline infusion, glucose infusion induced both hyperglycemia and hyperinsulinemia, increased plasma triglyceride levels, and increased TRL-apoB48 concentration and production rate (Plipoprotein production. Hyperglycemia may contribute to intestinal lipoprotein overproduction in type 2 diabetes. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02607839. © 2016 American Heart Association, Inc.

  17. Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion.

    Science.gov (United States)

    Kohler, Sylvia; Voß, Franziska; Gómez Mejia, Alejandro; Brown, Jeremy S; Hammerschmidt, Sven

    2016-11-01

    Streptococcus pneumoniae (pneumococcus) has evolved sophisticated strategies to survive in several niches within the human body either as a harmless commensal or as a serious pathogen causing a variety of diseases. The dynamic interaction between pneumococci and resident host cells during colonization of the upper respiratory tract and at the site of infection is critical for bacterial survival and the development of disease. Pneumococcal lipoproteins are peripherally anchored membrane proteins and have pivotal roles in bacterial fitness including envelope stability, cell division, nutrient acquisition, signal transduction, transport (as substrate-binding proteins of ABC transporter systems), resistance to oxidative stress and antibiotics, and protein folding. In addition, lipoproteins are directly involved in virulence-associated processes such as adhesion, colonization, and persistence through immune evasion. Conversely, lipoproteins are also targets for the host response both as ligands for toll-like receptors and as targets for acquired antibodies. This review summarizes the multifaceted roles of selected pneumococcal lipoproteins and how this knowledge can be exploited to combat pneumococcal infections. © 2016 Federation of European Biochemical Societies.

  18. Lipoprotein Particle Subclasses, Cardiovascular Disease and HIV Infection

    OpenAIRE

    Duprez, Daniel A.; Kuller, Lewis H.; Tracy, Russell; Otvos, James; Cooper, David; Hoy, Jennifer; Neuhaus, Jacqueline; Paton, Nicholas I; Friis-Moller, Nina; Lampe, Fiona; Liappis, Angelike P.; Neaton, James D.

    2009-01-01

    Both HIV and treatment for HIV have been associated with an increased risk of cardiovascular disease (CVD). Unfavorable lipid changes could offer a possible explanation for the increased risk of CVD. We examined the association of lipoprotein particles with CVD in HIV-infected patients.

  19. Lifecycle of a Lipoprotein from a Biophysical Perspective

    Science.gov (United States)

    Rutledge, John C.; Huser, Thomas; Voss, John; Chan, James; Parikh, Atul

    The goal of our project was to understand how lipids and lipoproteins interact with cell membranes. This chapter will present the five major areas in which we have focused our attention on understanding how lipids and lipoproteins interact with cell membranes (Fig. 11.1): (1) triglycerides and vascular injury, (2) single lipoprotein analysis, (3) apolipoprotein E (apoE) conformation changes in the postprandial state, (4) triglyceride-rich lipoproteins (TGRLs) and endothelial cell inflammation, and (5) TGRL lipolysis products and monocyte activation. For over a hundred years, Western civilization has questioned how the food we eat translates into disease, and specifically atherosclerotic cardiovascular disease. Although most information indicates that this basic pathophysiological process is mediated through consumption of excess saturated fats, much remains unknown. After humans eat a meal, there is an elevation of triglycerides in the blood in the postprandial state. In normal individuals, triglycerides can rise after a meal by 50 to 100%. This has been documented many times in the past, including a paper by Hyson et al, (1998) [1]. In that study, normal healthy individuals were given a 40%-fat meal. Plasma triglycerides, which were modestly elevated initially, rose about 60% higher three to four hours after ingestion of the meal. Subsequently plasma triglycerides fell to baseline levels six hours after the meal. Even in these healthy individuals, a significant elevation of triglycerides was noted after ingestion of a moder ately high-fat meal.

  20. Low-density lipoprotein cholesterol and risk of gallstone disease

    DEFF Research Database (Denmark)

    Stender, Stefan; Frikke-Schmidt, Ruth; Benn, Marianne

    2013-01-01

    Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone...

  1. Epidemiological reference ranges for low-density lipoprotein ...

    African Journals Online (AJOL)

    1991-04-06

    Apr 6, 1991 ... (LDL-C) and high-density lipoprotein cholesterol (HDL-C) is recommended for subjects .... with this differential precipitation method for LDL-C in non- fasting subjects did not ..... Henderson LO er al. Phase V Preliminary Repor!

  2. Lipoprotein(a) Management: Pharmacological and Apheretic Treatment.

    Science.gov (United States)

    Hanssen, Ruth; Gouni-Berthold, Ioanna

    2017-01-01

    Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle with an additional apolipoprotein, apolipoprotein (a), [apo(a)] attached to apolipoprotein B. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) is causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association between Lp(a) concentrations and CVD is still controversial but seems to be continuous and without an obvious threshold Lp(a) level. Circulating concentrations of Lp(a) are genetically determined; desirable levels are lipoprotein apheresis can decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends mainly on the healthcare reimbursement system. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial that evaluated whether decreasing Lp(a) concentrations translates to clinical benefits. Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by almost 80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Lipoprotein(a) as a cardiovascular risk factor : current status

    NARCIS (Netherlands)

    Nordestgaard, Børge G; Chapman, M John; Ray, Kausik; Borén, Jan; Andreotti, Felicita; Watts, Gerald F; Ginsberg, Henry; Amarenco, Pierre; Catapano, Alberico; Descamps, Olivier S; Fisher, Edward; Kovanen, Petri T; Kuivenhoven, Jan Albert; Lesnik, Philippe; Masana, Luis; Reiner, Zeljko; Taskinen, Marja-Riitta; Tokgözoglu, Lale; Tybjærg-Hansen, Anne

    2010-01-01

    AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between e

  4. [Residual risk: The roles of triglycerides and high density lipoproteins].

    Science.gov (United States)

    Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

    2016-06-01

    In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target.

  5. Effects of progestational agents on serum lipids and lipoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Krauss, R.M.

    1982-08-01

    Though progestins with relatively strong androgenic or antiestrogenic effects (e.g., levonorgestrel and norethindrone acetate) tend to have the greatest capacity to offset the major estrogen effects (e.g., on serum triglyceride and, to a greater extent, HDL-cholesterol), this association is not sufficiently strong to allow prediction of the effects of other progestins on lipid and lipoprotein metabolism.

  6. A Novel Anti-Inflammatory Effect for High Density Lipoprotein.

    Directory of Open Access Journals (Sweden)

    Scott J Cameron

    Full Text Available High density lipoprotein has anti-inflammatory effects in addition to mediating reverse cholesterol transport. While many of the chronic anti-inflammatory effects of high density lipoprotein (HDL are attributed to changes in cell adhesion molecules, little is known about acute signal transduction events elicited by HDL in endothelial cells. We now show that high density lipoprotein decreases endothelial cell exocytosis, the first step in leukocyte trafficking. ApoA-I, a major apolipoprotein of HDL, mediates inhibition of endothelial cell exocytosis by interacting with endothelial scavenger receptor-BI which triggers an intracellular protective signaling cascade involving protein kinase C (PKC. Other apolipoproteins within the HDL particle have only modest effects upon endothelial exocytosis. Using a human primary culture of endothelial cells and murine apo-AI knockout mice, we show that apo-AI prevents endothelial cell exocytosis which limits leukocyte recruitment. These data suggest that high density lipoprotein may inhibit diseases associated with vascular inflammation in part by blocking endothelial exocytosis.

  7. Interaction of low density lipoproteins with rat liver cells

    NARCIS (Netherlands)

    L. Harkes (Leendert)

    1985-01-01

    textabstractThe most marked conclusion is the establishment of the important role of non-parenchymal cells in the catabolism of the low density lipoproteins by the rat liver. Because the liver is responsible for 70-80% of the removal of LDL from blood this conclusion can be extended to total LDL tur

  8. Analyzing the molecular mechanism of lipoprotein localization in Brucella

    CSIR Research Space (South Africa)

    Goolab, S

    2015-10-01

    Full Text Available of Brucellalipoproteins and their potential use as vaccine candidates for the treatment of Brucellosis, the underlying route for the translocation of these lipoproteins to the outer surface of the Brucella (and other pathogens) outer membrane (OM) remains mostly unknown...

  9. 21 CFR 862.1475 - Lipoprotein test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Lipoprotein test system. 862.1475 Section 862.1475 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  10. Pitavastatin versus Pravastatin in Reduction of Remnant Lipoprotein Cholesterol in Patients with Dyslipidemias.

    Science.gov (United States)

    Roever, Leonardo

    2016-05-01

    Remnant lipoproteins cholesterol are products of partially catabolized chylomicrons and very-low-density lipoprotein, from which some triglycerides have been removed. These particles are smaller and are believed to be strongly atherogenic. Elevated Remnant lipoproteins cholesterol levels were reported to be associated with endothelial dysfunction and atherosclerotic disease.

  11. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro

    DEFF Research Database (Denmark)

    Niemeier, A; Willnow, T; Dieplinger, H

    1999-01-01

    Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein of unknown physiological function. The mechanism of Lp(a) atherogenicity as well as its catabolic pathways are only incompletely understood at present. In this report, we show that the low density lipoprotein receptor (LDLR) gene family member ...

  12. DMPD: Lipoprotein trafficking in vascular cells. Molecular Trojan horses and cellularsaboteurs. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 9287290 Lipoprotein trafficking in vascular cells. Molecular Trojan horses and cell...9287290 Title Lipoprotein trafficking in vascular cells. Molecular Trojan horses ...ularsaboteurs. Hajjar DP, Haberland ME. J Biol Chem. 1997 Sep 12;272(37):22975-8. (.png) (.svg) (.html) (.csml) Show Lipoprotein traf...ficking in vascular cells. Molecular Trojan horses and cellularsaboteurs. PubmedID

  13. Elevated Lipoprotein(A Impairs Platelet Radiolabeling Yield

    Directory of Open Access Journals (Sweden)

    Susanne Granegger

    2015-02-01

    Full Text Available Objectives: Platelet radiolabeling in clinical routine usually results in labeling efficiencies (LE above 80%. A variety of risk factors and clinical conditions are known to impair platelet labeling yield, among them elevated triglycerides and low-density lipoproteins. The potential influence of lipoprotein(a (Lp(a, an atherogenic lipoprotein particle containing a kringle subunit, which is widely found in the proteins of fibrinolysis pathway, has never been studied. Normal Lp(a levels range below 30 mg/ dl. The exact prevalence of elevated Lp(a is unknown, most likely ranging below 10%. Even more rare is an isolated elevation despite an otherwise normal lipoprotein profile. Methods: We examined the role of isolated elevated Lp(a (> 50 mg/dl, ranging up to 440 mg/dl compared to patients with normal lipid profile. Platelets were radiolabeled with in-111-oxine at 37 °C for 5 minutes using ISORBE-consensus methodology. Results: The findings indicate that already at levels below 100 mg/dl Lp(a decreases LE. LE assessment after cross-incubation of hyper-Lp(a platelets with normal Lp(a plasma and vice versa reveals that platelets rather than the plasmatic environment are responsible for the deterioration of labeling yield. This behavior already has been reported for elevated low-density lipoproteins. Apparently, the quantitative influence of LDL and Lp(a/mg is comparable. Plotting the sum of LDL and Lp(a versus LE reveals a clear significant negative correlation. Conclusion: As extremely elevated Lp(a, particularly above 150 mg/dl, may significantly impair labeling results. We therefore recommend to include extremely elevated Lp(a into the list of parameters, which should be known before performing radiolabeling of human platelets.

  14. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 and the intravascular processing of triglyceride-rich lipoproteins.

    Science.gov (United States)

    Adeyo, O; Goulbourne, C N; Bensadoun, A; Beigneux, A P; Fong, L G; Young, S G

    2012-12-01

    Lipoprotein lipase (LPL) is produced by parenchymal cells, mainly adipocytes and myocytes, but is involved in hydrolysing triglycerides in plasma lipoproteins at the capillary lumen. For decades, the mechanism by which LPL reaches its site of action in capillaries was unclear, but this mystery was recently solved. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, 'picks up' LPL from the interstitial spaces and shuttles it across endothelial cells to the capillary lumen. When GPIHBP1 is absent, LPL is mislocalized to the interstitial spaces, leading to severe hypertriglyceridaemia. Some cases of hypertriglyceridaemia in humans are caused by GPIHBP1 mutations that interfere with the ability of GPIHBP1 to bind to LPL, and some are caused by LPL mutations that impair the ability of LPL to bind to GPIHBP1. Here, we review recent progress in understanding the role of GPIHBP1 in health and disease and discuss some of the remaining unresolved issues regarding the processing of triglyceride-rich lipoproteins. © 2012 The Association for the Publication of the Journal of Internal Medicine.

  15. Advanced lipoprotein testing for cardiovascular diseases risk assessment: a review of the novel approaches in lipoprotein profiling.

    Science.gov (United States)

    Clouet-Foraison, Noémie; Gaie-Levrel, Francois; Gillery, Philippe; Delatour, Vincent

    2017-08-28

    With the increasing prevalence of cardiovascular diseases (CVD) worldwide, finding reliable and clinically relevant biomarkers to predict acute cardiovascular events has been a major aim of the scientific and medical community. Improvements of the understanding of the pathophysiological pathways of the disease highlighted the major role of lipoprotein particles, and these past decades have seen the emergence of a number of new methodologies to separate, measure and quantitate lipoproteins. Those methods, also known as advanced lipoprotein testing methods (ALT), have gained acceptance in the field of CVD risk assessment and have proven their clinical relevance. In the context of worldwide standardization and harmonization of biological assays, efforts have been initiated toward standardization of ALT methods. However, the complexity of lipoprotein particles and the multiple approaches and methodologies reported to quantify them have rendered these initiatives a critical issue. In this context and to better understand these challenges, this review presents a summary of the major methods available for ALT with the aim to point out the major differences in terms of procedures and quantities actually measured and to discuss the resulting comparability issues.

  16. Lipoprotein(a) and risk of myocardial infarction--genetic epidemiologic evidence of causality

    DEFF Research Database (Denmark)

    Kamstrup, Pia R; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2011-01-01

    Elevated levels of lipoprotein(a) are associated with an increased risk of myocardial infarction. Our study aimed to test whether genetic data are consistent with this association being causal. Accordingly, we developed a high-throughput realtime PCR assay to genotype for the lipoprotein(a) kringle...... effect on plasma levels of lipoprotein(a). The association of LPA KIV-2 genotypes raising plasma levels of lipoprotein(a) with increased risk of myocardial infarction strongly supports a causal association of lipoprotein(a) with risk of myocardial infarction....

  17. Sorting of bacterial lipoproteins to the outer membrane by the Lol system.

    Science.gov (United States)

    Narita, Shin-ichiro; Tokuda, Hajime

    2010-01-01

    Bacterial lipoproteins comprise a subset of membrane proteins with a lipid-modified cysteine residue at their amino termini through which they are anchored to the membrane. In Gram-negative bacteria, lipoproteins are localized on either the inner or the outer membrane. The Lol system is responsible for the transport of lipoproteins to the outer membrane.The Lol system comprises an inner-membrane ABC transporter LolCDE complex, a periplasmic carrier protein, LolA, and an outer membrane receptor protein, LolB. Lipoproteins are synthesized as precursors in the cytosol and then translocated across the inner membrane by the Sec translocon to the outer leaflet of the inner membrane, where lipoprotein precursors are processed to mature lipoproteins. The LolCDE complex then mediates the release of outer membrane-specific lipoproteins from the inner membrane while the inner membrane-specific lipoproteins possessing Asp at position 2 are not released by LolCDE because it functions as a LolCDE avoidance signal, causing the retention of these lipoproteins in the inner membrane. A water-soluble lipoprotein-LolA complex is formed as a result of the release reaction mediated by LolCDE. This complex traverses the hydrophilic periplasm to reach the outer membrane, where LolB accepts a lipoprotein from LolA and then catalyzes its incorporation into the inner leaflet of the outer membrane.

  18. Lipoprotein profiles of hepatic cell lines at various stages of differentiation.

    Science.gov (United States)

    Sasaki, Akira; Kimura, Fumiko; Miura, Mizuho; Toshima, Gen; Takahashi, Junichiro; Maruya, Sayuri; Kobayashi, Masayuki; Hata, Keishi

    2017-02-01

    We studied the lipoprotein profiles of human hepatic cells at various stages of differentiation. The production of three major classes of lipoproteins, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), was detected in three well-differentiated human hepatoma cell lines and primary human hepatocytes; however, these lipoproteins were not detected in the culture medium in which undifferentiated hepatoma cell lines were grown. Reverse transcription polymerase chain reaction analysis demonstrated that the expression levels of apolipoprotein A1 (ApoA1), ApoB100, and microsomal triglyceride transfer protein (MTP) were markedly lower in the undifferentiated hepatoma cell lines than in the well-differentiated hepatoma cell lines and primary hepatocytes. These results indicate that apolipoprotein synthesis, and triglyceride-transport by MTP might be rate-limiting steps in lipoprotein production in mature hepatic cells.

  19. Distinct Hepatic Receptors for Low Density Lipoprotein and Apolipoprotein E in Humans

    Science.gov (United States)

    Hoeg, Jeffrey M.; Demosky, Stephen J.; Gregg, Richard E.; Schaefer, Ernst J.; Brewer, H. Bryan

    1985-02-01

    Since the liver is a central organ for lipid and lipoprotein synthesis and catabolism, hepatic receptors for specific apolipoproteins on plasma lipoproteins would be expected to modulate lipid and lipoprotein metabolism. The role of hepatic receptors for low density lipoproteins and apolipoprotein E-containing lipoproteins was evaluated in patients with complementary disorders in lipoprotein metabolism: abetalipoproteinemia and homozygous familial hypercholesterolemia. In addition, hepatic membranes from a patient with familial hypercholesterolemia were studied and compared before and after portacaval shunt surgery. The results establish that the human liver has receptors for apolipoproteins B and E. Furthermore, in the human, hepatic receptors for low density lipoproteins and apolipoprotein E are genetically distinct and can undergo independent control.

  20. Remnant lipoprotein size distribution profiling via dynamic light scattering analysis.

    Science.gov (United States)

    Chandra, Richa; Mellis, Birgit; Garza, Kyana; Hameed, Samee A; Jurica, James M; Hernandez, Ana V; Nguyen, Mia N; Mittal, Chandra K

    2016-11-01

    Remnant lipoproteins (RLP) are a metabolically derived subpopulation of triglyceride-rich lipoproteins (TRL) in human blood that are involved in the metabolism of dietary fats or triglycerides. RLP, the smaller and denser variants of TRL particles, are strongly correlated with cardiovascular disease (CVD) and were listed as an emerging atherogenic risk factor by the AHA in 2001. Varying analytical techniques used in clinical studies in the size determination of RLP contribute to conflicting hypotheses in regard to whether larger or smaller RLP particles contribute to CVD progression, though multiple pathways may exist. We demonstrated a unique combinatorial bioanalytical approach involving the preparative immunoseparation of RLP, and dynamic light scattering for size distribution analysis. This is a new facile and robust methodology for the size distribution analysis of RLP that in conjunction with clinical studies may reveal the mechanisms by which RLP cause CVD progression. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Oxidized low-density lipoprotein in postmenopausal women

    DEFF Research Database (Denmark)

    Jankowski, Vera; Just, Alexander R; Pfeilschifter, Johannes;

    2014-01-01

    of this study was to determine the prevalence of serum oxLDL in postmenopausal women and to identify possible associations of clinical and laboratory features with oxLDL in these patients. METHOD: After clinical examination and completing a clinical questionnaire, an ultrasound examination of both carotid.......10-0.43). Although intima-media thickness did not differ, postmenopausal women with serous oxLDL had more often atherosclerotic plaques compared to women without oxLDL (6/66 vs. 0/467; P high-density lipoprotein, impaired glucose intolerance, and DBP were independently associated...... with the occurrence of oxLDL. If oxLDL was present, higher high-density lipoprotein and glucose intolerance were associated with higher concentrations of oxLDL. In contrast, higher blood urea concentrations were associated with lower concentrations of oxLDL. CONCLUSION: This study presents the prevalence...

  2. Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation

    Directory of Open Access Journals (Sweden)

    Klementina Fon Tacer

    2011-01-01

    Full Text Available Obesity with associated comorbidities is currently a worldwide epidemic and among the most challenging health conditions in the 21st century. A major metabolic consequence of obesity is insulin resistance which underlies the pathogenesis of the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD is the hepatic manifestation of obesity and metabolic syndrome. It comprises a disease spectrum ranging from simple steatosis (fatty liver, through nonalcoholic steatohepatitis (NASH to fibrosis, and ultimately liver cirrhosis. Abnormality in lipid and lipoprotein metabolism accompanied by chronic inflammation is the central pathway for the development of metabolic syndrome-related diseases, such as atherosclerosis, cardiovascular disease (CVD, and NAFLD. This paper focuses on pathogenic aspect of lipid and lipoprotein metabolism in NAFLD and the relevant mouse models of this complex multifactorial disease.

  3. [Various lipoprotein fractions and their relation to ischemic heart disease].

    Science.gov (United States)

    Palazzuoli, V; Mondillo, S; Kristodhullu, A; De Stefano, R; Amatucci, G

    1983-01-01

    In a study carried out on over 700 patients with three different manifestations of aterosclerosis (cerebrovascular, coronary and peripheral), we could not find any statistically significant difference between the total cholesterol and triglyceride concentration in these three groups. Also, there was o difference in cholesterol and triglyceride levels between these three groups and 200 normal subjects. The same held true when we compared a selected group of 76 patients with ischaemic heart disease who had no other risk factor, with a group of 80 control subjects. On the contrary, when we compared several fractions of serum lipoproteins and the ratios of apolipoprotein A to Apolipoprotein B, LDL Cholesterol to HDL Cholesterol, and total Cholesterol to HDL Cholesterol of the two groups, the differences were statistically significant. We conclude that when other risk factors are excluded, the protein component, rather than the lipid component of the plasma lipoproteins correlates the presence of coronary artery disease.

  4. [Lipoprotein metabolism in menopause. Effect of hormonal substitution therapy].

    Science.gov (United States)

    Heckers, H; Platt, D

    1991-06-20

    Oral administration of conjugated estrogens, estradiol valerate and micronized estradiol--but not the percutaneous application--in the postmenopause modifies the plasmic lipoprotein profile by lowering, dose-dependently, LDL and elevating HDL (HDL2). In parallel, the cardiovascular mortality is decreased by 50-66%, with smokers also benefiting to the same extent. On account of the increased risk for endometrial carcinoma associated with postmenopausal estrogen monotherapy, combination with a lowest-dose gestagen is imperative. However, the very numerous synthetic gestagens can antagonize the favorable effects of the estrogen on lipoprotein metabolism. This applies in particular to the gestagens of the 19-nortestosterone type, such as norethisterone acetate and, in particular, levonorgestrel, but less so the 17-hydroxyprogesterone derivatives medroxyprogesterone acetate and medrogestone with their very low androgenic effect.

  5. Lipoprotein Nanoplatform for Targeted Delivery of Diagnostic and Therapeutic Agents

    Directory of Open Access Journals (Sweden)

    Jerry D. Glickson

    2008-03-01

    Full Text Available Low-density lipoprotein (LDL provides a highly versatile natural nanoplatform for delivery of visible or near-infrared fluorescent optical and magnetic resonance imaging (MRI contrast agents and photodynamic therapy and chemotherapeutic agents to normal and neoplastic cells that overexpress low-density lipoprotein receptors (LDLRs. Extension to other lipoproteins ranging in diameter from about 10 nm (high-density lipoprotein [HDL] to over a micron (chylomicrons is feasible. Loading of contrast or therapeutic agents onto or into these particles has been achieved by protein loading (covalent attachment to protein side chains, surface loading (intercalation into the phospholipid monolayer, and core loading (extraction and reconstitution of the triglyceride/cholesterol ester core. Core and surface loading of LDL have been used for delivery of optical imaging agents to tumor cells in vivo and in culture. Surface loading was used for delivery of gadolinium-bis-stearylamide contrast agents for in vivo MRI detection in tumor-bearing mice. Chlorin and phthalocyanine near-infrared photodynamic therapy agents (≤ 400/LDL have been attached by core loading. Protein loading was used to reroute the LDL from its natural receptor (LDLR to folate receptors and could be used to target other receptors. A semisynthetic nanoparticle has been constructed by coating magnetite iron oxide nanoparticles with carboxylated cholesterol and overlaying a monolayer of phospholipid to which apolipoprotein A1 or E was adsorbed for targeting HDL or adsorbing synthetic amphipathic helical peptides ltargeting LDL or folate receptors. These particles can be used for in situ loading of magnetite into cells for MRI-monitored cell tracking or gene expression.

  6. Transgenic rabbit that expresses a functional human lipoprotein (a)

    Science.gov (United States)

    Rouy, Didier; Duverger, Nicolas; Emmanuel, Florence; Denefle, Patrice; Houdebine, Louis-Marie; Viglietta, Celine; Rubin, Edward M.; Hughes, Steven D.

    2003-01-01

    A transgenic rabbit which has in its genomic DNA sequences that encode apolipoprotein (a) and apolipoprotein B polypeptides which are capable of combining to produce lipoprotein (a), a process for creating such a rabbit, and the use of the rabbit to identify compounds which are effective in the treatment of human diseases which are associated with, induced and/or exacerbated by Lp(a) expression.

  7. Methods for studying rodent intestinal lipoprotein production and metabolism

    OpenAIRE

    Kohan, Alison B.; Howles, Philip N.; Tso, Patrick

    2012-01-01

    Lipid absorption begins with the digestion of dietary triacylglycerol and ultimately results in the secretion of triacylglycerol in chylomicrons into the lymphatics. Additionally, the intestine also secretes numerous proteins and peptides involved in lipid and lipoprotein metabolism in response to food. Ultimately, chylomicrons and these proteins, peptides, and hormones are found in lymph. The lymph fistula rat model has traditionally been used to study this intestinal absorption of nutrients...

  8. Lipoprotein Modification by Advanced Glycosylation Endproducts (AGEs): Role in Atherosclerosis.

    Science.gov (United States)

    Bucala, R

    1997-02-01

    Recent progress in our understanding of advanced glycosylation reactions in vivo has affirmed the hypothesis that these products play an important role in the evolution of both diabetic and nondiabetic vascular disease. Utilizing newly developed advanced glycosylation end-products (AGE)-specific enzyme-linked immunosorbent assay (ELISA) techniques, AGEs have been identified to be present on a variety of vascular wall, lipoprotein, and lipid constituents. Vascular wall AGEs contribute to vascular pathology by increasing vascular permeability, enhancing subintimal protein and lipoprotein deposition, and inactivating nitric oxide. Lipid-linked AGEs present in low-density lipoprotein (LDL) also have been shown to initiate oxidative modification, promoting oxidation reactions that may proceed without the involvement of free metals or other radical generating systems. AGE-specific ELISA analysis has demonstrated a significantly increased level of AGE-modified LDL in the plasma of diabetic patients when compared to normal controls. AGE-modification impairs LDL-receptor-mediated clearance mechanisms in vivo and may contribute to elevated LDL levels in patients with diabetes. This concept has been substantiated further by the recent clinical observations that administration of the advanced glycosylation inhibitor aminoguanidine to diabetic patients significantly decreases circulating LDL levels. (Trends Cardiovasc Med 1997;7:39-47). © 1997, Elsevier Science Inc.

  9. Leptin levels and lipoprotein profiles in patients with cholelithiasis.

    Science.gov (United States)

    Saraç, Serdar; Atamer, Aytaç; Atamer, Yildiz; Can, Ahmet Selçuk; Bilici, Aslan; Taçyildiz, İbrahim; Koçyiğit, Yüksel; Yenice, Necati

    2015-06-01

    To determine the relationships between serum leptin and levels of lipoprotein(a) [Lp(a)], apolipoprotein A-1 (ApoA-1) and apolipoprotein B (ApoB) in patients with cholelithiasis. Patients with ultrasound-confirmed cholelithiasis and controls frequency-matched for age, sex, body mass index, fasting blood glucose and haemoglobin A1c levels were recruited. Fasting blood samples from all study participants were assayed for glucose, haemoglobin A1c, total cholesterol, high density lipoprotein-cholesterol (HDL-C) and triglyceride. Serum Lp(a), ApoA-1 and ApoB levels were measured using nephelometric assays; serum leptin was measured using an enzyme-linked immunosorbent assay. A total of 90 patients with cholelithiasis and 50 controls were included in the study. Serum levels of leptin, Lp(a), total cholesterol, triglyceride and ApoB were significantly increased, and levels of ApoA-1 and HDL-C were significantly decreased, in patients with cholelithiasis compared with controls. Serum leptin in patients with cholelithiasis were significantly positively correlated with Lp(a) and ApoB and negatively correlated with ApoA-1. Patients with cholelithiasis have higher leptin levels and an altered lipoprotein profile compared with controls, with increased leptin levels being associated with increased Lp(a) and ApoB levels, and decreased ApoA-1 levels, in those with cholelithiasis. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  10. Central nervous system regulation of intestinal lipid and lipoprotein metabolism.

    Science.gov (United States)

    Farr, Sarah; Taher, Jennifer; Adeli, Khosrow

    2016-02-01

    In response to nutrient availability, the small intestine and brain closely communicate to modulate energy homeostasis and metabolism. The gut-brain axis involves complex nutrient sensing mechanisms and an integration of neuronal and hormonal signaling. This review summarizes recent evidence implicating the gut-brain axis in regulating lipoprotein metabolism, with potential implications for the dyslipidemia of insulin resistant states. The intestine and brain possess distinct mechanisms for sensing lipid availability, which triggers subsequent regulation of feeding, glucose homeostasis, and adipose tissue metabolism. More recently, central receptors, neuropeptides, and gut hormones that communicate with the brain have been shown to modulate hepatic and intestinal lipoprotein metabolism via parasympathetic and sympathetic signaling. Gut-derived glucagon-like peptides appear to be particularly important in modulating the intestinal secretion of chylomicron particles via a novel brain-gut axis. Dysregulation of these pathways may contribute to postprandial diabetic dyslipidemia. Emerging evidence implicates the central and enteric nervous systems in controlling many aspects of lipid and lipoprotein metabolism. Bidirectional communication between the gut and brain involving neuronal pathways and gut peptides is critical for regulating feeding and metabolism, and forms a neuroendocrine circuit to modulate dietary fat absorption and intestinal production of atherogenic chylomicron particles.

  11. Triglyceride-Rich Lipoproteins and Remnants: Targets for Therapy?

    Science.gov (United States)

    Dallinga-Thie, Geesje M; Kroon, Jeffrey; Borén, Jan; Chapman, M John

    2016-07-01

    It is now evident that elevated circulating levels of triglycerides in the non-fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin-like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC-III appear to hold considerable promise.

  12. Learning from biology: synthetic lipoproteins for drug delivery.

    Science.gov (United States)

    Huang, Huang; Cruz, William; Chen, Juan; Zheng, Gang

    2015-01-01

    Synthetic lipoproteins represent a relevant tool for targeted delivery of biological/chemical agents (chemotherapeutics, siRNAs, photosensitizers, and imaging contrast agents) into various cell types. These nanoparticles offer a number of advantages for drugs delivery over their native counterparts while retaining their natural characteristics and biological functions. Their ultra-small size (class B member 1 (SRB1) that are found in a number of pathological conditions (e.g., cancer, atherosclerosis), make them superior delivery strategies when compared with other nanoparticle systems. We review the various approaches that have been developed for the generation of synthetic lipoproteins and their respective applications in vitro and in vivo. More specifically, we summarize the approaches employed to address the limitation on use of reconstituted lipoproteins by means of natural or recombinant apolipoproteins, as well as apolipoprotein mimetic molecules. Finally, we provide an overview of the advantages and disadvantages of these approaches and discuss future perspectives for clinical translation of these nanoparticles. © 2014 Wiley Periodicals, Inc.

  13. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

    DEFF Research Database (Denmark)

    Chapman, M John; Ginsberg, Henry N; Amarenco, Pierre

    2011-01-01

    Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipop...

  14. Characteristics of Lipoprotein Peak x Eluted from a Column with the Eluent of High-magnesium Ion Concentration in Lipoprotein Analysis Using the Cation-exchange Chromatography

    Directory of Open Access Journals (Sweden)

    Yuji Hirowatari

    2005-01-01

    Full Text Available The new lipoprotein analysis method using a cation-exchange chromatography, which contains a sulfopropyl-ligand column and two magnesium ion-containing eluents was previously reported. This method can separate serum lipoproteins on the column gel with a magnesium ion concentration gradient and high-density lipoprotein (HDL, low-density lipoprotein (LDL, very-low-density lipoprotein (VLDL and an unspecified lipoprotein peak are eluted in order from the column. We have now characterized the unspecified lipoproteins, designated peak x, which is last eluted from the column with the eluent of high-magnesium ion concentration. The peak x was small size chylomicron fraction with a part of VLDL. Furthermore, the cholesterol values in the peak x were significantly correlated with remnant-like particle (RLP-cholesterol values. The peak x separated from a hyperlipidemic patient included apolipoprotein B-100, B-48, E, A-1 and Cs (C-I, C-II, C-III and its composition of free cholesterol, cholesteryl esters, triglyceride (TG and phospholipids in total lipids were 6, 15, 66 and 13%, respectively. These results suggest that a major part of the lipoprotein peak X may be composed of remnants of chylomicron and VLDL, but it remains to be elucidated.

  15. Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, Triglycerides, and Apolipoprotein B and Cardiovascular Risk in Patients With Manifest Arterial Disease

    NARCIS (Netherlands)

    van den Berg, M Johanneke; van der Graaf, Yolanda; de Borst, Gert Jan; Kappelle, L Jaap; Nathoe, Hendrik M; Visseren, Frank L J

    2016-01-01

    Low-density lipoprotein cholesterol (LDL-C) only partly represents the atherogenic lipid burden, and a growing body of evidence suggests that non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and apolipoprotein B (apoB) are more accurate in estimating lipid-related cardiovascular

  16. Quantitative fluorescence imaging reveals point of release for lipoproteins during LDLR-dependent uptake[S

    Science.gov (United States)

    Pompey, Shanica; Zhao, Zhenze; Luby-Phelps, Kate; Michaely, Peter

    2013-01-01

    The LDL receptor (LDLR) supports efficient uptake of both LDL and VLDL remnants by binding lipoprotein at the cell surface, internalizing lipoprotein through coated pits, and releasing lipoprotein in endocytic compartments before returning to the surface for further rounds of uptake. While many aspects of lipoprotein binding and receptor entry are well understood, it is less clear where, when, and how the LDLR releases lipoprotein. To address these questions, the current study employed quantitative fluorescence imaging to visualize the uptake and endosomal processing of LDL and the VLDL remnant β-VLDL. We find that lipoprotein release is rapid, with most release occurring prior to entry of lipoprotein into early endosomes. Published biochemical studies have identified two mechanisms of lipoprotein release: one that involves the β-propeller module of the LDLR and a second that is independent of this module. Quantitative imaging comparing uptake supported by the normal LDLR or by an LDLR variant incapable of β-propeller-dependent release shows that the β-propeller-independent process is sufficient for release for both lipoproteins but that the β-propeller process accelerates both LDL and β-VLDL release. Together these findings define where, when, and how lipoprotein release occurs and provide a generalizable methodology for visualizing endocytic handling in situ. PMID:23296879

  17. Quantitative fluorescence imaging reveals point of release for lipoproteins during LDLR-dependent uptake.

    Science.gov (United States)

    Pompey, Shanica; Zhao, Zhenze; Luby-Phelps, Kate; Michaely, Peter

    2013-03-01

    The LDL receptor (LDLR) supports efficient uptake of both LDL and VLDL remnants by binding lipoprotein at the cell surface, internalizing lipoprotein through coated pits, and releasing lipoprotein in endocytic compartments before returning to the surface for further rounds of uptake. While many aspects of lipoprotein binding and receptor entry are well understood, it is less clear where, when, and how the LDLR releases lipoprotein. To address these questions, the current study employed quantitative fluorescence imaging to visualize the uptake and endosomal processing of LDL and the VLDL remnant β-VLDL. We find that lipoprotein release is rapid, with most release occurring prior to entry of lipoprotein into early endosomes. Published biochemical studies have identified two mechanisms of lipoprotein release: one that involves the β-propeller module of the LDLR and a second that is independent of this module. Quantitative imaging comparing uptake supported by the normal LDLR or by an LDLR variant incapable of β-propeller-dependent release shows that the β-propeller-independent process is sufficient for release for both lipoproteins but that the β-propeller process accelerates both LDL and β-VLDL release. Together these findings define where, when, and how lipoprotein release occurs and provide a generalizable methodology for visualizing endocytic handling in situ.

  18. Lipoprotein subfractions highly associated with renal damage in familial lecithin:cholesterol acyltransferase deficiency.

    Science.gov (United States)

    Kuroda, Masayuki; Holleboom, Adriaan G; Stroes, Erik S G; Asada, Sakiyo; Aoyagi, Yasuyuki; Kamata, Kouju; Yamashita, Shizuya; Ishibashi, Shun; Saito, Yasushi; Bujo, Hideaki

    2014-08-01

    In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD. © 2014 American Heart Association, Inc.

  19. Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention

    Directory of Open Access Journals (Sweden)

    Jesús Millán

    2009-09-01

    Full Text Available Jesús Millán1, Xavier Pintó2, Anna Muñoz3, Manuel Zúñiga4, Joan Rubiés-Prat5, Luis Felipe Pallardo6, Luis Masana7, Alipio Mangas8, Antonio Hernández-Mijares9, Pedro González-Santos10, Juan F Ascaso11, Juan Pedro-Botet121Hospital Universitario Gregorio Marañón, Madrid, Spain; 2Hospital Universitario Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain; 3Solvay Pharma, Barcelona, Spain; 4Hospital Marqués de Valdecilla, Santander, Spain; 5Hospital Vall d’Hebrón, Barcelona, Spain; 6Hospital Universitario La Paz, Madrid, Spain; 7Hospital Sant Joan, Reus, Tarragona, Spain; 8Hospital Universitario Puerta del Mar, Cádiz, Spain; 9Hospital Universitario Dr Peset, Valencia, Spain; 10Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain; 11Hospital Clínico Universitario, Valencia, Spain; 12Hospital del Mar, Barcelona, SpainAbstract: Low-density lipoprotein (LDL cholesterol concentration has been the prime index of cardiovascular disease risk and the main target for therapy. However, several lipoprotein ratios or “atherogenic indices” have been defined in an attempt to optimize the predictive capacity of the lipid profile. In this review, we summarize their pathophysiological aspects, and highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy. Total/high-density lipoprotein (HDL cholesterol and LDL/HDL cholesterol ratios are risk indicators with greater predictive value than isolated parameters used independently, particularly LDL. Future recommendations regarding the diagnosis and treatment of dyslipidemia, including instruments for calculating cardiovascular risk or action guidelines, should include the lipoprotein ratios with greater predictive power which, in view of the evidence-based results, are none other than those which include HDL cholesterol.Keywords: apolipoproteins

  20. Lipoprotein Kinetics in Male Hemodialysis Patients Treated with Atorvastatin

    Science.gov (United States)

    Schwaiger, Johannes P.; Nakada, Yoshinobu; Berberich, Ramona; Ikewaki, Katsunori; Dieplinger, Benjamin; Zitt, Emanuel; Neyer, Ulrich; Salmhofer, Hermann; Kronenberg, Florian; Koenig, Paul

    2013-01-01

    Summary Background and objectives In vivo metabolism of atherogenic apolipoprotein B (apoB)–containing lipoproteins is severely impaired in patients undergoing hemodialysis (HD), resulting in markedly prolonged residence times of these particles. It is unclear whether treatment with statins improves LDL kinetics in HD patients as is known for the general population. Therefore, this kinetic study assessed apoB-containing lipoproteins in these patients. Design, setting, participants, & measurements Kinetic measures were analyzed with stable-isotope technology in six men undergoing HD before and after 3 months of daily administration of 10 mg of atorvastatin. Patients were 18–65 years of age, had LDL cholesterol levels between 90 and 200 mg/dl, and had been treated with HD for >6 months. They consumed a standardized isocaloric diet for 3 days before analysis. Fractional catabolic rates (FCRs) and production rates of very-low-density lipoprotein (VLDL)–apoB, intermediate-density lipoprotein–apoB, and LDL-apoB were determined using multicompartment modeling after plasma lipoprotein separation, precipitation of apoB, and determination of tracer-to-tracee ratios using mass spectrometry. Results Plasma concentrations of VLDL- and LDL-apoB were significantly lower (mean ± SD, 7.77±2.62 versus 11.27±6.15 mg/dl, P<0.05; 56.9±23.9 versus 84.0±21.1 mg/dl, P=0.03) and their FCRs were significantly higher (7.20±3.08 versus 5.20±2.98 days−1, P<0.05; 0.851±0.772 versus 0.446±0.232 days−1, P<0.05) after 3 months of atorvastatin treatment. Accordingly, the residence times in plasma of VLDL- and LDL-apoB were significantly lower after treatment (0.14 versus 0.19 day and 1.2 versus 2.2 days, respectively). Conclusion Lower plasma concentrations and improved kinetics of atherogenic lipoproteins were observed in HD patients after administration of low-dose atorvastatin. PMID:23599405

  1. Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase.

    Science.gov (United States)

    Nakajima, Katsuyuki; Tokita, Yoshiharu; Sakamaki, Koji; Shimomura, Younosuke; Kobayashi, Junji; Kamachi, Keiko; Tanaka, Akira; Stanhope, Kimber L; Havel, Peter J; Wang, Tao; Machida, Tetsuo; Murakami, Masami

    2017-02-01

    Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma. TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal. RLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal. Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Sorting of an integral outer membrane protein via the lipoprotein-specific Lol pathway and a dedicated lipoprotein pilotin.

    Science.gov (United States)

    Collin, Séverine; Guilvout, Ingrid; Nickerson, Nicholas N; Pugsley, Anthony P

    2011-05-01

    The lipoprotein PulS is a dedicated chaperone that is required to target the secretin PulD to the outer membrane in Klebsiella or Escherichia coli, and to protect it from proteolysis. Here, we present indirect evidence that PulD protomers do not assemble into the secretin dodecamer before they reach the outer membrane, and that PulS reaches the outer membrane in a soluble heterodimer with the general lipoprotein chaperone LolA. However, we could not find any direct evidence for PulD protomer association with the PulS-LolA heterodimer. Instead, in cells producing PulD and a permanently locked PulS-LolA dimer (in which LolA carries an R43L substitution that prevents lipoprotein transfer to LolB in the outer membrane), LolAR43L was found in the inner membrane, probably still associated with PulS bound to PulD that had been incorrectly targeted because of the LolAR43L substitution. It is speculated that PulD protomers normally cross the periplasm together with PulS bound to LolA but when the latter cannot be separated (due to the mutation in lolA), the PulD protomers form dodecamers that insert into the inner membrane.

  3. Expression of scavenger receptor-BI and low-density lipoprotein receptor and differential use of lipoproteins to support early steroidogenesis in luteinizing macaque granulosa cells.

    Science.gov (United States)

    Cherian-Shaw, Mary; Puttabyatappa, Muraly; Greason, Erin; Rodriguez, Annabelle; VandeVoort, Catherine A; Chaffin, Charles L

    2009-02-01

    An ovulatory hCG stimulus to rhesus macaques undergoing controlled ovarian stimulation protocols results in a rapid and sustained increase in progesterone synthesis. The use of lipoproteins as a substrate for progesterone synthesis remains unclear, and the expression of lipoprotein receptors [very-low-density lipoprotein receptor (VLDLR), low-density lipoprotein receptor (LDLR), and scavenger receptor-BI (SR-BI)] soon after human chorionic gonadotropin (hCG) (lipoprotein receptor expression and lipoprotein (VLDL, LDL, and HDL) support of steroidogenesis during luteinization of macaque granulosa cells. Granulosa cells were aspirated from rhesus monkeys undergoing controlled ovarian stimulation before or up to 24 h after an ovulatory hCG stimulus. The expression of VLDLR decreased within 3 h of hCG, whereas LDLR and SR-BI increased at 3 and 12 h, respectively. Granulosa cells isolated before hCG were cultured for 24 h in the presence of FSH or FSH plus hCG with or without VLDL, LDL, or HDL. Progesterone levels increased in the presence of hCG regardless of lipoprotein addition, although LDL, but not HDL, further augmented hCG-induced progesterone. Other cells were cultured with FSH or FSH plus hCG without an exogenous source of lipoprotein for 24 h, followed by an additional 24 h culture with or without lipoproteins. Cells treated with hCG in the absence of any lipoprotein were unable to maintain progesterone levels through 48 h, whereas LDL (but not HDL) sustained progesterone synthesis. These data suggest that an ovulatory stimulus rapidly mobilizes stored cholesterol esters for use as a progesterone substrate and that as these are depleted, new cholesterol esters are obtained through an LDLR- and/or SR-BI-mediated mechanism.

  4. Remnant lipoproteins induced proliferation of human prostate cancer cell, PC-3 but not LNCaP, via low density lipoprotein receptor.

    Science.gov (United States)

    Sekine, Yoshitaka; Koike, Hidekazu; Nakano, Takamitsu; Nakajima, Katsuyuki; Takahashi, Sadao; Suzuki, Kazuhiro

    2009-07-01

    Hypertriglyceridemia has been shown to be one of the risk factors for prostate cancer. In this study, we investigated the effect of remnant lipoproteins on cell growth in prostate cancer cell lines. Remnant lipoproteins were isolated as remnant like particles (RLP) from human plasma. We used RLP for TG-rich lipoproteins and low density lipoproteins (LDL) for cholesterol-rich lipoproteins respectively and examined the effect of lipoproteins on proliferation of PC-3 and LNCaP cells using MTS assays. Moreover, we studied the effect of RLP and LDL treatment on the regulation of lipoprotein receptors in prostate cancer cells to investigate the relationship between lipoprotein-induced cell proliferation and lipoprotein receptor expression using real-time PCR, Western blotting assays and siRNA. RLP effectively induced PC-3 cell proliferation more than LDL, whereas both RLP and LDL could not induce LNCaP cell proliferation except at a higher concentration of RLP. LDL receptor (LDLr) was expressed in both prostate cancer cells but there was a sharp difference of sterol regulation between two cells. In PC-3 cells, LDL decreased the LDLr expression in some degree, but RLP did not. Meanwhile LDLr expression in LNCaP was easily downregulated by RLP and LDL. Blocking LDLr function significantly inhibited both RLP- and LDL-induced PC-3 cell proliferation. This study demonstrated that RLP-induced PC-3 cell proliferation more than LDL; however, both RLP and LDL hardly induced LNCaP cell proliferation. The differences of proliferation by lipoproteins might be involved in the regulation of LDLr expression.

  5. Identification of a New Lipoprotein Export Signal in Gram-Negative Bacteria.

    Science.gov (United States)

    Lauber, Frédéric; Cornelis, Guy Richard; Renzi, Francesco

    2016-10-25

    Bacteria of the phylum Bacteroidetes, including commensal organisms and opportunistic pathogens, harbor abundant surface-exposed multiprotein membrane complexes (Sus-like systems) involved in carbohydrate acquisition. These complexes have been mostly linked to commensalism, and in some instances, they have also been shown to play a role in pathogenesis. Sus-like systems are mainly composed of lipoproteins anchored to the outer membrane and facing the external milieu. This lipoprotein localization is uncommon in most studied Gram-negative bacteria, while it is widespread in Bacteroidetes Little is known about how these complexes assemble and particularly about how lipoproteins reach the bacterial surface. Here, by bioinformatic analyses, we identify a lipoprotein export signal (LES) at the N termini of surface-exposed lipoproteins of the human pathogen Capnocytophaga canimorsus corresponding to K-(D/E)2 or Q-A-(D/E)2 We show that, when introduced in sialidase SiaC, an intracellular lipoprotein, this signal is sufficient to target the protein to the cell surface. Mutational analysis of the LES in this reporter system showed that the amino acid composition, position of the signal sequence, and global charge are critical for lipoprotein surface transport. These findings were further confirmed by the analysis of the LES of mucinase MucG, a naturally surface-exposed C. canimorsus lipoprotein. Furthermore, we identify a LES in Bacteroides fragilis and Flavobacterium johnsoniae surface lipoproteins that allow C. canimorsus surface protein exposure, thus suggesting that Bacteroidetes share a new bacterial lipoprotein export pathway that flips lipoproteins across the outer membrane. Bacteria of the phylum Bacteroidetes are important human commensals and pathogens. Understanding their biology is therefore a key question for human health. A main feature of these bacteria is the presence of abundant lipoproteins at their surface that play a role in nutrient acquisition. To

  6. Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection

    DEFF Research Database (Denmark)

    Stylianou, E; Aukrust, P; Bendtzen, K;

    2000-01-01

    Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV...... seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-alpha in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART....

  7. Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome.

    Science.gov (United States)

    Arca, Marcello

    2015-02-01

    Diabetes and metabolic syndrome are associated with abnormal postprandial lipoprotein metabolism, with a significant delay in the clearance of many lipid parameters, including triglycerides and chylomicrons. Abnormal concentrations of plasma lipids can result from changes in the production, conversion, or catabolism of lipoprotein particles. Whereas the liver is involved in controlling serum lipid levels through synthesis of liver derived triglyceride-rich lipoproteins and low-density lipoprotein metabolism, the intestine also has a major role in lipoprotein production. Postprandial lipemia results from increases in apoB-48 availability, lipogenesis, and the synthesis and absorption of cholesterol in the enterocytes. Increased intestinal lipoprotein production prolongs postprandial lipemia in patients with diabetes and MetS, and may contribute directly to atherogenesis in these patients. © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women.

    Science.gov (United States)

    Mutlu-Türkoğlu, U; Oztezcan, S; Telci, A; Orhan, Y; Aykaç-Toker, G; Sivas, A; Uysal, M

    2003-02-01

    Endogenous malondialdehyde and diene conjugate levels, the susceptibility of apolipoprotein B-containing lipoproteins to copper-induced lipid peroxidation, and antibody titer against oxidized low-density lipoproteins were increased, but serum antioxidant activity was unchanged in obese women. Serum cholesterol, low-density lipoproteincholesterol, and trigliceride levels were also elevated, but high-density lipoprotein-cholesterol levels remained unchanged in obese women. In vitro, oxidation of apolipoprotein B-containing lipoproteins and levels of antibody against oxidized low-density lipoprotein correlated with body mass index, serum total cholesterol, and low-density lipoproteincholesterol levels in obese women. These results indicate that obesity is associated with increases in endogenous lipid peroxides, oxidation of low-density lipoproteins, and lipids in serum.

  9. Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia.

    Science.gov (United States)

    Kockx, Maaike; Glaros, Elias; Leung, Betty; Ng, Theodore W; Berbée, Jimmy F P; Deswaerte, Virginie; Nawara, Diana; Quinn, Carmel; Rye, Kerry-Anne; Jessup, Wendy; Rensen, Patrick C N; Meikle, Peter J; Kritharides, Leonard

    2016-07-01

    Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)). Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing

  10. LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients.

    Science.gov (United States)

    Vongpromek, Ranitha; Bujo, Hideaki; Hoekstra, Menno; Schneider, Wolfgang J; van der Zee, Leonie; Schinkel, Arend F L; Korporaal, Suzanne J A; Dik, Willem A; Ebinuma, Hiroyuki; Jiang, Meizi; Verhoeven, Adrie J M; Sijbrands, Eric J G; Mulder, Monique T

    2015-12-01

    Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr(-/-)) mice. In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr(-/-) and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr(-/-) in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe(-/-) mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL. Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Lipoprotein Subfractions in Metabolic Syndrome and Obesity: Clinical Significance and Therapeutic Approaches

    OpenAIRE

    Manfredi Rizzo; Mikhailidis, Dimitri P.; Isenovic, Esma R.; Dragana Nikolic; Niki Katsiki; Giuseppe Montalto

    2013-01-01

    Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) ...

  12. Studies on the Formation of Murein-Bound Lipoprotein in Escherichia coli

    Science.gov (United States)

    1992-05-15

    Proteus mirabilis, Morqanella morqanii, Erwinia amylovora and serratia marcescens, and in Pseudomonas aeruqinosa lipoprotein I (Fig. 5., YU, 1987... Erwinia amylovora lipoprotein gene. J. Biol. Chern. 256:2194-2198. Yamaguchi, K., and Inouye, M. (1988). Lipoprotein 28, an inner membrane protein of...et AI., 1983), ~. amylovora (Yamagata et li., 1981) and ~. marcescens (Braun et al., 1970), and in .E. aeruginosa (Mizuno and Kageyama, 1979). Like

  13. Recurrent Embolic Strokes of Undetermined Source in a Patient with Extreme Lipoprotein(a) Levels.

    Science.gov (United States)

    Bulwa, Zachary; Kim, Audrey; Singh, Karandeep; Kantorovich, Alexander; Suhail, Faten

    2016-01-01

    Lipoprotein(a) is a plasma lipoprotein and known cardiovascular risk factor, most recently implicated in the development of high-risk carotid atherosclerotic plaques without significant carotid stenosis. We present a case of a young African-American female with recurrent embolic strokes of undetermined source. After our thorough investigation, we identified the link between a small, irregular plaque in the right internal carotid artery, and an extremely elevated plasma level of lipoprotein(a) as the source of her embolic strokes.

  14. Characterization of the Pseudomonas aeruginosa Lol system as a lipoprotein sorting mechanism.

    Science.gov (United States)

    Tanaka, Shin-Ya; Narita, Shin-Ichiro; Tokuda, Hajime

    2007-05-04

    Escherichia coli lipoproteins are localized to either the inner or the outer membrane depending on the residue that is present next to the N-terminal acylated Cys. Asp at position 2 causes the retention of lipoproteins in the inner membrane. In contrast, the accompanying study (9) revealed that the residues at positions 3 and 4 determine the membrane specificity of lipoproteins in Pseudomonas aeruginosa. Since the five Lol proteins involved in the sorting of E. coli lipoproteins are conserved in P. aeruginosa, we examined whether or not the Lol proteins of P. aeruginosa are also involved in lipoprotein sorting but utilize different signals. The genes encoding LolCDE, LolA, and LolB homologues were cloned and expressed. The LolCDE homologue thus purified was reconstituted into proteoliposomes with lipoproteins. When incubated in the presence of ATP and a LolA homologue, the reconstituted LolCDE homologue released lipoproteins, leading to the formation of a LolA-lipoprotein complex. Lipoproteins were then incorporated into the outer membrane depending on a LolB homologue. As revealed in vivo, lipoproteins with Lys and Ser at positions 3 and 4, respectively, remained in proteoliposomes. On the other hand, E. coli LolCDE released lipoproteins with this signal and transferred them to LolA of not only E. coli but also P. aeruginosa. These results indicate that Lol proteins are responsible for the sorting of lipoproteins to the outer membrane of P. aeruginosa, as in the case of E. coli, but respond differently to inner membrane retention signals.

  15. Lipoprotein particle subclass profiles among metabolically healthy and unhealthy obese and non-obese adults: does size matter?

    Science.gov (United States)

    Phillips, Catherine M; Perry, Ivan J

    2015-10-01

    No data regards lipoprotein particle profiles in obese and non-obese metabolic health subtypes exist. We characterised lipoprotein size, particle and subclass concentrations among metabolically healthy and unhealthy obese and non-obese adults. Cross-sectional sample of 1834 middle-aged Irish adults were classified as obese (BMI ≥30 kg/m(2)) and non-obese (BMI Lipoprotein size, particle and subclass concentrations were determined using nuclear magnetic resonance (NMR) spectroscopy. Lipoprotein profiling identified a range of adverse phenotypes among the metabolically unhealthy individuals, regardless of BMI and metabolic health definition, including increased numbers of small low density lipoprotein (LDL) (P lipoprotein (HDL) particles (P lipoprotein (VLDL) particles (P lipoprotein related insulin resistance (P lipoprotein particle profiles, irrespective of BMI and metabolic health definition. These findings underscore the importance of maintaining a healthy lipid profile in the context of overall cardiometabolic health. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Recent advances in lipoprotein and atherosclerosis: A nutrigenomic approach

    Directory of Open Access Journals (Sweden)

    López, Sergio

    2009-03-01

    Full Text Available Atherosclerosis is a disease in which multiple factors contribute to the degeneration of the vascular wall. Many risk factors have been identified as having influence on the progression of atherosclerosis among them, the type of diet. Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognised as the basis of atherogenesis. Dietary intake affects lipoprotein concentration and composition providing risk or protection at several stages of atherosclerosis. More intriguingly, it has been demonstrated that the extent to which each lipid or lipoprotein is associated with cardiovascular disease depends on the time to last meal; thus, postprandial lipoproteins, main lipoproteins in blood after a high-fat meal, have been shown to strongly influence atherogenesis. As a complex biological process, the full cellular and molecular characterization of atherosclerosis derived by diet, calls for application of the newly developing “omics” techniques of analysis. This review will considered recent studies using high-throughput technologies and a nutrigenomic approach to reveal the patho-physiological effects that the fasting and postprandial lipoproteins may exert on the vascular wall.La aterosclerosis es una enfermedad en la que múltiples factores, entre los que se encuentra la dieta, contribuyen a la degradación de la pared vascular. En la etiología de la aterogénesis son determinantes las lipoproteínas plasmáticas y los distintos tipos celulares de la pared vascular, incluyendo una respuesta inflamatoria. La ingesta de alimentos afecta la concentración y composición de las lipoproteínas, ejerciendo un papel de riesgo o protector durante las diferentes etapas del proceso aterosclerótico. Es importante destacar que la naturaleza de las lipoproteínas y por lo tanto su papel en la enfermedad cardiovascular, también depende del tiempo transcurrido entre comidas. Por ejemplo, las lipoprote

  17. Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice.

    Science.gov (United States)

    Sberna, Anne-Laure; Assem, Mahfoud; Xiao, Rui; Ayers, Steve; Gautier, Thomas; Guiu, Boris; Deckert, Valérie; Chevriaux, Angélique; Grober, Jacques; Le Guern, Naig; Pais de Barros, Jean-Paul; Moore, David D; Lagrost, Laurent; Masson, David

    2011-10-01

    The goal of this study was to determine the impact of the nuclear receptor constitutive androstane receptor (CAR) on lipoprotein metabolism and atherosclerosis in hyperlipidemic mice. Low-density lipoprotein receptor-deficient (Ldlr(-/-)) and apolipoprotein E-deficient (ApoE(-/-)) mice fed a Western-type diet were treated weekly with the Car agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or the vehicle only for 8 weeks. In Ldlr(-/-) mice, treatment with TCPOBOP induced a decrease in plasma triglyceride and intermediate-density lipoprotein/low-density lipoprotein cholesterol levels (≈30% decrease in both cases after 2 months, Plipoproteins associated with a decrease in hepatic triglyceride content and the repression of several genes involved in lipogenesis. TCPOBOP treatment also induced a marked increase in the very-low-density lipoprotein receptor in the liver, which probably contributed to the decrease in intermediate-density lipoprotein/low-density lipoprotein levels. Atherosclerotic lesions in the aortic valves of TCPOBOP-treated Ldlr(-/-) mice were also reduced (-60%, Plipoprotein receptor, the effect of TCPOBOP on plasma cholesterol levels and the development of atherosclerotic lesions was markedly attenuated. CAR is a potential target in the prevention and treatment of hypercholesterolemia and atherosclerosis.

  18. Apolipoprotein-containing lipoprotein subclasses and subclinical atherosclerosis in systemic lupus erythematosus.

    Science.gov (United States)

    Kiani, Adnan N; Fang, Hong; Akhter, Ehtisham; Quiroga, Carmen; Simpson, Nancy; Alaupovic, Petar; Magder, Laurence S; Petri, Michelle

    2015-03-01

    Traditional classification of hyperlipidemia using high-density lipoprotein, low-density lipoprotein (LDL), and very low-density lipoprotein does not provide information on lipoprotein function. Apolipoproteins (Apos), which are protein components of plasma lipoproteins (including A, B, C, D, E) with their different composition, metabolic, and atherogenic properties, provide insight on lipoprotein functioning. In particular, the Apo B/A-I ratio is associated with atherogenic LDL and development of cardiovascular disease. We explored the baseline association between these nontraditional risk factors with subclinical measures of atherosclerosis (coronary artery calcification [CAC] and carotid intima-media thickness [IMT]) in systemic lupus erythematosus (SLE). A total of 58 SLE patients (97% women, 58% white, 40% African American, and 2% other, mean ± SD age 44 ± 11 years) had measurement of Apo and lipoproteins by immunoturbidimetric procedures, electroimmunoassays, and immunoprecipitation. CAC was measured by helical computed tomography and carotid IMT by carotid duplex. This study was based on the baseline assessment of subclinical atherosclerosis in the Lupus Atherosclerosis Prevention Study. The measurement of the lipoproteins was made on sera collected at the same time. There was no association between cardioprotective Apos (Apo A-I, LpA-I, LpA-I:A-II) and CAC (P Systemic Lupus Erythematosus Disease Activity Index, were not associated with CAC or carotid IMT. Neither cardioprotective nor atherogenic lipoproteins were associated with measures of subclinical atherosclerosis in this series of SLE patients. Further studies with a larger sample size are warranted to confirm our findings.

  19. Analysis of lipoprotein profiles of healthy cats by gel-permeation high-performance liquid chromatography.

    Science.gov (United States)

    Mizutani, Hisashi; Sako, Toshinori; Okuda, Hiroko; Arai, Nobuaki; Kuriyama, Koji; Mori, Akihiro; Yoshimura, Itaru; Koyama, Hidekazu

    2016-09-01

    Density gradient ultracentrifugation (DGUC) and gel electrophoresis are conventionally used to obtain lipoprotein profiles of animals. We recently applied high-performance liquid chromatography with a gel permeation column (GP-HPLC) and an on-line dual enzymatic system to dogs for lipoprotein profile analysis. We compared the GP-HPLC with DGUC as a method to obtain a feline lipoprotein profile. The lipoprotein profiles showed large and small peaks, which corresponded to high-density lipoprotein (HDL) and low-density lipoprotein (LDL), respectively, whereas very low-density lipoprotein (VLDL) and chylomicron (CM) were only marginally detected. This profile was very similar to that of dogs reported previously. Healthy cats also had a small amount of cholesterol-rich particles distinct from the normal LDL or HDL profile. There was no difference in lipoprotein profiles between the sexes, but males had a significantly larger LDL particle size (P=0.015). This study shows the feasibility of GP-HPLC for obtaining accurate lipoprotein profiles with small sample volumes and provides valuable reference data for healthy cats that should facilitate diagnoses.

  20. Native and Reconstituted Plasma Lipoproteins in Nanomedicine: Physicochemical Determinants of Nanoparticle Structure, Stability, and Metabolism.

    Science.gov (United States)

    Pownall, Henry J; Rosales, Corina; Gillard, Baiba K; Ferrari, Mauro

    2016-09-01

    Although many acute and chronic diseases are managed via pharmacological means, challenges remain regarding appropriate drug targeting and maintenance of therapeutic levels within target tissues. Advances in nanotechnology will overcome these challenges through the development of lipidic particles, including liposomes, lipoproteins, and reconstituted high-density lipoproteins (rHDL) that are potential carriers of water-soluble, hydrophobic, and amphiphilic molecules. Herein we summarize the properties of human plasma lipoproteins and rHDL, identify the physicochemical determinants of lipid transfer between phospholipid surfaces, and discuss strategies for increasing the plasma half-life of lipoprotein- and liposome-associated molecules.

  1. Macrophage uptake of a lipoprotein-sequestered toxicant: a potential route of immunotoxicity.

    Science.gov (United States)

    Kaminski, N E; Wells, D S; Dauterman, W C; Roberts, J F; Guthrie, F E

    1986-03-15

    An experimental system was chosen to investigate the bioactivity of a lipoprotein-sequestered toxicant at the cellular level based on recent studies demonstrating receptor-mediated uptake of lipoproteins by macrophages. Rat peritoneal exudate cell suspensions (PEC) were exposed to DDT and lipoprotein-sequestered DDT, followed by measurement of DDT uptake, metabolism, and cellular toxicity. In vitro uptake assays demonstrated that PEC suspensions treated for 10, 20, and 30 min with 2.5 microM lipoprotein-sequestered DDT had approximately a twofold increase over the amount of DDT associated with PEC treated with 2.5 microM free DDT. PEC were assayed for DDT metabolites to serve as a measure of the cellular internalization of the toxicant after treatment in vitro for 18 hr with either 1.5 microM DDT or lipoprotein-sequestered DDT. Evidence of DDT metabolism was only observed with PEC which had been treated with lipoprotein-sequestered DDT. These cells contained significantly higher amounts of DDT metabolites as compared to cells treated with unsequestered DDT (over an eightfold difference). Assays measuring macrophage phagocytic activity indicated that macrophages treated for 4.5 hr in vitro with 2.5 microM lipoprotein-sequestered DDT showed significant inhibition in their ability to phagocytize yeast particles. These results suggest that serum lipoproteins may facilitate the cellular uptake of lipoprotein-sequestered toxicants leading to altered cellular function (phagocytosis).

  2. In vitro studies on the distribution of probucol among human plasma lipoproteins.

    Science.gov (United States)

    Urien, S; Riant, P; Albengres, E; Brioude, R; Tillement, J P

    1984-09-01

    The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.

  3. Expression, purification and evaluation of recombinant lipoprotein of Salmonella typhi as a vaccine candidate.

    Science.gov (United States)

    Kumar, Anand; Kundu, Subir; Debnath Das, Mira

    2017-03-01

    Lipoprotein has been reported as a vaccine candidate against many pathogenic bacteria, it plays direct role as a virulence-associated function. Here the approach is toward the expression of recombinant lipoprotein of Salmonella typhi in prokaryotic host and its evaluation as a vaccine candidate. Lipoprotein gene (lp1) was cloned in pET32a expression vector in addition to Bam HI and Hind III restriction sites, and BL21(pLysS) was used as prokaryotic expression host for transformation. Lipoprotein induction was performed by IPTG and 55 kDa (31 kDa of Gene +24 kDa of vector additional protein with His-tag) was analyzed by 12% SDS-PAGE. The recombinant lipoprotein was purified by Ni-NTA affinity chromatography due to the addition of 6X His-tag in recombinant lipoprotein. Western blot analysis using anti-His tag polyclonal antibodies confirmed the specificity of recombinant lipoprotein. Immunogenicity and protection study of recombinant lipoprotein against S. Typhi was performed in BALB/c mice. Adjuvants IFA and alum salts were used to enhance the immune response. ELISA results proved that biologically active truncated recombinant lipoprotein (31 kDa) is a suitable immunogen. Alum salts used as adjuvant was effective for long-lasting immunity. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  4. In vitro lipid transfer between lipoproteins and midgut-diverticula in the spider Polybetes pythagoricus.

    Science.gov (United States)

    Laino, Aldana; Cunningham, Mónica L; Heras, Horacio; Garcia, Fernando

    2011-12-01

    It has been already reported that most hemolymphatic lipids in the spider Polybetes pythagoricus are transported by HDL1 and VHDL lipoproteins. We studied in vitro the lipid transfer among midgut-diverticula (M-diverticula), and either hemolymph or purified lipoproteins as well as between hemolymphatic lipoproteins. M-diverticula and hemolymph were labeled by in vivo (14)C-palmitic acid injection. In vitro incubations were performed between M-diverticula and either hemolymph or isolated lipoproteins. Hemolymph lipid uptake was associated to HDL1 (67%) and VHDL (32%). Release from hemolymph towards M-diverticula showed the opposite trend, VHDL 75% and HDL1 45%. Isolated lipoproteins showed a similar behavior to that observed with whole hemolymph. Lipid transfer between lipoproteins showed that HDL1 transfer more (14)C-lipids to VHDL than vice versa. Only 38% FFA and 18% TAG were transferred from M-diverticula to lipoproteins, while on the contrary 75% and 73% of these lipids, respectively, were taken up from hemolymph. A similar trend was observed regarding lipoprotein phospholipids. This study supports the hypothesis that HDL1 and hemocyanin-containing VHDL are involved in the uptake and release of FFA, phospholipids and triacylglycerols in the spider P. pythagoricus. The data support a directional flow of lipids from HDL1 and VHDL suggesting a mode of lipid transport between lipoproteins and M-diverticula.

  5. Transport of phytanic acid on lipoproteins in Refsum disease.

    Science.gov (United States)

    Wierzbicki, A S; Sankaralingam, A; Lumb, P J; Hardman, T C; Sidey, M C; Gibberd, F B

    1999-02-01

    Patients with Refsum disease accumulate significant quantities of phytanic acid in adipose and neural tissue. The accumulation can be reversed by following a diet low in phytanic acid, yet the mechanism of transport of this fatty acid is obscure. We investigated the distribution of phytanic acid in different lipoprotein subfractions in 11 patients with Refsum disease and 9 unaffected siblings. Plasma phytanic acid was distributed on VLDL (16.2% +/- 12.2%), IDL (1.77% +/- 1.64%), LDL (34.8% +/- 12.6%) and HDL (14.3% +/- 7.87%). No correlations with any parameter were seen with total phytanic acid content. Weak nonsignificant correlations were found with the fractional distribution of phytanic acid and VLDL triglyceride (r = 0.35; p = 0.12) and plasma HDL-cholesterol (r = 0.32; p = 0.16) and with LDL:HDL cholesterol ratio (r = 0.33; p = 0.14). Significant correlation of the fractional distribution of phytanic acid on lipoprotein particles was noted with the ratio of apolipoprotein B: apolipoprotein A1-containing particles (r = 0.46; p = 0.03) and apolipoprotein B: apolipoprotein A1 in HDL2 (r = 0.53; p = 0.01). This suggests that the import-export balance for phytanic acid in plasma is related to forward and reverse cholesterol transport on lipoprotein particles, and only weakly to plasma cholesterol and triglycerides. These ratios of apolipoprotein particles may play a significant role in determining the rate of phytanic acid elimination in patients with Refsum disease.

  6. The influence of lipoprotein(a on fibrinolytic activity

    Directory of Open Access Journals (Sweden)

    Rahajuningsih D. Setiabudy

    2004-09-01

    Full Text Available Lipoprotein(a is a plasma lipoprotein whose structure and composition are similar with low density lipoprotein (LDL with an addition of apo(a that is bound to apo B100. The structure of apo(a is similar with plasminogen, a proenzym in fibrinolytic system. Due to this similarity, it is assumed that Lp(a can inhibit plasminogen activity and decreases fibrinolytic activity. The purpose of this study is to prove that addition of Lp(a to normal plasma can inhibit fibrinolytic activity. Four healthy people whose fibrinogen levels, plasminogen activities and euglobulin clot lysis time were within normal range were enrolled in this study. Fibrinolytic activity were assessed by euglobulin clot lysis time (ECLT. In the first experiment, the addition of Lp(a was done before centrifugation to obtain euglobulin precipitates, while in the second experiment, Lp(a was added to the euglobulin precipitates. As a control, ECLT was performed in the plasma with the addition of NaCl 0.9% in the same volume with Lp(a. The results of the study showed that in the first experiment, there was no clot formation. It is assumed that Lp(a can bind fibrinogen and both of them floated in the supernatant, so there was no fibrinogen in the euglobulin precipitate that can be clotted by thrombin. In the second experiment, the clot did not dissolve until the fourth day. In conclusion, the addition of Lp(a to normal plasma can inhibit the activity of fibrinolytic system. (Med J Indones 2004; 13: 135-9 Keywords: plasminogen, fibrinogen, apo(a, euglobulin clot lysis time (ECLT

  7. Lipoprotein(a: Metabolismus und Beeinflussung des Plasmaspiegels

    Directory of Open Access Journals (Sweden)

    Kostner GM

    2002-01-01

    Full Text Available Lipoprotein(a [Lp(a] ist eines der atherogensten Lipoproteine. Es besteht aus einem Core Low Density Lipoprotein (LDL und dem spezifischen Antigen, Apo(a. Letzteres ist ein extrem polymorphes Glykoprotein, welches aus zwischen 11 und mehr als 40 Kringel-IV-Einheiten besteht, die homolog zum Kringel-IV des Plasminogens sind. Die Atherogenität von Lp(a, die einerseits auf seine Strukturähnlichkeit mit Plas-minogen, andererseits auf seine extrem hohe Affinität zu Proteoglykanen der Blutgefäße zurückzuführen ist, wurde in zahlreichen prospektiven Studien dokumentiert. Die Mittel- bzw. Medianwerte für Lp(a in der weißen Bevölkerung betragen 17 bzw. 9 mg/dl. Als Grenzwert, ab welchem ein erhöhtes Atheroskleroserisiko auftritt, gilt allgemein 25?30 mg/dl. Die Plasmakonzentration von Lp(a ist streng genetisch determiniert und korreliert negativ mit der Kringelzahl. Andererseits wird die Plasmakonzentration von der Syntheserate und nicht vom Katabolismus bestimmt. Hormone wie T3/T4, Steroid- und im besonderen Wachstumshormone und ILG-1 zeigen sehr deutliche Einflüsse auf den Lp(a-Metabolismus. Leberpatienten haben im Verhältnis zu ihrer Kringelzahl stark erniedrigte und Nierenpatienten stark erhöhte Plasma-Lp(a-Spiegel. Die stärkste pharmakologische Wirkung auf Lp(a haben anabole Steroide. Aber auch Alkohol, Acetylsalicylsäure, Ascorbinsäure und vor allem Nikotinsäure wirken Lp(a-senkend. Die herkömmlichen Lipidsenker zeigen - wenn überhaupt - nur eine geringe Wirkung. Bisher ist kein nennenswert Lp(a-senkendes Statin gefunden worden. Eine futuristische Möglichkeit, therapeutisch einzugreifen, wurde von uns mittels "anti-sense Oligonucleotide"-Therapie an Versuchstieren getestet. Es gelang damit, die Apo(a-Synthese praktisch auf Null zu senken.

  8. Correlation studies between serum concentrations of zinc and lipoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Saiki, Mitiko; Alves, Edson R.; Vasconcellos, M.B.A. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)], e-mail: mitiko@ipen.br, e-mail: eralves@ipen.br, e-mail: mbvascon@ipen.br; Sumita, Nairo M. [Universidade de Sao Paulo (USP), SP (Brazil). Hospital das Clinicas.Central Lab. Division and Laboratories of Medical Investigation (LIM-03)], e-mail: dlc.bioquimica@hcnet.usp.br; Jaluul, Omar; Jacob-Filho, Wilson [Universidade de Sao Paulo (USP), SP (Brazil). Faculdade de Medicina], e-mail: jaluul@uol.com.br, wiljac@usp.br

    2009-07-01

    In this study, serum zinc and lipoprotein concentrations were determined in order to assess the health status of an elderly population residing in Sao Paulo city, SP, Brazil. This population consisted of elderly considered healthy and participating of a 'Successful Ageing' program of the Sao Paulo University Medical School. Fasting blood samples were collected from 87 elderly individuals (63 females and 24 males) aged 60-91 and mean age of 72 +- 7 years. Zn concentrations were determined by neutron activation analysis at the IPEN/CNEN/ SP and, the lipoprotein (HDL, LDL and total cholesterol) concentrations were determined using routine analysis methods of the Central Laboratory Division, Hospital das Clinicas, FMUSP. Results obtained for Zn indicated that all the individuals presented this element within the recommended value. For total cholesterol and HDL-cholesterol concentrations, 96 % of elderly presented levels within the desired range but for LDL cholesterol concentrations only about 70.0 % of individuals were in the desired range. Serum concentration of Zn were positively correlated to LDL-cholesterol levels (correlation coefficient r = 0.21, p < 0.06). Furthermore, the ratios of [HDL-cholesterol] / [LDL-cholesterol] were negatively correlated with Zn concentrations (r = - 0.234, p < 0.04). The positive correlation found between the serum concentrations of Zn and LDL-cholesterol indicates the possible effect of this element in serum lipoprotein profiles. Thus ,these findings suggest that more investigations should be conducted on Zn supplementation in elderly subjects with cardiovascular diseases. (author)

  9. Wolbachia lipoproteins: abundance, localisation and serology of Wolbachia peptidoglycan associated lipoprotein and the Type IV Secretion System component, VirB6 from Brugia malayi and Aedes albopictus.

    Science.gov (United States)

    Voronin, Denis; Guimarães, Ana F; Molyneux, Gemma R; Johnston, Kelly L; Ford, Louise; Taylor, Mark J

    2014-10-06

    Lipoproteins are the major agonists of Wolbachia-dependent inflammatory pathogenesis in filariasis and a validated target for drug discovery. Here we characterise the abundance, localisation and serology of the Wolbachia lipoproteins: Wolbachia peptidoglycan associated lipoprotein and the Type IV Secretion System component, VirB6. We used proteomics to confirm lipoprotein presence and relative abundance; fractionation, immunoblotting and confocal and electron immuno-microscopy for localisation and ELISA for serological analysis. Proteomic analysis of Brugia malayi adult female protein extracts confirmed the presence of two lipoproteins, previously predicted through bioinformatics: Wolbachia peptidoglycan associated lipoprotein (wBmPAL) and the Type IV Secretion System component, VirB6 (wBmVirB6). wBmPAL was among the most abundant Wolbachia proteins present in an extract of adult female worms with wBmVirB6 only detected at a much lower abundance. This differential abundance was reflected in the immunogold-labelling, which showed wBmPAL localised at numerous sites within the bacterial membranes, whereas wBmVirB6 was present as a single cluster on each bacterial cell and also located within the bacterial membranes. Immunoblotting of fractionated extracts confirmed the localisation of wBmPAL to membranes and its absence from cytosolic fractions of C6/36 mosquito cells infected with wAlbB. In whole worm mounts, antibody labelling of both lipoproteins were associated with Wolbachia. Serological analysis showed that both proteins were immunogenic and raised antibody responses in the majority of individuals infected with Wuchereria bancrofti. Two Wolbachia lipoproteins, wBmPAL and wBmVirB6, are present in extracts of Brugia malayi with wBmPAL among the most abundant of Wolbachia proteins. Both lipoproteins localised to bacterial membranes with wBmVirB6 present as a single cluster suggesting a single Type IV Secretory System on each Wolbachia cell.

  10. Lipoprotein (a) as a cause of cardiovascular disease

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Langsted, Anne

    2016-01-01

    Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly supports that elevated lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve......-2 in Lp(a) could be through wound healing during childbirth, infections, and injury, a role that, in addition, could lead to more blood clots promoting stenosis of arteries and the aortic valve, and myocardial infarction. Randomized placebo-controlled trials of Lp(a) reduction in individuals...

  11. Biomimetic High Density Lipoprotein Nanoparticles For Nucleic Acid Delivery

    Science.gov (United States)

    McMahon, Kaylin M.; Mutharasan, R. Kannan; Tripathy, Sushant; Veliceasa, Dorina; Bobeica, Mariana; Shumaker, Dale K.; Luthi, Andrea J.; Helfand, Brian T.; Ardehali, Hossein; Mirkin, Chad A.; Volpert, Olga; Thaxton, C. Shad

    2014-01-01

    We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy which combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy (TEM), and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery. PMID:21319839

  12. Different effects of diets rich in olive oil, rapeseed oil and sunflower-seed oil on postprandial lipid and lipoprotein concentrations and on lipoprotein oxidation susceptibility

    DEFF Research Database (Denmark)

    Nielsen, Nina Skall; Pedersen, A.; Sandstrøm, B.

    2002-01-01

    Elevated concentrations of fasting and non-fasting triacylglycerol-rich lipoproteins (TRL) as well as oxidative changes of lipoproteins may increase the risk of ischaemic heart disease. To compare the effects of different diets rich in unsaturated fatty acids on the concentrations and in vitro...... oxidation of fasting and postprandial lipoproteins eighteen males consumed diets enriched with rapeseed oil (RO), olive oil (OO), or sunflower-seed oil (SO) in randomised order for periods of 3 weeks followed by a RO test meal. In the postprandial state the concentrations of cholesterol and triacylglycerol...

  13. Lipoprotein apheresis in the management of severe hypercholesterolemia and of elevation of lipoprotein(a): current perspectives and patient selection

    Science.gov (United States)

    Julius, Ulrich

    2016-01-01

    This review reports the current situation with respect to therapeutic options (lifestyle and drugs) reducing the concentrations of atherogenic low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]). Three lipoprotein apheresis (LA) principles have been realized: precipitation, filtration, and adsorption. Available LA methods are herein described in detail – major components, pumps, extracorporeal volume, treated volume, and anticoagulation. General features of all LA methods as well as pleotropic effects are elaborated. Indications for LA therapy are quoted: homozygous familial hypercholesterolemia (HCH), severe HCH, and isolated elevation of Lp(a) and progress of atherosclerotic disease. A major focus is on the evidence of the effect of LA on cardiovascular outcome data, and the most important publications are cited in this context. The best studies have been performed in patients with elevated Lp(a) in whom cardiovascular events were reduced by more than 80%. Major adverse effects and contraindications are listed. The impact of an LA therapy on patient quality of life and the requirements they have to fulfill are also highlighted. Finally, the future role of LA in treating high-risk patients with high LDL-C and/or high Lp(a) is discussed. It is probable that the significance of LA for treating patients with elevated LDL-C will decrease (with the exception of homozygous familial HCH) due to the application of PCSK9 inhibitors. The antisense oligonucleotide against apolipoprotein(a) could replace LA in patients with high Lp(a), provided positive outcome data are generated. PMID:27785114

  14. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

    OpenAIRE

    Kathiresan, Sekar; Melander, Olle; Guiducci, Candace; Surti, Aarti; Burtt, Noël P.; Rieder, Mark J; Cooper, Gregory M.; Roos, Charlotta; Benjamin F Voight; Havulinna, Aki S.; Wahlstrand, Björn; Hedner, Thomas; Corella, Dolores; Tai, E Shyong; Ordovas, Jose M.

    2008-01-01

    Blood concentrations of lipoproteins and lipids are heritable1 risk factors for cardiovascular disease2,3. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue4) and targeted replication associat...

  15. Brain lipoprotein lipase as a regulator of energy balance.

    Science.gov (United States)

    Cruciani-Guglielmacci, Céline; Magnan, Christophe

    2017-07-24

    The central nervous system is an essential actor in the control of the energy balance. Indeed, many signals of nervous (vagal afferent for example) or circulating (hormone, nutrients) origin converge towards the brain to inform it permanently of the energetic status of the organism. In turn, the brain sends information to the periphery (sympathetic vagal balance, thyroid or corticotropic axis) which allows a fine regulation of the energy fluxes by acting on the hepatic glucose production, the secretion of the pancreatic hormones (glucagon, insulin) or food behavior. Among the nutrients, increasing amount of data assigns a signal molecule role to lipids such as fatty acids. These fatty acids may originate from the bloodstream but may also be the product of the hydrolysis of lipoproteins such as chylomicrons or VLDLs. Indeed, the identification of lipoprotein lipase (LPL) in the brain has led to the hypothesis that the LPL-dependent degradation of TG-enriched particles, and the addition of fatty acids, as informative molecules, to sensitive cells (neurons and/or astrocytes), plays a key role in maintaining the energy balance at equilibrium. Other lipases could also participate in these regulatory mechanisms. This review will summarize the state of the art and open up perspectives. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  16. Hypertriglyceridemia and unusual lipoprotein subclass distributions associated with late pregnancy

    Energy Technology Data Exchange (ETDEWEB)

    Forte, T.M.; Kretchmer, N.; Silliman, K. (Lawrence Berkeley Lab., CA (United States))

    1991-03-15

    In the human adult population elevated plasma triglyceride (TG) levels are associated with decreased high density lipoprotein-cholesterol (HDL-C) levels and decreased HDL and LDL particle sizes. Late pregnancy is a hypertriglyceridemic state where little is known about LDL and HDL subpopulation distribution. Plasma lipids, apolipoproteins (apo) and lipoprotein subpopulations were examined in 36 pregnant women at 36 wk pregnancy and 6 wk postpartum and correlated with HDL and LDL size. There was a significant decrease in LDL diameter at 36 wk pre, 25 {plus minus} 0.7 nm compared, with 6 wk post, 26.4 {plus minus} 0.8 nm. A total of 97% of the 36 wk pre subjects had small dense LDL which paralleled increases in apoB concentration. Unlike LDL HDL at 36 wks pre showed a significant increase in larger sized particles where HDL{sub 2b} predominated. There was a positive correlation between HDL{sub 2b} mass and apoAl and HDL-C concentrations. Late pregnancy is a metabolic state where the predominance of large, HDL{sub 2b} particles is discordant with the predominance of small LDL and elevated TG. This annual metabolic pattern may in part be due to hormonal changes occurring in late pregnancy.

  17. Triacylglycerol kinetics in endotoxic rats with suppressed lipoprotein lipase activity

    Energy Technology Data Exchange (ETDEWEB)

    Bagby, G.J.; Corll, C.B.; Martinez, R.R.

    1987-07-01

    Hypertriglyceridemia observed in animals after bacterial endotoxin administration and some forms of sepsis can result from increased hepatic triacylglycerol (TG) output or decreased TG clearance by extrahepatic tissues. To differentiate between these two possibilities, TG and free fatty acid (FFA) kinetics were determined in control and endotoxin-injected rats 18 h after treatment. Plasma TG and FFA kinetics were assessed by a constant intravenous infusion with (9,10-/sup 3/H)palmitate-labeled very low-density lipoprotein and (1-/sup 14/C)palmitate bound to albumin, respectively. In addition, lipoprotein lipase (LPL) activity was determined in heart, skeletal muscle, and adipose tissue as well as in postheparin plasma of functionally hepatectomized, adrenalectomized, and gonadectomized rats. Plasma FFA acid concentrations were slightly increased in endotoxin-treated rats but their turnover did not differ from control. Endotoxin-treated rats had a threefold increase in plasma TG concentrations and decreased heart, skeletal muscle, and post-heparin plasma LPL activity. Plasma TG turnover was decreased, indicating that hypertriglyceridemia was not due to an increased TG output by the liver. Instead, the endotoxin-induced increase in plasma TG concentration was consequence of the 80% reduction in TG metabolic clearance rate. Thus, suppression of LPL activity in endotoxic animals impairs TG clearance resulting in hypertriglyceridemia. Furthermore, endotoxin administration reduced the delivery of TG-FFA to extrahepatic tissues because hepatic synthesis and secretion of TG from plasma FFA was decreased and LPL activity was suppressed.

  18. Lipid profiling of lipoprotein X: Implications for dyslipidemia in cholestasis.

    Science.gov (United States)

    Heimerl, Susanne; Boettcher, Alfred; Kaul, Harald; Liebisch, Gerhard

    2016-08-01

    Lipoprotein X (Lp-X) is an abnormal lipoprotein that may typically be formed in intra- and extrahepatic cholestasis and potentially interfere with lipid analysis in the routine lab. To gain insight into lipid class and species composition, Lp-X, LDL and HDL from cholestatic and control serum samples were subjected to mass spectrometric analysis including phospholipids (PL), sphingolipids, free cholesterol (FC), cholesteryl esters (CE) and bile acids. Our analysis of Lp-X revealed a content of 46% FC, 49% PL with 34% phosphatidylcholine (PC) as main PL component. The lipid species pattern of Lp-X showed remarkable high fractions of mono-unsaturated species including PC 32:1 and PC 34:1 and phosphatidylethanolamine (PE) 32:1 and 34:1. LDL and HDL lipid composition in the same specimens strongly reflected the lipid composition of Lp-X with increased PC 32:1, PC 34:1, PE 32:1, PE 34:1 and FC accompanied by decreased CE compared to controls. Comparison of Lp-X and biliary lipid composition clearly indicates that Lp-X does not originate from a sole release of bile lipids. Moreover, these data present evidence for increased hepatic fatty acid and PL synthesis which may represent a reaction to high hepatic FC level observed during cholestasis.

  19. Lipoprotein (a) and cardiovascular risk factors in children and adolescents

    Science.gov (United States)

    Palmeira, Ástrid Camêlo; Leal, Adriana Amorim de F.; Ramos, Nathaly de Medeiros N.; de Alencar F., José; Simões, Mônica Oliveira da S.; Medeiros, Carla Campos M.

    2013-01-01

    OBJECTIVE: To review the relationship between lipoprotein (a) [Lp(a)] and other risk factors for cardiovascular disease (CVD) in children and adolescents. DATA SOURCES: This systematic review included studies from 2001 to 2011, a ten-year time period. Epidemiological studies with children and/or adolescents published in English, Portuguese or Spanish and fully available online were included. The searches were performed in Science Direct, PubMed/Medline, BVS (Biblioteca Virtual em Saúde) and Cochrane Library databases, using the following combination of key-words: "lipoprotein a" and "cardiovascular diseases" and "obesity". DATA SYNTHESIS: Overall, 672 studies were obtained but only seven were included. Some studies assessed the family history for CVD. In all of them, Lp(a) levels were increased in patients with family history for CVD. There was also a positive correlation between Lp(a) and LDL-cholesterol, total cholesterol, and apolipoprotein B levels, suggesting an association between Lp(a) levels and the lipid profile. CONCLUSIONS: The evidence that CVD may originate in childhood and adolescence leads to the need for investigating the risk factors during this period in order to propose earlier and possibly more effective interventions to reduce morbidity and mortality rates. PMID:24473960

  20. Low density lipoproteins as circulating fast temperature sensors.

    Directory of Open Access Journals (Sweden)

    Ruth Prassl

    Full Text Available BACKGROUND: The potential physiological significance of the nanophase transition of neutral lipids in the core of low density lipoprotein (LDL particles is dependent on whether the rate is fast enough to integrate small (+/-2 degrees C temperature changes in the blood circulation. METHODOLOGY/PRINCIPAL FINDINGS: Using sub-second, time-resolved small-angle X-ray scattering technology with synchrotron radiation, we have monitored the dynamics of structural changes within LDL, which were triggered by temperature-jumps and -drops, respectively. Our findings reveal that the melting transition is complete within less than 10 milliseconds. The freezing transition proceeds slowly with a half-time of approximately two seconds. Thus, the time period over which LDL particles reside in cooler regions of the body readily facilitates structural reorientation of the apolar core lipids. CONCLUSIONS/SIGNIFICANCE: Low density lipoproteins, the biological nanoparticles responsible for the transport of cholesterol in blood, are shown to act as intrinsic nano-thermometers, which can follow the periodic temperature changes during blood circulation. Our results demonstrate that the lipid core in LDL changes from a liquid crystalline to an oily state within fractions of seconds. This may, through the coupling to the protein structure of LDL, have important repercussions on current theories of the role of LDL in the pathogenesis of atherosclerosis.

  1. SELDI-TOF mass spectrometry of High-Density Lipoprotein

    Directory of Open Access Journals (Sweden)

    Rezaee Farhad

    2007-09-01

    Full Text Available Abstract Background High-Density Lipoprotein (HDL, one of the main plasma lipoproteins, serves as a docking station for proteins involved in inflammation, coagulation, and lipid metabolism. Methods To elucidate the protein composition of HDL, we employed SELDI-TOF mass spectrometry as a potential high-throughput proteomic candidate for protein profiling of HDL. HDL derived from normolipemic individuals was captured on PS20 protein-chips using covalently bound antibodies against apo A-I or A-II. Results After optimisation, on-chip capture of HDL particles directly from plasma or from pre-purified HDL resulted in comparable fingerprints confirming specific capture of HDL. Depending on the capture antibody some differences in the fingerprint were observed. The most detailed fingerprint was observed up to 50 kDa; approximately 95 peaks were detected in the 3–50 kDa molecular mass range. Between 50 and 160 kDa, 27 more peaks were detected. Conclusion Based on these results, SELDI-TOF MS may be a suitable high-throughput candidate for HDL protein profiling and marker search. This approach may be used to i investigate the underlying mechanisms that lead to increased atherothrombotic risk and ii to investigate the atherothrombotic state of an individual.

  2. Lipoprotein (a and cardiovascular risk factors in children and adolescents

    Directory of Open Access Journals (Sweden)

    Ástrid Camêlo Palmeira

    2013-12-01

    Full Text Available OBJECTIVE: To review the relationship between lipoprotein (a [Lp(a] and other risk factors for cardiovascular disease (CVD in children and adolescents. DATA SOURCES: This systematic review included studies from 2001 to 2011, a ten-year time period. Epidemiological studies with children and/or adolescents published in English, Portuguese or Spanish and fully available online were included. The searches were performed in Science Direct, PubMed/Medline, BVS (Biblioteca Virtual em Saúde and Cochrane Library databases, using the following combination of key-words: "lipoprotein a" and "cardiovascular diseases" and "obesity". DATA SYNTHESIS: Overall, 672 studies were obtained but only seven were included. Some studies assessed the family history for CVD. In all of them, Lp(a levels were increased in patients with family history for CVD. There was also a positive correlation between Lp(a and LDL-cholesterol, total cholesterol, and apolipoprotein B levels, suggesting an association between Lp(a levels and the lipid profile. CONCLUSIONS: The evidence that CVD may originate in childhood and adolescence leads to the need for investigating the risk factors during this period in order to propose earlier and possibly more effective interventions to reduce morbidity and mortality rates.

  3. Lipoprotein (a) and cardiovascular risk factors in children and adolescents.

    Science.gov (United States)

    Palmeira, Ástrid Camêlo; Leal, Adriana Amorim de F; Ramos, Nathaly de Medeiros N; Neto, José de Alencar F; Simões, Mônica Oliveira da S; Medeiros, Carla Campos M

    2013-12-01

    To review the relationship between lipoprotein (a) [Lp(a)] and other risk factors for cardiovascular disease (CVD) in children and adolescents. This systematic review included studies from 2001 to 2011, a ten-year time period. Epidemiological studies with children and/or adolescents published in English, Portuguese or Spanish and fully available online were included. The searches were performed in Science Direct, PubMed/Medline, BVS (Biblioteca Virtual em Saúde) and Cochrane Library databases, using the following combination of key-words: "lipoprotein a" and "cardiovascular diseases" and "obesity". Overall, 672 studies were obtained but only seven were included. Some studies assessed the family history for CVD. In all of them, Lp(a) levels were increased in patients with family history for CVD. There was also a positive correlation between Lp(a) and LDL-cholesterol, total cholesterol, and apolipoprotein B levels, suggesting an association between Lp(a) levels and the lipid profile. The evidence that CVD may originate in childhood and adolescence leads to the need for investigating the risk factors during this period in order to propose earlier and possibly more effective interventions to reduce morbidity and mortality rates.

  4. N-methyl-D-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein.

    Science.gov (United States)

    Sheng, Zhenyu; Prorok, Mary; Brown, Brigid E; Castellino, Francis J

    2008-08-01

    The effects of a synthetic apoE peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, have been investigated. The activity of apoE[133-149] was found to depend on the low-density lipoprotein receptor-related protein (LRP). Competition experiments with receptor-associated protein (RAP) and activated alpha(2)-macroglobulin (alpha(2)M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE[133-149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and alpha(2)M*. A coreceptor of LRP, cell surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE[133-149] was threefold greater for NMDAR-transfected wild-type Chinese hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

  5. Patients with Rheumatoid Arthritis Show Altered Lipoprotein Profiles with Dysfunctional High-Density Lipoproteins that Can Exacerbate Inflammatory and Atherogenic Process.

    Science.gov (United States)

    Kim, Jae-Yong; Lee, Eun-Young; Park, Jin Kyun; Song, Yeong Wook; Kim, Jae-Ryong; Cho, Kyung-Hyun

    2016-01-01

    In order to identify putative biomarkers in lipoprotein, we compared lipid and lipoprotein properties between rheumatoid arthritis (RA) patients and control with similar age. We analyzed four classes of lipoproteins (VLDL, LDL, HDL2, HDL3) from both male (n = 8, 69±4 year-old) and female (n = 25, 53±7 year-old) rheumatoid arthritis (RA) patients as well as controls with similar age (n = 13). Although RA group showed normal levels of total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and glucose, however, the RA group showed significantly reduced high-density lipoprotein (HDL)-C level and ratio of HDL-C/TC. The RA group showed significantly elevated levels of blood triglyceride (TG), uric acid, and cholesteryl ester transfer protein (CETP) activity. The RA group also showed elevated levels of advanced glycated end (AGE) products in all lipoproteins and severe aggregation of apoA-I in HDL. As CETP activity and TG contents were 2-fold increased in HDL from RA group, paraoxonase activity was reduced upto 20%. Electron microscopy revealed that RA group showed much less HDL2 particle number than control. LDL from the RA group was severely oxidized and glycated with greater fragmentation of apo-B, especially in female group, it was more atherogenic via phagocytosis. Lipoproteins from the RA patients showed severely altered structure with impaired functionality, which is very similar to that observed in coronary heart patients. These dysfunctional properties in lipoproteins from the RA patients might be associated with high incidence of cardiovascular events in RA patients.

  6. PLASMA-LIPOPROTEIN ABNORMALITIES IN TYPE-1 (INSULIN-DEPENDENT) DIABETES-MELLITUS

    NARCIS (Netherlands)

    DULLAART, RPF

    1995-01-01

    Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The pla

  7. Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol?

    NARCIS (Netherlands)

    J.S. Rana; S.M. Boekholdt

    2010-01-01

    Purpose of review Despite aggressive low-density lipoprotein cholesterol lowering, patients continue to be at significant risk of cardiovascular events. Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the

  8. Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

    NARCIS (Netherlands)

    van Tienhoven-Wind, Lynnda; Dullaart, Robin P. F.

    2015-01-01

    Objectives: Low-normal thyroid function may relate to increases in plasma cholesterol and triglycerides, but effects on lipoprotein subfractions are largely unknown. Associations of alterations in lipoprotein metabolism and functionality with low-normal thyroid function could be more pronounced in T

  9. Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

    NARCIS (Netherlands)

    Vu, Chi Hai; Kolata, Julia; Stentzel, Sebastian; Beyer, Anica; Salazar, Manuela Gesell; Steil, Leif; Pané-Farré, Jan; Rühmling, Vanessa; Engelmann, Susanne; Götz, Friedrich; van Dijl, Jan Maarten; Hecker, Michael; Mäder, Ulrike; Schmidt, Frank; Völker, Uwe; Bröker, Barbara M

    2016-01-01

    Staphylococcus aureus is a frequent commensal but also a dangerous pathogen, causing many forms of infection ranging from mild to life-threatening conditions. Among its virulence factors are lipoproteins, which are anchored in the bacterial cell membrane. Lipoproteins perform various functions in co

  10. Changes in lipids and lipoprotein particle concentrations after interruption of antiretroviral therapy

    DEFF Research Database (Denmark)

    Lampe, Fiona C; Duprez, Daniel A; Kuller, Lewis H

    2010-01-01

    The effect of interruption of antiretroviral therapy (ART) on lipoprotein particle subclasses has not been studied. We examined short-term changes in lipids and lipoprotein particles among 332 HIV-infected individuals randomized to interrupt or continue ART in the "Strategies for Management...... of Antiretroviral Therapy" trial....

  11. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis

    DEFF Research Database (Denmark)

    Kamstrup, Pia R; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2012-01-01

    The aim of the present study was to determine whether lipoprotein(a) [Lp(a)], considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis.......The aim of the present study was to determine whether lipoprotein(a) [Lp(a)], considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis....

  12. Subunit II of Bacillus subtilis cytochrome c oxidase is a lipoprotein

    NARCIS (Netherlands)

    Bengtsson, J; Tjalsma, H; Rivolta, C; Hederstedt, L

    1999-01-01

    The sequence of the N-terminal end of the deduced ctaC gene product of Bacillus species has the features of a bacterial lipoprotein. CtaC is the subunit II of cytochrome caa(3), which is a cytochrome c oxidase. Using Bacillus subtilis mutants blocked in lipoprotein synthesis, we show that CtaC is a

  13. Mycobacterium tuberculosis lipoproteins in virulence and immunity - fighting with a double-edged sword.

    Science.gov (United States)

    Becker, Katja; Sander, Peter

    2016-11-01

    Bacterial lipoproteins are secreted membrane-anchored proteins characterized by a lipobox motif. This lipobox motif directs post-translational modifications at the conserved cysteine through the consecutive action of three enzymes: Lgt, LspA and Lnt, which results in di- or triacylated forms. Lipoproteins are abundant in all bacteria including Mycobacterium tuberculosis and often involved in virulence and immunoregulatory processes. On the one hand, disruption of the biosynthesis pathway of lipoproteins leads to attenuation of M. tuberculosis in vivo, and mycobacteria deficient for certain lipoproteins have been assessed as attenuated live vaccine candidates. On the other hand, several mycobacterial lipoproteins form immunodominant antigens which promote an immune response. Some of these have been explored in DNA or subunit vaccination approaches against tuberculosis. The immune recognition of specific lipoproteins, however, might also benefit long-term survival of M. tuberculosis through immune modulation, while others induce protective responses. Exploiting lipoproteins as vaccines is thus a complex matter which requires deliberative investigation. The dual role of lipoproteins in the immunity to and pathogenicity of mycobacteria is discussed here. © 2016 Federation of European Biochemical Societies.

  14. Serum amyloid A is found on ApoB-containing lipoproteins in obese humans with diabetes.

    Science.gov (United States)

    Jahangiri, Anisa; Wilson, Patricia G; Hou, Tianfei; Brown, Aparna; King, Victoria L; Tannock, Lisa R

    2013-05-01

    In murine models of obesity/diabetes, there is an increase in plasma serum amyloid A (SAA) levels along with redistribution of SAA from high-density lipoprotein (HDL) to apolipoprotein B (apoB)-containing lipoprotein particles, namely, low-density lipoprotein and very low-density lipoprotein. The goal of this study was to determine if obesity is associated with similar SAA lipoprotein redistribution in humans. Three groups of obese individuals were recruited from a weight loss clinic: healthy obese (n = 14), metabolic syndrome (MetS) obese (n = 8), and obese with type 2 diabetes (n = 6). Plasma was separated into lipoprotein fractions by fast protein liquid chromatography, and SAA was measured in lipid fractions using enzyme-linked immunosorbent assay and Western blotting. Only the obese diabetic group had SAA detectable in apoB-containing lipoproteins, and SAA reverted back to HDL with active weight loss. In human subjects, SAA is found in apoB-containing lipoprotein particles only in obese subjects with type 2 diabetes, but not in healthy obese or obese subjects with MetS. Copyright © 2012 The Obesity Society.

  15. Opposing effects of apolipoprotein m on catabolism of apolipoprotein B-containing lipoproteins and atherosclerosis

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Pedersen, Tanja Xenia; Gordts, Philip L S M

    2010-01-01

    Rationale: Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL). HDL-bound apoM is antiatherogenic in vitro. However, plasma apoM is not associated with coronary heart disease in humans, perhaps because of a positive correlation with plasma low-density lipoprotein...

  16. Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

    NARCIS (Netherlands)

    van Tienhoven-Wind, Lynnda; Dullaart, Robin P. F.

    Objectives: Low-normal thyroid function may relate to increases in plasma cholesterol and triglycerides, but effects on lipoprotein subfractions are largely unknown. Associations of alterations in lipoprotein metabolism and functionality with low-normal thyroid function could be more pronounced in

  17. PLASMA-LIPOPROTEIN ABNORMALITIES IN TYPE-1 (INSULIN-DEPENDENT) DIABETES-MELLITUS

    NARCIS (Netherlands)

    DULLAART, RPF

    Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The

  18. In vivo transfer of lipoprotein(a) into human atherosclerotic carotid arterial intima

    DEFF Research Database (Denmark)

    Nielsen, Lars Bo; Grønholdt, Marie-Louise; Schroeder, T V;

    1997-01-01

    The aim of this study was to compare the atherogenic potential of lipoprotein(a) [Lp(a)] and LDL by measuring the intimal clearance of these two plasma lipoproteins in the atherosclerotic intima of the human carotid artery in vivo. Autologous 131I-Lp(a) and 125I-LDL were mixed and reinjected intr...

  19. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality

    DEFF Research Database (Denmark)

    (Tybjaerg-Hansen, A.) The Fibrinogen Studies Collaboration.The Copenhagen City Heart Study; Tybjærg-Hansen, Anne

    2009-01-01

    CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular ...

  20. Screening for apolipoprotein E gene mutations in 4 patients with lipoprotein glomerulopathy

    Institute of Scientific and Technical Information of China (English)

    潘永利

    2006-01-01

    Objective To study the mutations of apolipoprotein E (apoE) gene in 4 Chinese lipoprotein glomerulopathy (LPG) patients and their family members, and to investigate the pathogenesis of LPG. Methods Urinalysis was performed on the family members of two patients, and they were screened for the level of serum creatinine, serum lipid and serum lipoprotein. The mutation of apoE

  1. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality

    DEFF Research Database (Denmark)

    Collaboration, Emerging Risk Factors; Erqou, Sebhat; Kaptoge, Stephen

    2009-01-01

    CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular...

  2. Fractionation of human serum lipoproteins and simultaneous enzymatic determination of cholesterol and triglycerides

    NARCIS (Netherlands)

    Qureshi, R.N.; Kok, W.T.; Schoenmakers, P.J.

    2009-01-01

    A method based on Asymmetric Flow Field-Flow Fractionation (AF4) was developed to separate different types of lipoproteins from human serum. The emphasis in the method optimization was on the possibilities to characterize the largest lipoprotein fractions (LDL and VLDL), which is usually not

  3. Nanoporous carbon sorbent for molecular-sieve chromatography of lipoprotein complex

    Science.gov (United States)

    Kerimkulova, A. R.; Mansurova, B. B.; Gil'manov, M. K.; Mansurov, Z. A.

    2012-06-01

    The physicochemical characteristics of carbon sorbents are investigated. Electron microscopy data for the sorbent and separated lipoprotein complex are presented. It is found that the obtained carbon sorbent possess high porosity. Nanoporous carbon sorbents for the chromatography of molecular-sieve markers are obtained and tested. The applicability of nanoporous carbon sorbents for separation of lipoprotein complexes (LPC) is investigated.

  4. Application of directly coupled HPLC MMR to separation and characterization of lipoproteins from human serum

    DEFF Research Database (Denmark)

    Daykin, C. A.; Corcoran, O.; Hansen, S. H.;

    2001-01-01

    Disorders in lipoprotein metabolism are critical in the etiology of several disease states such as coronary heart disease and atherosclerosis, Thus, there is considerable interest in the development of novel methods for the analysis of lipoprotein complexes. We report here a simple chromatographi...

  5. Identification and quantification of regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein.

    Science.gov (United States)

    Kenar, J A; Havrilla, C M; Porter, N A; Guyton, J R; Brown, S A; Klemp, K F; Selinger, E

    1996-06-01

    Oxidation of human LDL is implicated as an initiator of atherosclerosis. Isolated low density lipoprotein (LDL) and high density lipoprotein (HDL2) were exposed to aqueous radicals generated from the thermolabile azo compound 2,2'-azobis(2-amidinopropane) dihydrochloride. The primary nonpolar lipid products formed from the autoxidation of LDL and HDL were the regioisomeric cholesteryl linoleate hydroperoxides. In LDL oxidations, 9- and 13-hydroperoxides with trans,cis conjugated diene were formed as the major oxidation products if endogenous alpha-tocopheral was present in the LDL. After extended oxidation of LDL, at the time when endogenous alpha-tocopherol was consumed, the two trans,cis conjugated diene hydroperoxides began to disappear and the 9- and 13-hydroperoxides with trans,trans conjugated diene appeared. At very long oxidation times, none of the primary products, the conjugated diene hydroperoxides, were present. In HDL2, which has only very low levels of antioxidants, both the 9- and 13-hydroperoxides with trans,cis conjugated diene and the 9- and 13-hydroperoxides with trans,trans conjugated diene were formed at early stages of oxidation. The corresponding alcohols were also formed in the HDL2 oxidations. A mechanistic hypothesis consistent with these observations is presented.

  6. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Jauhiainen, Matti; Moser, Markus

    2008-01-01

    To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM(-/-)) mice. Plasma apoM was predominantly associated with 10-12-nm alpha-migrating HDL particles. Human apoM overexpression (11-fold...... of alpha- to pre-alpha-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-beta-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 +/- 1.1%, p = 0.06) and decreased in apoM(-/-) mice (0.5 +/- 0.3%, p = 0.......03) versus controls (1.8 +/- 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with approximately 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic...

  7. Outer membrane protein A, peptidoglycan-associated lipoprotein, and murein lipoprotein are released by Escherichia coli bacteria into serum.

    Science.gov (United States)

    Hellman, J; Loiselle, P M; Tehan, M M; Allaire, J E; Boyle, L A; Kurnick, J T; Andrews, D M; Sik Kim, K; Warren, H S

    2000-05-01

    Complexes containing lipopolysaccharide (LPS) and three outer membrane proteins (OMPs) are released by gram-negative bacteria incubated in human serum and into the circulation in an experimental model of sepsis. The same OMPs are bound by immunoglobulin G (IgG) in the cross-protective antiserum raised to Escherichia coli J5 (anti-J5 IgG). This study was performed to identify the three OMPs. The 35-kDa OMP was identified as outer membrane protein A (OmpA) by immunoblotting studies using OmpA-deficient bacteria and recombinant OmpA protein. The 18-kDa OMP was identified as peptidoglycan-associated lipoprotein (PAL) based on peptide sequences from the purified protein and immunoblotting studies using PAL-deficient bacteria. The 5- to 9-kDa OMP was identified as murein lipoprotein (MLP) based on immunoblotting studies using MLP-deficient bacteria. The studies identify the OMPs released into human serum and into the circulation in an experimental model of sepsis as OmpA, PAL, and MLP.

  8. [Elevated Lipoprotein(a) Cncentration and Presence of Subfractions of Small Dense Low Density Lipoproteins as Independent Factors of Risk of Ischemic Heart Disease].

    Science.gov (United States)

    Afanasieva, O I; Utkina, E A; Artemieva, N V; Ezhov, M V; Adamova, I Yu; Pokrovsky, S N

    2016-06-01

    To study relation of lipoproteina - Lp(a) and subfractional composition of apoB containing lipoproteins to the presence of ischemic heart disease (IHD). Manerial and methods. Parameters of lipid spectrum, Lp(a), and subfractions of apoB containing lipoproteins were determined in blood serum of 187 patients with known data of instrumental examination. Lp(a) concentration was not linked to any of risk factors, levels total cholesterol (TC), low and high density lipoprotein CH, and subfractions of lipoproteins. In total group triglyceride (TGG) level correlated with content of small dense LDL (sdLDL) (r=0.445, 2 mg/dl in blood plasma (atherogenic profile B), as well as lowering of concentration of large LDL subfractions significantly increased probability of IHD presence in patients with elevated Lp(a) concentration Lp(a) concentration. Lp(a) is an independent factor of risk of coronary atherosclerosis more significant than shifts in subfractional composition of apoB containing lipoproteins. In patients with Lp(a) concentration less or equal 30 mg/dl subfractions of sdLDL were directly related to TG. Level of sdLDL and large lipoproteins of intermediate density are directly related to the presence of IHD. Large LDL correlates with concentration of HDL DL C and probably is cardioprotective. sdLDL content>2 mg/l or hypertriglyceridemia (TG>1.7 mmol/l) significantly increase chances of detection of confirmed IHD in patients with elevated Lp(a).

  9. Effect of omega-3 fatty acids on the oxylipin composition of lipoproteins in hypertriglyceridemic, statin-treated subjects

    Science.gov (United States)

    Background: Oxylipins mediate many physiological processes, including inflammation and vascular function. Generally considered local and transient, we suggest their presence in lipoproteins indicates they also mediate the effects lipoproteins have on inflammation and vascular biology. To support th...

  10. Characterization of Lipoprotein Lipases interactions with Sortilin and SorLA

    DEFF Research Database (Denmark)

    Klinger, Stine Christensen

    . The present study describes their trafficking of two ligands, lipoprotein lipase and apolipoprotein A-V, which are integral parts of the lipid metabolism. Lipoprotein lipase is found at the luminal side of capillary endothelial cells, where it is involved in the conversion of circulating triglycerides to free...... fatty acids, which in turn are used as an energy source in muscle cells or as an energy reserve in adipose tissue. Lack of lipoprotein lipase leads to an elevated level of plasma lipids and results in increased risk of cardiovascular diseases. The regulation of lipoprotein lipase expression takes place...... at both transcriptional and posttranslational levels. While the transcriptional regulation of the lipase is well described, the posttranslational mechanisms affecting lipoprotein lipase expression are far from understood. The functions of the recently discovered apolipoprotein A-V are still a subject...

  11. NMR and interval PLS as reliable methods for determination of cholesterol in rodent lipoprotein fractions

    DEFF Research Database (Denmark)

    Kristensen, Mette; Savorani, Francesco; Ravn-Haren, Gitte

    2010-01-01

    Risk of cardiovascular disease is related to cholesterol distribution in different lipoprotein fractions. Lipoproteins in rodent model studies can only reliably be measured by time- and plasma-consuming fractionation. An alternative method to measure cholesterol distribution in the lipoprotein...... fractions in rat plasma is presented in this paper. Plasma from two rat studies (n = 68) was used in determining the lipoprotein profile by an established ultracentrifugation method and proton nuclear magnetic resonance (NMR) spectra of replicate samples was obtained. From the ultracentrifugation reference...... data and the NMR spectra, an interval partial least-square (iPLS) regression model to predict the amount of cholesterol in the different lipoprotein fractions was developed. The relative errors of the prediction models were between 12 and 33% and had correlation coefficients (r) between 0.96 and 0...

  12. Diagnosis of type III hyperlipoproteinemia by chromatography of plasma lipoproteins on columns containing agarose.

    Science.gov (United States)

    Shepherd, J; Packard, C J; Dryburgh, F J; Third, J L

    1975-12-01

    Agarose column chromatography has been used to separate plasma lipoproteins into very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Applied to the diagnosis of primary type III hyperlipoproteinemia, the procedure is capable of demonstrating three characteristic and specific changes from normality in the elution pattern of lipoproteins from patients with this condition. In the type III profile there is (a) incomplete separation of VLDL from putative LDL material, (b) early elution of the type III LDL with respect to a normal LDL marker, and (c) relative deficiency of type III LDL with elution characteristics of normal LDL. We advocate the use of this method in the diagnosis of type III hyperlipoproteinemia.

  13. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Langsted, Anne; Kamstrup, Pia Rørbœk; Benn, Marianne

    2016-01-01

    BACKGROUND: The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA risk genotypes are a possible cause of clinical familial hypercholesterolaemia......, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction. METHODS: We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein......(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein...

  14. Roles of lipoprotein receptors in the entry of hepatitis C virus

    Institute of Scientific and Technical Information of China (English)

    Jingya; Lyu; Hitomi; Imachi; Kensaku; Fukunaga; Takuo; Yoshimoto; Huanxiang; Zhang; Koji; Murao

    2015-01-01

    Infection by hepatitis C virus(HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multistep complex process and correlated with abnormal metabolism of lipoprotein. In addition, virus attacks hepatocytes by the initial attaching viral envelop glycoprotein E1/E2 to receptors of lipoproteins on host cells. With the development of HCV model system, mechanisms of HCV cell entry through lipoprotein uptake and its receptor have been extensively studied in detail. Here we summarize recent knowledge about the role of lipoprotein receptors, scavenger receptor class B type Ⅰ and low-density lipoprotein receptor in the entry of HCV, providing a foundation of novel targeting therapeutic tools against HCV infection.

  15. Amphotericin B toxicity as related to the formation of oxidatively modified low-density lipoproteins.

    Science.gov (United States)

    Barwicz, J; Dumont, I; Ouellet, C; Gruda, I

    1998-01-01

    The effect of amphotericin B on the oxidation and degradation of low- and high-density lipoproteins was investigated by UV-vis spectroscopy, electron microscopy, electrophoresis, and size-exclusion chromatography. Two formulations of the drug were used: the commercial Fungizone and a new, less toxic, liposomal formulation, AmBisome. It was shown that Fungizone strongly enhanced the oxidative deformation of low-density lipoprotein structure while AmBisome did not bind to this lipoprotein fraction and did not affect its oxidation. It was shown that amphotericin B contained in Fungizone extracted cholesterol from low-density lipoproteins which sensitized them to oxidation. Both formulations of amphotericin B studied here did not bind to high-density lipoprotein and did not affect the process of its oxidation.

  16. Characterization and Purification of Polydisperse Reconstituted Lipoproteins and Nanolipoprotein Particles

    Directory of Open Access Journals (Sweden)

    Paul D. Hoeprich

    2009-07-01

    Full Text Available Heterogeneity is a fact that plagues the characterization and application of many self-assembled biological constructs. The importance of obtaining particle homogeneity in biological assemblies is a critical goal, as bulk analysis tools often require identical species for reliable interpretation of the results—indeed, important tools of analysis such as x-ray diffraction typically require over 90% purity for effectiveness. This issue bears particular importance in the case of lipoproteins. Lipid-binding proteins known as apolipoproteins can self assemble with liposomes to form reconstituted high density lipoproteins (rHDLs or nanolipoprotein particles (NLPs when used for biotechnology applications such as the solubilization of membrane proteins. Typically, the apolipoprotein and phospholipids reactants are self assembled and even with careful assembly protocols the product often contains heterogeneous particles. In fact, size polydispersity in rHDLs and NLPs published in the literature are frequently observed, which may confound the accurate use of analytical methods. In this article, we demonstrate a procedure for producing a pure, monodisperse NLP subpopulation from a polydisperse self-assembly using size exclusion chromatography (SEC coupled with high resolution particle imaging by atomic force microscopy (AFM. In addition, NLPs have been shown to self assemble both in the presence and absence of detergents such as cholate, yet the effects of cholate on NLP polydispersity and separation has not been systematically examined. Therefore, we examined the separation properties of NLPs assembled in both the absence and presence of cholate using SEC and native gel electrophoresis. From this analysis, NLPs prepared with and without cholate showed particles with well defined diameters spanning a similar size range. However, cholate was shown to have a dramatic affect on NLP separation by SEC and native gel electrophoresis. Furthermore, under

  17. The ppm operon is essential for acylation and glycosylation of lipoproteins in Corynebacterium glutamicum.

    Directory of Open Access Journals (Sweden)

    Niloofar Mohiman

    Full Text Available BACKGROUND: Due to their contribution to bacterial virulence, lipoproteins and members of the lipoprotein biogenesis pathway represent potent drug targets. Following translocation across the inner membrane, lipoprotein precursors are acylated by lipoprotein diacylglycerol transferase (Lgt, cleaved off their signal peptides by lipoprotein signal peptidase (Lsp and, in Gram-negative bacteria, further triacylated by lipoprotein N-acyl transferase (Lnt. The existence of an active apolipoprotein N-acyltransferase (Ms-Ppm2 involved in the N-acylation of LppX was recently reported in M. smegmatis. Ms-Ppm2 is part of the ppm operon in which Ppm1, a polyprenol-monophosphomannose synthase, has been shown to be essential in lipoglycans synthesis but whose function in lipoprotein biosynthesis is completely unknown. RESULTS: In order to clarify the role of the ppm operon in lipoprotein biosynthesis, we investigated the post-translational modifications of two model lipoproteins (AmyE and LppX in C. glutamicum Δppm1 and Δppm2 mutants. Our results show that both proteins are anchored into the membrane and that their N-termini are N-acylated by Cg-Ppm2. The acylated N-terminal peptide of LppX was also found to be modified by hexose moieties. This O-glycosylation is localized in the N-terminal peptide of LppX and disappeared in the Δppm1 mutant. While compromised in the absence of Cg-Ppm2, LppX O-glycosylation could be restored when Cg-Ppm1, Cg-Ppm2 or the homologous Mt-Ppm1 of M. tuberculosis was overexpressed. CONCLUSION: Together, these results show for the first time that Cg-Ppm1 (Ppm synthase and Cg-Ppm2 (Lnt operate in a common biosynthetic pathway in which lipoprotein N-acylation and glycosylation are tightly coupled.

  18. Stability of serum high-density lipoprotein-microRNAs for preanalytical conditions.

    Science.gov (United States)

    Ishikawa, Hiroaki; Yamada, Hiroya; Taromaru, Nao; Kondo, Kanako; Nagura, Ayuri; Yamazaki, Mirai; Ando, Yoshitaka; Munetsuna, Eiji; Suzuki, Koji; Ohashi, Koji; Teradaira, Ryoji

    2017-01-01

    Background Recently, several studies have shown that microRNAs are present in high-density lipoprotein, and high-density lipoprotein-microRNA may be a promising disease biomarker. We investigated the stability of high-density lipoprotein-microRNAs in different storage conditions as this is an important issue for its application to the field of clinical research. Methods microRNAs were extracted from the high-density lipoprotein fraction that was purified from the serum. miR-135 a and miR-223, which are known to be present in high-density lipoprotein, were quantified by quantitative real-time PCR. The influence of preanalytical parameters on the analysis of high-density lipoprotein-miRNAs was examined by the effect of RNase, storage conditions, and freezing and thawing. Results The concentrations of microRNA in high-density lipoprotein were not altered by RNase A treatment (0-100 U/mL). No significant change in these microRNAs was observed after storing serum at room temperature or 4℃ for 0-24 h, and there was a similar result in the cryopreservation for up to two weeks. Also, high-density lipoprotein-microRNAs were stable for, at least, up to five freeze-thaw cycles. Conclusions These results demonstrated that high-density lipoprotein-microRNAs are relatively resistant to various storage conditions. This study provides new and important information on the stability of high-density lipoprotein-microRNAs.

  19. Bio F1B hamster: a unique animal model with reduced lipoprotein lipase activity to investigate nutrient mediated regulation of lipoprotein metabolism

    Directory of Open Access Journals (Sweden)

    Cornish Marion L

    2007-12-01

    Full Text Available Abstract Background Bio F1B hamster is an inbred hybrid strain that is highly susceptible to diet-induced atherosclerosis. We previously reported that feeding a high fat fish oil diet to Bio F1B hamster caused severe hyperlipidaemia. In this study we compared the effects of various diets in the Bio F1B hamster and the Golden Syrian hamster, which is an outbred hamster strain to investigate whether genetic background plays an important role in dietary fat mediated regulation of lipoprotein metabolism. We further investigated the mechanisms behind diet-induced hyperlipidaemia in F1B hamster. Methods The Bio F1B and Golden Syrian hamsters, 8 weeks old, were fed high fat diets rich in either monounsaturated fatty acids, an n-6: n-3 ratio of 5 or a fish oil diet for 4 weeks. Animals were fasted overnight and blood and tissue samples were collected. Plasma was fractionated into various lipoprotein fractions and assayed for triacylglycerol and cholesterol concentrations. Plasma lipoprotein lipase activity was measured using radioisotope method. Microsomal triglyceride transfer protein activity was measured in the liver and intestine. Plasma apolipoproteinB48, -B100 and apolipoprotein E was measured using Western blots. Two-way ANOVA was used to determine the effect of diet type and animal strain. Results The fish oil fed F1B hamsters showed milky plasma after a 14-hour fast. Fish oil feeding caused accumulation of apolipoproteinB48 containing lipoprotein particles suggesting hindrance of triglyceride-rich lipoprotein clearance. There was no significant effect of diet or strain on hepatic or intestinal microsomal triglyceride transfer protein activity indicating that hyperlipidaemia is not due to an increase in the assembly or secretion of lipoprotein particles. F1B hamsters showed significantly reduced levels of lipoprotein lipase activity, which was inhibited by fish oil feeding. Conclusion Evidence is presented for the first time that alterations in

  20. Genetic risk scores associated with baseline lipoprotein subfraction concentrations do not associate with their responses to fenofibrate

    Science.gov (United States)

    Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewid...

  1. [Cholesterol in serum high density lipoprotein fraction (author's transl)].

    Science.gov (United States)

    Schatz, C; Jeanblanc, B; Offner, M

    1980-11-22

    The risk of atheroma can be assessed and valid epidemiological surveys can be carried out by measuring cholesterol in serum high density lipoprotein fraction (HDL) and calculating the HDL cholesterol: VLDL + LDL ratio. This was done in 39 patients free from surgically confirmed atheromatous lesions and in 51 patients presenting with such lesions. Of the four different techniques used for separation in these patients (ultracentrifugation, precipitation with heparin-Mn2+, precipitation with phosphotungstate-Mg2+ and electrophoresis), precipitation with phosphotungstate-Mg/2+ seems to be the most suitable, since there is no degradation of the HDL fraction as during electrophoresis on polyacrylamide gel, and less floculation of the supernatant after separation. Contrary to ultracentrifugation, which requires sophisticated equipment and good technical skill, the technique is easily carried out.

  2. Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution.

    Science.gov (United States)

    Sánchez-Quesada, José L; Vinagre, Irene; de Juan-Franco, Elena; Sánchez-Hernández, Juan; Blanco-Vaca, Francisco; Ordóñez-Llanos, Jordi; Pérez, Antonio

    2012-07-01

    The aim of this study was to determine the effect of intensified hypoglycemic therapy in patients with type 2 diabetes mellitus on the distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity between high-density lipoprotein and low-density lipoprotein (LDL) and its relation with the lipid profile and other qualitative properties of LDL. Forty-two patients with type 2 diabetes on the basis of poor glycemic control and normal or near normal LDL cholesterol were recruited. Lifestyle counseling and pharmacologic hypoglycemic therapy were intensified to improve glycemic control, but lipid-lowering therapy was unchanged. At 4 ± 2 months, glycosylated hemoglobin had decreased by a mean of 2.1%, but the only effect on the lipid profile were statistically significant decreases in nonesterified fatty acids and apolipoprotein B concentration. LDL size increased and the proportion of electronegative LDL decreased significantly. In parallel, total Lp-PLA2 activity decreased significantly, promoting a redistribution of Lp-PLA2 activity toward a higher proportion in high-density lipoprotein. Improvements in glycemic control led to more marked changes in Lp-PLA2 activity and distribution in patients with diabetes who had not received previous lipid-lowering therapy. In conclusion, optimizing glycemic control in patients with type 2 diabetes promotes atheroprotective changes, including larger LDL size, decreased electronegative LDL, and a higher proportion of Lp-PLA2 activity in high-density lipoprotein.

  3. Association between plasma lipoprotein levels and bioprosthetic valve structural degeneration.

    Science.gov (United States)

    Nsaibia, Mohamed Jalloul; Mahmut, Ablajan; Mahjoub, Haifa; Dahou, Abdellaziz; Bouchareb, Rihab; Boulanger, Marie-Chloé; Després, Jean-Pierre; Bossé, Yohan; Arsenault, Benoît J; Larose, Eric; Pibarot, Philippe; Mathieu, Patrick

    2016-12-01

    Structural valve degeneration (SVD) leads to the failure of aortic valve bioprostheses. It is suspected that lipid-derived factors could play a role in SVD. We hypothesised that oxidised low-density lipoprotein (OxLDL), OxLDL/LDL, OxLDL/high-density lipoprotein (OxLDL/HDL) and proprotein convertase subtilisin/kexin 9 (PCSK9) may be associated with SVD. We included 199 patients who underwent an aortic valve replacement with a bioprosthesis and had an echocardiography follow-up to evaluate the function of the prosthesis. SVD was defined as an increase in mean transprosthetic gradient (≥10 mm Hg) or a worsening of transprosthetic regurgitation (≥1/3) during the follow-up. After a mean follow-up of 8±3.5 years, 41(21%) patients developed SVD. The univariate predictors of SVD were LDL (p=0.03), apolipoprotein B (p=0.01), OxLDL (p=0.02), OxLDL/HDL (p=0.009) and LDL associated with small, dense particles (LDL-CSVD. There was a significant interaction between OxLDL/HDL and PCSK9 on SVD (p=0.05). After adjustment, compared with patients with low OxLDL/HDL (median, SVD (OR 2.93, 95% CI 1.02 to 9.29, p=0.04). OxLDL/HDL ratio is independently associated with SVD. 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/.

  4. Insulin Resistance Predicts Atherogenic Lipoprotein Profile in Nondiabetic Subjects

    Directory of Open Access Journals (Sweden)

    Flávia De C. Cartolano

    2017-01-01

    Full Text Available Background. Atherogenic diabetes is associated with an increased cardiovascular risk and mortality in diabetic individuals; however, the impact of insulin resistance (IR in lipid metabolism in preclinical stages is generally underreported. For that, we evaluated the capacity of IR to predict an atherogenic lipid subfraction profile. Methods. Complete clinical evaluation and biochemical analysis (lipid, glucose profile, LDL, and HDL subfractions and LDL phenotype and size were performed in 181 patients. The impact of IR as a predictor of atherogenic lipoproteins was tested by logistic regression analysis in raw and adjusted models. Results. HDL-C and Apo AI were significantly lower in individuals with IR. Individuals with IR had a higher percentage of small HDL particles, lower percentage in the larger ones, and reduced frequency of phenotype A (IR = 62%; non-IR = 83%. IR individuals had reduced probability to have large HDL (OR = 0.213; CI = 0.999–0.457 and had twice more chances to show increased small HDL (OR = 2.486; CI = 1.341–7.051. IR was a significant predictor of small LDL (OR = 3.075; CI = 1.341–7.051 and atherogenic phenotype (OR = 3.176; CI = 1.469–6.867. Conclusion. IR, previously DM2 diagnosis, is a strong predictor of quantitative and qualitative features of lipoproteins directly associated with an increased atherogenic risk.

  5. Interaction of variable bacterial outer membrane lipoproteins with brain endothelium.

    Directory of Open Access Journals (Sweden)

    Gaurav Gandhi

    Full Text Available BACKGROUND: Previously we reported that the variable outer membrane lipoprotein Vsp1 from the relapsing fever spirochete Borrelia turicatae disseminates from blood to brain better than the closely related Vsp2 [1]. Here we studied the interaction between Vsp1 and Vsp2 with brain endothelium in more detail. METHODOLOGY/PRINCIPAL FINDINGS: We compared Vsp1 to Vsp2 using human brain microvascular endothelial cell (HBMEC association assays with aminoacid radiolabeled Vsp-expressing clones of recombinant Borrelia burgdorferi and lanthanide-labeled purified lipidated Vsp1 (LVsp1 and Vsp2 (LVsp2 and inoculations of the lanthanide-labeled proteins into mice. The results showed that heterologous expression of LVsp1 or LVsp2 in B. burgdorferi increased its association with HBMEC to a similar degree. Purified lanthanide-labeled lipidated Vsp1 (LVsp1 and LVsp2 by themselves were capable of associating with HBMEC. The association of LVsp1 with brain endothelium was time-dependent, saturable, and required the lipidation. The association of Vsp1 with HBMEC was inhibited by incubation at lower temperature or with excess unlabeled LVsp1 or LVsp2 but not with excess rVsp1 or mouse albumin or an anti Vsp1 monoclonal antibody. The association of LVsp2 with HBMEC and its movement from blood to brain parenchyma significantly increased in the presence of LVsp1. CONCLUSIONS/SIGNIFICANCE: Variable bacterial outer membrane lipoproteins interact with brain endothelium differently; the lipidation and variable features at the protein dome region are key modulators of this interaction.

  6. Biominetic High Density Lipoproteins for the Delivery of Therapeutic Oligonucleotides

    Science.gov (United States)

    Tripathy, Sushant

    Advances in nanotechnology have brought about novel inorganic and hybrid nanoparticles with unique physico-chemical properties that make them suitable for a broad range of applications---from nano-circuitry to drug delivery. A significant part of those advancements have led to ground-breaking discoveries that have changed the approaches to formulation of therapeutics against diseases, such as cancer. Now-a-days the focus does not lie solely on finding a candidate small-molecule therapeutic with minimal adverse effects, but researchers are looking up to nanoparticles to improve biodistribution and biocompatibility profile of clinically proven therapeutics. The plethora of conjugation chemistries offered by currently extant inorganic nanoparticles have, in recent years, led to great leaps in the field of biomimicry---a modality that promises high biocompatibility. Further, in the pursuit of highly specific therapeutic molecules, researchers have turned to silencing oligonucleotides and some have already brought together the strengths of nanoparticles and silencing oligonucleotides in search of an efficacious therapy for cancer with minimal adverse effects. This dissertation work focuses on such a biomimetic platform---a gold nanoparticle based high density lipoprotein biomimetic (HDL NP), for the delivery of therapeutic oligonucleotides. The first chapter of this body of work introduces the molecular target of the silencing oligonucleotides---VEGFR2, and its role in the progression of solid tumor cancers. The background information also covers important aspects of natural high density lipoproteins (HDL), especially their innate capacity to bind and deliver exogenous and endogenous silencing oligonucleotides to tissues that express their high affinity receptor SRB1. We subsequently describe the synthesis of the biomimetic HDL NP and its oligonucleotide conjugates, and establish their biocompatibility. Further on, experimental data demonstrate the efficacy of silencing

  7. Study of the relationship between IL-10 polymorphism and serum lipoprotein levels in Han Chinese individuals.

    Science.gov (United States)

    Yang, W Q

    2016-06-03

    Previous studies have shown that cytokines can affect serum lipoprotein concentrations. The aim of this study was to examine the association between IL-10 gene polymorphisms and serum lipoprotein levels of Han Chinese individuals. A total of 359 Han Chinese people were enrolled in this investigation. IL-10 -592, -819, and -1082 genotypes were established using polymerase chain reaction-restriction fragment length polymorphism analysis. An automatic biochemistry analyzer was used to determine serum concentrations of total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) in each individual. We observed that the three IL-10 polymorphisms did not significantly differ in terms of age or age of carrier (P > 0.05), and the -592 and -819 variants did not significantly affect serum lipoprotein levels (P > 0.05). HDL concentrations were higher and TG levels were lower in carriers of the -1082 GA genotype compared to those with the AA genotype, and these differences were statistically significant (P 0.05). Our results suggest that the polymorphism at position -1082 in the promoter region of IL-10 may affect serum HDL and TG concentrations, while other variants of this gene appear to have no relationship with serum lipoprotein levels.

  8. Thermal transitions in the low-density lipoprotein and lipids of the egg yolk of hens.

    Science.gov (United States)

    Smith, M B; Back, J F

    1975-05-22

    1. Differential sanning calorimetry and light-scattering have been used to investigate temperature-dependent transitions in low-density lipoprotein and in lipids from hens' egg yolk. Yolks of different fatty acid composition were obtained by varying the dietary lipid and by adding methyl sterculate to the hen's diet. 2. Lipoprotein solutions in 50 percent glycerol/water gave characteristic melting curves between -25 degrees C and 50 degrees C, and on cooling showed increases in light-scattering between 10 degrees C and -20 degrees C. The temperatures at which major changes occurred depended on the proportions of saturated and unsaturated fatty acids. 3. The thermal transitions in the intact lipoprotein in glycerol solution were reversible, but with marked hysteresis. Lipid extracted from the lipoprotein did not show temperature hystersis but the transition heats and melting curves similar to those of the intact lipoprotein. The results support the hypothesis of a "lipid-core" structure for low-density lipoproteins. 4. Scanning calorimetry of egg-yolk lecithins indicated a strong dependence of transition temperature on water content in the rane 3 percent-20 percent water. A rise in the mid-temperature of the liquid-crystalline to gel transition as the water content is lowered on freezing may be the primary event in the irreversible gelation of egg yolk and aggregation of lipoprotein.

  9. Effect of Antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood.

    Science.gov (United States)

    Aynaci, F M; Orhan, F; Orem, A; Yildirmis, S; Gedik, Y

    2001-05-01

    Antiepileptic drugs may alter plasma lipid status in epileptic patients. We conducted a study to assess the effect of phenobarbital, carbamazepine, and valproate on plasma levels of lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A, and apolipoprotein B in 22 epileptic children. The children were separated as group 1, seven children, mean age 1.6+/-0.2 years, treated with phenobarbital, 5 mg/kg/day, twice daily; group 2, seven children, mean age 9.8+/-1.2 years, treated with carbamazepine, 20 mg/kg/day, twice daily; and group 3, eight children, mean age 6.8+/-0.6 years, treated with valproate, 20 mg/kg/day, twice daily. Plasma lipoprotein (a) and other lipid levels were studied before (pretreatment) and at 3 and 6 months of treatment. Friedman two-way analysis of variance and Wilcoxon's signed-rank test were used for statistical analysis, and the results were expressed as the mean and standard error of the mean. The mean age of children in group 1 was significantly low, compared with groups 2 and, 3 (P < .001). The mean pretreatment lipid levels between the groups were not significant. The increase in lipoprotein (a) at 3 and 6 months and high-density lipoprotein cholesterol at 6 months was statistically significant in group 1 (P < .025). We suggest a careful monitoring of plasma levels of lipoprotein (a) and other lipids in epileptic children treated with antiepileptic drugs.

  10. Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes.

    Science.gov (United States)

    Sonmez, Fatma Mujgan; Demir, Ercan; Orem, Asim; Yildirmis, Sermet; Orhan, Fazil; Aslan, Adnan; Topbas, Murat

    2006-01-01

    We conducted a study to assess the effect of phenobarbital, carbamazepine, and valproate on serum lipid profiles and lipoprotein (a) in 64 children with epilepsy (aged between 1 and 15 years) admitted to the child neurology outpatient clinic between July 2000 and July 2002. The children were separated as group 1 (18 children), treated with phenobarbital, 5 mg/kg/day; group 2 (22 children), treated with carbamazepine, 10 to 15 mg/kg/day; and group 3 (24 children), treated with sodium valproate, 20 mg/kg/day. Plasma lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A and apolipoprotein B levels, and liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase were determined before the initiation of the treatment and at 3, 6, and 12 months of the treatment period. The mean age of children in group 1 was significantly low compared with those in groups 2 and 3 (P 30 mg/dL) were observed only in carbamazepine-treated patients at 6 and 12 months. The percentage of children with lipoprotein (a) levels over 30 mg/dL was 44%, 63%, and 33% in the phenobarbital-, carbamazepine-, and valproate-treated children, respectively. Antiepileptic drugs significantly increase the level of lipoprotein (a), which is a major risk factor for atherosclerosis, and also have variable effects on other lipid parameters. Lipoprotein (a) levels should be closely followed in patients receiving antiepileptic drugs. (J Child Neurol 2006;21:70-74).

  11. High density lipoprotein level is negatively associated with the increase of oxidized low density lipoprotein lipids after a fatty meal.

    Science.gov (United States)

    Tiainen, Sanna; Ahotupa, Markku; Ylinen, Petteri; Vasankari, Tommi

    2014-12-01

    Recent reports show that a fatty meal can substantially increase the concentration of oxidized lipids in low density lipoprotein (LDL). Knowing the LDL-specific antioxidant effects of high density lipoprotein (HDL), we aimed to investigate whether HDL can modify the postprandial oxidative stress after a fatty meal. Subjects of the study (n = 71) consumed a test meal (a standard hamburger meal) rich in lipid peroxides, and blood samples were taken before, 120, 240, and 360 min after the meal. The study subjects were divided into four subgroups according to the pre-meal HDL cholesterol value (HDL subgroup 1, 0.66-0.91; subgroup 2, 0.93-1.13; subgroup 3, 1.16-1.35; subgroup 4, 1.40-2.65 mmol/L). The test meal induced a marked postprandial increase in the concentration of oxidized LDL lipids in all four subgroups. The pre-meal HDL level was associated with the extent of the postprandial rise in oxidized LDL lipids. From baseline to 6 h after the meal, the concentration of ox-LDL increased by 48, 31, 24, and 16% in the HDL subgroup 1, 2, 3, and 4, respectively, and the increase was higher in subgroup 1 compared to subgroup 3 (p = 0.028) and subgroup 4 (p = 0.0081), respectively. The pre-meal HDL correlated with both the amount and the rate of increase of oxidized LDL lipids. Results of the present study show that HDL is associated with the postprandial appearance of lipid peroxides in LDL. It is therefore likely that the sequestration and transport of atherogenic lipid peroxides is another significant mechanism contributing to cardioprotection by HDL.

  12. Apolipoprotein AV Accelerates Plasma Hydrolysis OfTriglyceride-Rich Lipoproteins By Interaction With Proteoglycan BoundLipoprotein Lipase

    Energy Technology Data Exchange (ETDEWEB)

    Merkel, Martin; Loeffler, Britta; Kluger, Malte; Fabig, Nathalie; Geppert, Gesa; Pennacchio, Len A.; Laatsch, Alexander; Heeren, Joerg

    2005-02-22

    Apolipoprotein A5 (APOA5) is associated with differences intriglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasmatriglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In hAPOA5 transgenic mice(hAPOA5tr), catabolism of chylomicrons and VLDL was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL).Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by crossbreeding a human LPL transgene with the apoa5 knockout, and the hAPOA5tr to an LPL deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5 deficient mice,however, over expression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr HDL, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line.A direct interaction between LPL and apoAV was found by ligand blotting.It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycans bound LPL for lipolysis.

  13. Measurement of cholesterol and other lipoprotein constituents in the clinical laboratory.

    Science.gov (United States)

    Warnick, G R

    2000-04-01

    Measurements of lipids and lipoproteins in the clinical laboratory have become increasingly important because of their predictive association with cardiovascular diseases, especially coronary artery disease. The US National Institutes of Health-sponsored National Cholesterol Education Program and counterparts in other countries have developed national consensus guidelines for diagnosis and treatment of coronary artery disease which provide risk cut-points and define use of the lipid/lipoprotein analytes in case finding and therapy. Total and low density lipoprotein cholesterol and triglycerides are measured as positive risk factors and high density lipoprotein cholesterol as an inverse risk factor for coronary artery disease. A National Cholesterol Education Program-sponsored expert laboratory panel has developed guidelines for measurements with requisite analytical performance targets for total error and corresponding precision and bias. The US Centers for Disease Control and Prevention have established reference methods for total and high density lipoprotein cholesterol and for triglycerides, with a method for low density lipoprotein cholesterol in development. Standardization programs for research laboratories and a Cholesterol Reference Method Laboratory Network for diagnostic manufacturers and clinical laboratories provide reliable access and documentation of traceability to accepted reference methods. Methods for the lipid/lipoprotein analytes have improved dramatically in recent years and, coupled with improved chemistry analyzer systems and more attention to standardization by manufacturers, offer considerable improvement in analytical performance. Fully automated homogeneous assays for high density lipoprotein cholesterol and newer similar assays for low-density lipoprotein cholesterol have potential for better precision as well as more convenient and cost-effective measurements. Attention to pre-analytical sources of variation is also important in making

  14. Lipidomic analysis of plasma lipoprotein fractions in myocardial infarction-prone rabbits.

    Science.gov (United States)

    Takeda, Hiroaki; Koike, Tomonari; Izumi, Yoshihiro; Yamada, Takayuki; Yoshida, Masaru; Shiomi, Masashi; Fukusaki, Eiichiro; Bamba, Takeshi

    2015-10-01

    Lipids play important roles in the body and are transported to various tissues via lipoproteins. It is commonly assumed that alteration of lipid levels in lipoproteins leads to dyslipidemia and serious diseases such as coronary artery disease (CAD). However, lipid compositions in each lipoprotein fraction induced by lipoprotein metabolism are poorly understood. Lipidomics, which involves the comprehensive and quantitative analysis of lipids, is expected to provide valuable information regarding the pathogenic mechanism of CAD. Here, we performed a lipidomic analysis of plasma and its lipoprotein fractions in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. In total, 172 lipids in plasma obtained from normal and WHHLMI rabbits were quantified with high throughput and accuracy using supercritical fluid chromatography hybrid quadrupole-Orbitrap mass spectrometry (SFC/Q-Orbitrap-MS). Plasma levels of each lipid class (i.e., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, ceramide, triacylglycerol, diacylglycerol, and cholesterol ester, except for free fatty acids) in 21-month-old WHHLMI rabbits were significantly higher than those in normal rabbits. High levels of functional lipids, such as alkyl-phosphatidylcholines, phospholipids including ω-6 fatty acids, and plasmalogens, were also observed in WHHLMI rabbit plasma. In addition, high-resolution lipidomic analysis using very low density lipoprotein (VLDL) and low density lipoprotein (LDL) provided information on the specific molecular species of lipids in each lipoprotein fraction. In particular, higher levels of phosphatidylethanolamine plasmalogens were detected in LDL than in VLDL. Our lipidomics approach for plasma lipoprotein fractions will be useful for in-depth studies on the pathogenesis of CAD. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights

  15. Dietary fatty acids were not independently associated with lipoprotein subclasses in elderly women.

    Science.gov (United States)

    Alaghehband, Fatemeh Ramezan; Lankinen, Maria; Värri, Miika; Sirola, Joonas; Kröger, Heikki; Erkkilä, Arja T

    2017-07-01

    Dietary fatty acids are known to affect serum lipoproteins; however, little is known about the associations between consumption of dietary fatty acids and lipoprotein subclasses. In this study, we hypothesized that there is an association between dietary fatty acids and lipoprotein subclasses and investigated the cross-sectional association of dietary fat intake with subclasses of lipoproteins in elderly women. Altogether, 547 women (aged ≥65 years) who were part of OSTPRE cohort participated. Dietary intake was assessed by 3-day food records, lifestyle, and health information obtained through self-administrated questionnaires, and lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. To analyze the associations between fatty acids and lipoprotein subclasses, we used Pearson and Spearman correlation coefficients and the analysis of covariance (ANCOVA) test with, adjustment for physical activity, body mass index, age, smoking status, and intake of lipid-lowering drugs. There were significant correlations between saturated fatty acids (SFA; % of energy) and concentrations of large, medium, and small low-density lipoproteins (LDL); total cholesterol in large, medium, and small LDL; and phospholipids in large, medium, and small LDL, after correction for multiple testing. After adjustment for covariates, the higher intake of SFA was associated with smaller size of LDL particles (P = .04, ANCOVA) and lower amount of triglycerides in small very low-density lipoproteins (P = .046, ANCOVA). However, these associations did not remain significant after correction for multiple testing. In conclusion, high intake of SFA may be associated with the size of LDL particles, but the results do not support significant, independent associations between dietary fatty acids and lipoprotein subclasses. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Estrogen receptor-related receptor a and bone metabolism%雌激素受体相关受体α与骨代谢

    Institute of Scientific and Technical Information of China (English)

    蔡川; 陈昕; 丁寅

    2010-01-01

    雌激素受体相关受体α(estrogen receptor-related receptor α,ERRα)是最早发现的一种孤儿核受体,是核受体超家族中一员.它与雌激素受体(estrogen receptors,ERs)有着一定的同源性,但尚未发现任何配体.目前研究证明ERRα在骨代谢、能量代谢的调节以及乳腺癌发生中都起到重要作用.本文主要综述ERRα在骨代谢方面的研究进展,特别是在骨组织中对受体介导的雌激素信号途径的参与,以求进一步了解雌激素调控骨改建的机制,以及展望ERRα作为靶点治疗雌激素相关的骨代谢病的前景.

  17. Sexual differences in lipoprotein composition in a family with dyslipidemic hypertension with premature atheroschlerosis: deficiency of high-density lipoprotein-L and high-density lipoprotein-M "apolipoprotein-I alone" particle.

    Science.gov (United States)

    Hughes, T A; Moore, M A; Joyce, M; Go, R C; Segrest, J P; Blackwell, T

    1992-01-01

    This article describes a family with a high incidence of premature atherosclerosis and primary hypertriglyceridemia in the women. The lipoprotein composition of this family was investigated with a new methodology that combines gradient ultracentrifugation to isolate lipoprotein subfractions with high-performance liquid chromatography to quantitate apolipoproteins. The major lipoprotein abnormalities that were identified in the hyperlipidemic women in this family were (1) an increased mass of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) with triglyceriderich VLDL but normal IDL composition; (2) triglyceride-rich low-density lipoprotein (LDL) with normal cholesterol and apolipoprotein B concentrations; (3) a relatively normal total mass of high-density lipoprotein (HDL)-L and HDL-M but with a reduction in the apolipoprotein A-I/A-II ratio and a decrease in the cholesterol to triglyceride ratio; (4) an elevation of HDL-D apolipoprotein A-I. The reduction in the apolipoprotein A-I/A-II ratio was also seen in the hyperlipidemic men and in most of nonhyperlipidemic family members and was the most common lipoprotein abnormality that was identified in this family (9 of 11 family members who were not on lipid-lowering medications were affected). The hypertriglyceridemic women appeared to have an increase in the "A-I + A-II" HDL particles in all subfractions and an increase in the "A-I alone" particles in HDL-D. These increases provided the apparently normal total mass of HDL that was observed in these women. These increases in HDL were not seen in the hypertriglyceridemic men. We conclude that a deficiency of the "A-I alone" particle in HDL-L and HDL-M may contribute to the premature atherosclerosis that was seen in this family and that it appears to precede the appearance of hypertriglyceridemia. The increase in the "A-I + A-II" HDL particles did not appear to provide the same protection as would be expected from "A-I alone" HDL.

  18. Crystal structures of bacterial lipoprotein localization factors, LolA and LolB

    OpenAIRE

    Takeda, Kazuki; Miyatake, Hideyuki; Yokota, Naoko; Matsuyama, Shin-ichi; Tokuda, Hajime; Miki, Kunio

    2003-01-01

    Lipoproteins having a lipid-modified cysteine at the N-terminus are localized on either the inner or the outer membrane of Escherichia coli depending on the residue at position 2. Five Lol proteins involved in the sorting and membrane localization of lipoprotein are highly conserved in Gram-negative bacteria. We determined the crystal structures of a periplasmic chaperone, LolA, and an outer membrane lipoprotein receptor, LolB. Despite their dissimilar amino acid sequences, the structures of ...

  19. [Lipoproteins HDL and coronary artery disease: a molecular mechanism of fibrate].

    Science.gov (United States)

    Kaletha, Krystian; Chodorowski, Zygmunt; Anand, Izabela Sein; Rybakowska, Iwona; Nagel-Starczynowska, Gabriela

    2003-01-01

    The importance of dyslipidemia in the development of cardiovascular disease is now recognized as a central factor of equal, if not greater significance than any other risk factor. Although correction of high level of low-density lipoproteins (LDL) has been regarded now as the main goal of therapy, it has now been reaffirmed that the contribution of low level of high-density lipoproteins (HDL) to the risk of ischaemic heart disease should also be considered. In the therapy of dislipidemias with hipertriglyceridemia and decreased level of HDL lipoprotein fibrates play an especially important role. In the article the molecular mechanism of fibrates action is presented.

  20. Obstructive jaundice leads to accumulation of oxidized low density lipoprotein in human liver tissue

    Institute of Scientific and Technical Information of China (English)

    Mustafa Comert; Yucel Ustundag; Ishak Ozel Tekin; Banu Dogan Gun; Figen Barut

    2006-01-01

    Oxidized low density lipoprotein (ox-LDL) molecule is one of the most important modified lipoproteins produced during the oxidative stress. Modified lipoproteins have been defined as being part of the immune inflammatory mechanisms in association with oxidant stress. We have reported the accumulation of ox-LDL in Balb/c mice liver after bile duct ligation previously. Here, we investigated this finding in human beings with obstructive jaundice.Our study demonstrates that obstructive jaundice results in tremendous accumulation of ox-LDL in the liver tissue of patients.

  1. Recurrent Embolic Strokes of Undetermined Source in a Patient with Extreme Lipoprotein(a Levels

    Directory of Open Access Journals (Sweden)

    Zachary Bulwa

    2016-08-01

    Full Text Available Lipoprotein(a is a plasma lipoprotein and known cardiovascular risk factor most recently implicated in the development of high-risk carotid atherosclerotic plaques without significant carotid stenosis. We present a case of a young African-American female with recurrent embolic strokes of undetermined source. After our thorough investigation we identified the link between a small, irregular plaque in the right internal carotid artery and an extremely elevated plasma level of lipoprotein(a as the source of her embolic strokes.

  2. High-density lipoprotein cholesterol on a roller coaster: where will the ride end?

    Science.gov (United States)

    Kronenberg, Florian

    2016-04-01

    Bowe et al. report an association between low high-density lipoprotein cholesterol concentrations and various incident chronic kidney disease end points in a cohort of almost 2 million US veterans followed for 9 years. These impressive data should be a starting point for further investigations including genetic epidemiologic investigations as well as post hoc analyses of interventional trials that target high-density lipoprotein cholesterol and, finally, studies that focus on the functionality of high-density lipoprotein particles.

  3. Secretion of bacterial lipoproteins: through the cytoplasmic membrane, the periplasm and beyond.

    Science.gov (United States)

    Zückert, Wolfram R

    2014-08-01

    Bacterial lipoproteins are peripherally anchored membrane proteins that play a variety of roles in bacterial physiology and virulence in monoderm (single membrane-enveloped, e.g., gram-positive) and diderm (double membrane-enveloped, e.g., gram-negative) bacteria. After export of prolipoproteins through the cytoplasmic membrane, which occurs predominantly but not exclusively via the general secretory or Sec pathway, the proteins are lipid-modified at the cytoplasmic membrane in a multistep process that involves sequential modification of a cysteine residue and cleavage of the signal peptide by the signal II peptidase Lsp. In both monoderms and diderms, signal peptide processing is preceded by acylation with a diacylglycerol through preprolipoprotein diacylglycerol transferase (Lgt). In diderms but also some monoderms, lipoproteins are further modified with a third acyl chain through lipoprotein N-acyl transferase (Lnt). Fully modified lipoproteins that are destined to be anchored in the inner leaflet of the outer membrane (OM) are selected, transported and inserted by the Lol (lipoprotein outer membrane localization) pathway machinery, which consists of the inner-membrane (IM) ABC transporter-like LolCDE complex, the periplasmic LolA chaperone and the OM LolB lipoprotein receptor. Retention of lipoproteins in the cytoplasmic membrane results from Lol avoidance signals that were originally described as the "+2 rule". Surface localization of lipoproteins in diderms is rare in most bacteria, with the exception of several spirochetal species. Type 2 (T2SS) and type 5 (T5SS) secretion systems are involved in secretion of specific surface lipoproteins of γ-proteobacteria. In the model spirochete Borrelia burgdorferi, surface lipoprotein secretion does not follow established sorting rules, but remains dependent on N-terminal peptide sequences. Secretion through the outer membrane requires maintenance of lipoproteins in a translocation-competent unfolded conformation

  4. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population

    DEFF Research Database (Denmark)

    Kamstrup, Pia R; Benn, Marianne; Tybjaerg-Hansen, Anne

    2008-01-01

    Elevated lipoprotein(a) levels are associated with myocardial infarction (MI) in some but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) levels, measurements in long-term frozen samples, no correction for regression dilution bias, and lack...... of absolute risk estimates in the general population. We tested the hypothesis that extreme lipoprotein(a) levels predict MI in the general population, measuring levels shortly after sampling, correcting for regression dilution bias, and calculating hazard ratios and absolute risk estimates....

  5. Comparison of Interferon gamma inducible protein-10 and Interferon gamma based QuantiFERON TB Gold assays with tuberculin skin test in HIV infected subjects

    Science.gov (United States)

    Basirudeen, S; Rajasekaran, S; Alamelu, R

    2011-01-01

    We aimed to compare the positivity of the QuantiFERON TB gold in-tube (QFT-IT antigens) specific Interferon gamma (IFN-γ/QFT-IT) and IFN-γ nducible protein-10 (IP-10/QFT-IT) assays with tuberculin skin test (TST) among human immunodeficiency virus (HIV) infected individuals in a TB endemic setting. A total of 180 HIV infected subjects, with no evidence of active TB were recruited. IFN-γ nd IP-10 levels specific to QFT-IT antigens were measured in plasma from QFT-IT tubes. The overall positivity of TST at 5mm cut-off point (19%) was significantly lower when compared to IFN-γ/QFT-IT (38%) and IP-10/QFT-IT (45%) assays. The positivity of IP-10/QFT-IT was significantly higher than IFN-γ/QFT-IT (p=0.038). Indeterminate results for IFN-γ/QFT-IT and IP-10/QFT-IT were more frequent in subjects with CD4 count 100 cells/µl. IFN-γ/QFT-IT (9%) yielded significantly higher number of indeterminate results than IP-10/QFT-IT (5%). The frequency of these responses is higher than the proportion of individuals with positive TST results. However, 6 IFN-γ/QFT-IT or IP-10/QFT-IT negative subjects were positive for TST at 5mm cut-off point. Prospective and prognostic studies are required to clarify the significance of these data. PMID:21996360

  6. Changes of inducible protein-10 and regulated upon activation, normal T cell expressed and secreted protein in acute rejection of pancreas transplantation in rats

    Institute of Scientific and Technical Information of China (English)

    Jun Zhu; Ze-Kuan Xu; Yi Miao; Xun-Liang Liu; Hong Zhang

    2006-01-01

    AIM: To investigate the role of IFN-γ inducible protein -10 (Ip-10) and regulated upon activation, normal T cell expressed and secreted (RANTES) protein in acute pancreatic allograft rejection in rats.METHODS: An experimental pancreas transplantation model was established using diabetic SD rats as the recipient, induced by applying streptozocin (STZ).Pancreas transplantation was performed with a physiologic method of portal venous and enteric drainage. Rats were divided into two groups, isograft group (group A, n = 24) and allograft group (group B, n = 24) in which either healthy SD rats or Wistar rats served as donors, respectively. Twelve diabetic or healthy SD rats were used as controls. At d 1, 4, 7, and 10 post transplantation, serum IP-10 and RANTES were assessed by ELISA and their expression in the allografts was determined by immunohistochemistry.RESULTS: In group B (allograft group), the development of acute rejection was significantly correlated with increased serum concentration and tissue expression of IP-10 and RANTES, with a peak level at d 7 post transplantation. In contrast, there was no obvious change before and after transplantation in group A (isograft group).CONCLUSION: Our study suggests a possible role of IP-10 and RANTES in acute rejection and early monitoring of chemokines may be helpful in predicting the outcome of pancreas transplantation.

  7. Role of alpha-crystallin, early-secreted antigenic target 6-kDa protein and culture filtrate protein 10 as novel diagnostic markers in osteoarticular tuberculosis

    Directory of Open Access Journals (Sweden)

    Nazia Rizvi

    2016-07-01

    Full Text Available Osteoarticular tuberculosis constitutes about 3% of all tuberculosis cases. Early and accurate diagnosis of tuberculosis is a challenging problem especially in the case of osteoarticular tuberculosis owing to the lower number of bacilli. However, an accurate and timely diagnosis of the disease results in an improved efficacy of the given treatment. Besides the limitations of conventional methods, nowadays molecular diagnostic techniques have emerged as a major breakthrough for the early diagnosis of tuberculosis with high sensitivity and specificity. Alpha-crystallin is a dominantly expressed protein responsible for the long viability of the pathogen during the latent phase under certain stress conditions such as hypoxia and nitric oxide stress. Two other proteins—early secreted antigenic target-6 and culture filtrate protein-10—show high expression in the active infective phase of Mycobacterium tuberculosis. In this article, we focus on the different proteins expressed dominantly in latent/active tuberculosis, and which may be further used as prognostic biomarkers for diagnosing tuberculosis, both in latent and active phases.

  8. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

    DEFF Research Database (Denmark)

    Chapman, M John; Ginsberg, Henry N; Amarenco, Pierre;

    2011-01-01

    Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipop......Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high......-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic...... studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated...

  9. [Lipoprotein (a)--a mysterious factor in atherogenesis].

    Science.gov (United States)

    Jelaković, Bojan; Laganović, Mario; Kuzmanić, Dusko

    2002-01-01

    Etiopathogenesis of arterial hypertension and coronary disease involves interaction of numerous exogenous factors which determine the clinical course and therapeutic response in genetically predisposed individuals. The role of numerous cardiovascular risk factors has been reevaluated during the past few years, yet some unresolved issues and gaps still remain. One of the still insufficiently studied factors is lipoprotein (a) [Lp (a)] which belongs to a subclass of LDL lipoproteins. Its important component is apolipoprotein (a) which is structurally similar to plasminogen. This characteristic can be followed through evolution and is probably crucial for its physiologic but also pathophysiologic role. Actually, through its competition with plasminogen, Lp (a) interferes with the process of fibrinolysis and may contribute to tissue healing and restoration but also support and accelerate atherothrombotic process. Lp (a) concentration is stable and genetically determined in an individual and the indication that persons with elevated levels are permanently exposed to increased risk is supported by the data on twofold incidence of myocardial infarction in mothers of children with highest Lp (a) concentrations. Apart from competing with plasminogen via apolipoprotein (a), Lp (a) increases the activity of inhibitors of plasminogen-I activator and reduces the activity of transforming growth factor-beta. This results both in the absence of fibrinolysis and promotion of migration and proliferation of media smooth muscle cells, which are important in the onset of atherosclerotic process. Lp (a) binds to elastin via apolipoprotein B, resulting in oxidation and facilitated entry into macrophages and their transition into the so-called foam cells, also an important sign of early atherosclerosis. Although many pathophysiologic processes by which Lp (a) contributes to atherosclerosis have also been confirmed by animal experiments as well as by the presence of histologic evidence

  10. Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy

    Directory of Open Access Journals (Sweden)

    Orlando Robert A

    2007-10-01

    Full Text Available Abstract Background A major portion of available fatty acids for adipocyte uptake is derived from lipoprotein lipase (LPL-mediated hydrolysis of circulating lipoprotein particles. In vivo studies aimed at identifying the precise role of adipocyte-derived LPL in fat storage function of adipose tissue have been unable to provide conclusive evidence due to compensatory mechanisms that activate endogenous fatty acid synthesis. To address this gap in knowledge, we have measured the effect of reducing adipocyte LPL expression on intracellular lipid accumulation using a well-established cultured model of adipocyte differentiation. Methods siRNA specific for mouse LPL was transfected into 3T3-L1 adipocytes. Expression of LPL was measured by quantitative real-time PCR and cell surface-associated LPL enzymatic activity was measured by colorimetric detection following substrate (p-nitrophenyl butyrate hydrolysis. Apolipoprotein CII and CIII expression ratios were also measured by qRT-PCR. Intracellular lipid accumulation was quantified by Nile Red staining. Results During differentiation of 3T3-L1 pre-adipocytes, LPL mRNA expression increases 6-fold resulting in a 2-fold increase in cell surface-associated LPL enzymatic activity. Parallel to this increase in LPL expression, we found that intracellular lipids increased ~10-fold demonstrating a direct correlation between adipocyte-derived LPL expression and lipid storage. We next reduced LPL expression in adipocytes using siRNA transfections to directly quantify the contributions of adipocyte-derived LPL to lipid storage, This treatment reduced LPL mRNA expression and cell surface-associated LPL enzymatic activity to ~50% of non-treated controls while intracellular lipid levels were reduced by 80%. Exogenous addition of purified LPL (to restore extracellular lipolytic activity or palmitate (as a source of free fatty acids to siRNA-treated cells restored intracellular lipid levels to those measured for non

  11. Behavioral versus genetic determination of lipoproteins andidentical twins discordant for exercise

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Paul T.; Blanche, Patricia J.; Krauss, Ronald M.

    2004-06-01

    Lipoprotein and weight differences between vigorously active and sedentary MZ twins are used to: (1) estimate the effects of training while controlling for genotype; (2) estimate genetic concordance in the presence of divergent lifestyles.

  12. Severe acute necrotizing pancreatitis associated with lipoprotein lipase deficiency in childhood

    NARCIS (Netherlands)

    L.A. van Walraven (L.); J.B.C. de Klerk (Johannes); R.R. Postema (Roelf)

    2003-01-01

    textabstractAn 11-year-old girl with lipoprotein lipase deficiency experienced recurring episodes of abdominal pain. She initially underwent appendectomy for suspected appendicitis; however, the appendix was normal. Pancreatitis was subsequently identified as the cause of her pain.

  13. Lipoprotein(a) and ischemic heart disease-A causal association? A review

    DEFF Research Database (Denmark)

    Kamstrup, P.R.

    2010-01-01

    The aim of this review is to summarize present evidence of a causal association of lipoprotein(a) with risk of ischemic heart disease (IHD). Evidence for causality includes reproducible associations of a proposed risk factor with risk of disease in epidemiological studies, evidence from in vitro...... and animal studies in support of pathophysiological effects of the risk factor, and preferably evidence from randomized clinical trials documenting reduced morbidity in response to interventions targeting the risk factor. Elevated and in particular extreme lipoprotein(a) levels have in prospective studies...... repeatedly been associated with increased risk of IHD, although results from early studies are inconsistent. Data from in vitro and animal studies implicate lipoprotein(a), consisting of a low density lipoprotein particle covalently bound to the plasminogen-like glycoprotein apolipoprotein(a), in both...

  14. Quantitative profiling of endocannabinoids in lipoproteins by LC-MS/MS.

    Science.gov (United States)

    Bilgin, Mesut; Bindila, Laura; Graessler, Juergen; Shevchenko, Andrej

    2015-07-01

    Endocannabinoids belong to a diverse family of endogenous lipid bioregulators acting as physiological ligands of cannabinoid receptor type 1 and cannabinoid receptor type 2 in the central and peripheral nervous system. They are also present in nmol L(-1) concentrations in human blood plasma; however, their association with possible molecular carriers remains poorly characterized. Here we report on the quantification of 46 endogenous molecular species from five major classes of endocannabinoids and endocannabinoid-related compounds in three lipoprotein fractions of human blood plasma: VLDL, LDL, HDL, and in the plasma lipoprotein-free fraction. Although sizable quantities of endocannabinoid-related molecules are associated with lipoproteins, we identified the lipoprotein-free fraction as a major carrier of endocannabinoids in blood circulation with the exception of 2-acylglycerols, which are markedly abundant in VLDL.

  15. Assessing the functional properties of high-density lipoproteins : an emerging concept in cardiovascular research

    NARCIS (Netherlands)

    Triolo, Michela; Annema, Wijtske; Dullaart, Robin P. F.; Tietge, Uwe J. F.

    2013-01-01

    Although plasma concentrations of high-density lipoprotein (HDL) cholesterol correlate inversely with the incidence of atherosclerotic cardiovascular disease, results from recent epidemiological, genetic and pharmacological intervention studies resulted in a shift of concept. Rather than HDL cholest

  16. Quantitative Lipoproteomics in Clostridium difficile Reveals a Role for Lipoproteins in Sporulation.

    Science.gov (United States)

    Charlton, Thomas M; Kovacs-Simon, Andrea; Michell, Stephen L; Fairweather, Neil F; Tate, Edward W

    2015-11-19

    Bacterial lipoproteins are surface exposed, anchored to the membrane by S-diacylglyceryl modification of the N-terminal cysteine thiol. They play important roles in many essential cellular processes and in bacterial pathogenesis. For example, Clostridium difficile is a Gram-positive anaerobe that causes severe gastrointestinal disease; however, its lipoproteome remains poorly characterized. Here we describe the application of metabolic tagging with alkyne-tagged lipid analogs, in combination with quantitative proteomics, to profile protein lipidation across diverse C. difficile strains and on inactivation of specific components of the lipoprotein biogenesis pathway. These studies provide the first comprehensive map of the C. difficile lipoproteome, demonstrate the existence of two active lipoprotein signal peptidases, and provide insights into lipoprotein function, implicating the lipoproteome in transmission of this pathogen.

  17. High Density Lipoproteins and Arteriosclerosis: Role of Cholesterol Efflux and Reverse Cholesterol Transport

    National Research Council Canada - National Science Library

    von Eckardstein, Arnold; Nofer, Jerzy Roch; Assmann, Gerd

    2001-01-01

    Abstract—High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol...

  18. A brief history of lipid and lipoprotein measurements and their contribution to clinical chemistry.

    Science.gov (United States)

    McNamara, Judith R; Warnick, G Russell; Cooper, Gerald R

    2006-07-23

    The study of modern lipid chemistry began in the 17th and 18th centuries with early observations by Robert Boyle, Poulletier de la Salle, Antoine François de Fourcroy and others. The 19th century chemist, Chevreul, identified several fatty acids, suggested the name 'cholesterine' for the fatty substance in gallstones, coined the word 'glycerine', and showed that fats were comprised of glycerol and fatty acids. The 20th century brought many advances in the understanding of lipoprotein structure and function, and explored relationships between lipoproteins and disease states. The development of the ultracentrifuge and other lipoprotein separation techniques, and reagents for accurate, standardized quantitative measurement have steadily increased our understanding of the important role of lipoprotein metabolism in both healthy and disease states.

  19. Moderate doses of alcoholic beverages with dinner and postprandial high density lipoprotein composition

    NARCIS (Netherlands)

    Hendriks, H.F.J.; Veenstra, J.; Tol, A. van; Groener, J.E.M.; Schaafsma, G.

    1998-01-01

    Moderate alcohol consumption is associated with a reduced risk of coronary heart disease. In this study, postprandial changes in plasma lipids, high-density lipoprotein (HDL) composition and cholesteryl ester transfer protein (CETP) and lecithin: cholesterol acyltransferase (LCAT) activity levels

  20. Lipoprotein(a) and ischemic heart disease-A causal association? A review

    DEFF Research Database (Denmark)

    Kamstrup, P.R.

    2010-01-01

    The aim of this review is to summarize present evidence of a causal association of lipoprotein(a) with risk of ischemic heart disease (IHD). Evidence for causality includes reproducible associations of a proposed risk factor with risk of disease in epidemiological studies, evidence from in vitro...... and animal studies in support of pathophysiological effects of the risk factor, and preferably evidence from randomized clinical trials documenting reduced morbidity in response to interventions targeting the risk factor. Elevated and in particular extreme lipoprotein(a) levels have in prospective studies...... clinical trials, genetic studies, such as Mendelian randomization studies, can also support claims of causality. Levels of lipoprotein(a) are primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety of lipoprotein(a), and genetic epidemiologic studies have documented...

  1. Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood

    Directory of Open Access Journals (Sweden)

    Heuck, Claus-Chr.

    2011-01-01

    Full Text Available Polyacrylate (PAA adsorbents selectively bind low density lipoproteins (LDL from human plasma and blood, whereas very low density lipoproteins (VLDL are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw of the polyanion ligand. Ca++ and Mg++ inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid-chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL are repelled from the adsorbents due to their higher negative surface charge density.

  2. Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood.

    Science.gov (United States)

    Heuck, Claus-Chr

    2011-01-24

    Polyacrylate (PAA) adsorbents selectively bind low density lipoproteins (LDL) from human plasma and blood, whereas very low density lipoproteins (VLDL) are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw) of the polyanion ligand. Ca(++) and Mg(++) inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid-chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL) are repelled from the adsorbents due to their higher negative surface charge density.

  3. Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A(2) mass in type 2 diabetes mellitus : Relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity

    NARCIS (Netherlands)

    Constantinides, Alexander; de Vries, Rindert; van Leeuwen, Jeroen J. J.; Gautier, Thomas; van Pelt, L. Joost; Tselepis, Alexandros D.; Lagrost, Laurent; Dullaart, Robin P. F.

    2012-01-01

    Objective: Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels predict incident cardiovascular disease, impacting Lp-PLA(2) as an emerging therapeutic target. We determined Lp-PLA(2) responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationship

  4. Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A(2) mass in type 2 diabetes mellitus : Relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity

    NARCIS (Netherlands)

    Constantinides, Alexander; de Vries, Rindert; van Leeuwen, Jeroen J. J.; Gautier, Thomas; van Pelt, L. Joost; Tselepis, Alexandros D.; Lagrost, Laurent; Dullaart, Robin P. F.

    2012-01-01

    Objective: Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels predict incident cardiovascular disease, impacting Lp-PLA(2) as an emerging therapeutic target. We determined Lp-PLA(2) responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed

  5. Effects of atorvastatin and simvastatin on low-density lipoprotein subfraction profile, low-density lipoprotein oxidizability, and antibodies to oxidized low-density lipoprotein in relation to carotid intima media thickness in familial hypercholesterolemia.

    NARCIS (Netherlands)

    Tits, L.J.H. van; Smilde, T.J.; Wissen, S. van; Graaf, J. de; Kastelein, J.J.P.; Stalenhoef, A.F.H.

    2004-01-01

    BACKGROUND: Little is known about the effects of statins on the quality of circulating low-density lipoprotein (LDL) in relation to atherosclerosis progression. METHODS: In a double-blind, randomized trial of 325 patients with familial hypercholesterolemia (FH), we assessed the effects of high-dose

  6. Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells.

    Science.gov (United States)

    Miao, Lin; Shi, Jiandang; Wang, Chun-Yu; Zhu, Yan; Du, Xiaoling; Jiao, Hongli; Mo, Zengnan; Klocker, Helmut; Lee, Chung; Zhang, Ju

    2010-06-01

    Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRalpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRalpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRalpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRalpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRalpha activity by chlordane (an antagonist of ERRalpha) or small interfering RNA knockdown of ERRalpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRalpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRalpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRalpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17Beta-estradiol concentration in WPMY-1 medium was up-regulated by ERRalpha expression, and that was further increased by PGE2. Our results provided evidence that ERRalpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRalpha in estrogen-related prostatic diseases.

  7. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

    Science.gov (United States)

    Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

    2014-04-01

    Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this

  8. Both CXCR3 and CXCL10/IFN-inducible protein 10 are required for resistance to primary infection by dengue virus.

    Science.gov (United States)

    Hsieh, Ming-Fang; Lai, Szu-Liang; Chen, Jia-Perng; Sung, Jui-Ming; Lin, Yi-Ling; Wu-Hsieh, Betty A; Gerard, Craig; Luster, Andrew; Liao, Fang

    2006-08-01

    We examined the extent to which CXCR3 mediates resistance to dengue infection. Following intracerebral infection with dengue virus, CXCR3-deficient (CXCR3(-/-)) mice showed significantly higher mortality rates than wild-type (WT) mice; moreover, surviving CXCR3(-/-) mice, but not WT mice, often developed severe hind-limb paralysis. The brains of CXCR3(-/-) mice showed higher viral loads than those of WT mice, and quantitative analysis using real-time PCR, flow cytometry, and immunohistochemistry revealed fewer T cells, CD8(+) T cells in particular, in the brains of CXCR3(-/-) mice. This suggests that recruitment of effector T cells to sites of dengue infection was diminished in CXCR3(-/-) mice, which impaired elimination of the virus from the brain and thus increased the likelihood of paralysis and/or death. These results indicate that CXCR3 plays a protective rather than an immunopathological role in dengue virus infection. In studies to identify critical CXCR3 ligands, CXCL10/IFN-inducible protein 10-deficient (CXCL10/IP-10(-/-)) mice infected with dengue virus showed a higher mortality rate than that of the CXCR3(-/-) mice. Although CXCL10/IP-10, CXCL9/monokine induced by IFN-gamma, and CXCL11/IFN-inducible T cell alpha chemoattractant share a single receptor and all three of these chemokines are induced by dengue virus infection, the latter two could not compensate for the absence of CXCL10/IP-10 in this in vivo model. Our results suggest that both CXCR3 and CXCL10/IP-10 contribute to resistance against primary dengue virus infection and that chemokines that are indistinguishable in in vitro assays differ in their activities in vivo.

  9. Intercorrelations of lipoprotein subfractions and their covariation with lifestyle factors in healthy men

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Eckoldt, J.; Winkler, K.;

    2014-01-01

    So far, little is known about the effect of nutrition and lifestyle on the composition of circulating lipoprotein subfractions. In the current study, we measured the correlations among physical activity, nutrient intake, smoking, body-mass index (BMI), and age with the concentration...... with physical activity, moderate alcohol consumption, and dietary intake of MUFA, which might be exploited in future interventions for prevention of age- and BMI-associated atherogenic shifts of lipoprotein subfractions....

  10. Preparation and Adsorption Properties of PAM Based Adsorbents for Plasma Lipoproteins

    Institute of Scientific and Technical Information of China (English)

    Hai Tao LI; Zhi YUAN; Xin Fu CHEN; Bin LIU; Bin SHEN; Bing Lin HE

    2004-01-01

    Crosslinked macroporous polyacrylamide(PAM)was prepared with inverse phase suspension polymerization technique.After treatment with hydrazine,the polymer was functionalized with chloroacetic acid,trifluoroacetic acid diethylenetriaminepentaacetic acid (DEPAA), and maleic acid, respectively,and PAM based adsorbents bearing carboxyl functional groups for low density lipoprotein(LDL)apheresis use were obtained.The blood compatibility and the adsorption properties for plasma lipoproteins of PAM based adsorbents were investigated.

  11. Apolipoprotein E synthesized by adipocyte and apolipoprotein E carried on lipoproteins modulate adipocyte triglyceride content

    OpenAIRE

    Li, Yan-Hong; Liu, Ling

    2014-01-01

    Excessive energy storage of adipose tissue makes contribution to the occurrence and progression of obesity, which accompanies with multiple adverse complications, such as metabolic syndrome, cardiovascular diseases. It is well known that apolipoprotein E, as a component of lipoproteins, performs a key role in maintaining plasma lipoproteins homeostasis. Interestingly, apolipoprotein E is highly expressed in adipocyte and has positive relation with body fat mass. Apolipoprotein E knock-out mic...

  12. Relationship between Serum Lipoprotein Ratios and Insulin Resistance in Polycystic Ovary Syndrome

    OpenAIRE

    Shou-Kui Xiang; Fei Hua; Ying Tang; Xiao-Hong Jiang; Qi Zhuang; Feng-Juan Qian

    2012-01-01

    Objective. To investigate the association between serum lipoprotein ratios and insulin resistance in women with polycystic ovarian syndrome (PCOS). Methods. 105 PCOS patients and 109 controls were randomly enrolled in the study. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), total testosterone (T), fasting glucose (FBG), fasting insulin (FINS), serum triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL-C), and low-density lip...

  13. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

    OpenAIRE

    Kim, Jason K.; Fillmore, Jonathan J.; Chen, Yan; Yu, Chunli; Moore, Irene K.; Pypaert, Marc; Lutz, E. Peer; Kako, Yuko; Velez-Carrasco, Wanda; Goldberg, Ira J.; Breslow, Jan L.; Shulman, Gerald I.

    2001-01-01

    Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic–euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle–lipoprotein lipase mice had a 3...

  14. Effects of acute hypoxia on human adipose tissue lipoprotein lipase activity and lipolysis

    OpenAIRE

    Mahat, Bimit; Chassé, Étienne; Mauger, Jean-François; Imbeault, Pascal

    2016-01-01

    Background Adipose tissue regulates postprandial lipid metabolism by storing dietary fat through lipoprotein lipase-mediated hydrolysis of exogenous triglycerides, and by inhibiting delivery of endogenous non-esterified fatty acid to nonadipose tissues. Animal studies show that acute hypoxia, a model of obstructive sleep apnea, reduces adipose tissue lipoprotein lipase activity and increases non-esterified fatty acid release, adversely affecting postprandial lipemia. These observations remain...

  15. Native low density lipoprotein promotes lipid raft formation in macrophages.

    Science.gov (United States)

    Song, Jian; Ping, Ling-Yan; Duong, Duc M; Gao, Xiao-Yan; He, Chun-Yan; Wei, Lei; Wu, Jun-Zhu

    2016-03-01

    Oxidized low‑density lipoprotein (LDL) has an important role in atherogenesis; however, the mechanisms underlying cell‑mediated LDL oxidation remain to be elucidated. The present study investigated whether native‑LDL induced lipid raft formation, in order to gain further insight into LDL oxidation. Confocal microscopic analysis revealed that lipid rafts were aggregated or clustered in the membrane, which were colocalized with myeloperoxidase (MPO) upon native LDL stimulation; however, in the presence of methyl‑β‑cyclodextrin (MβCD), LDL‑stimulated aggregation, translocation, and colocalization of lipid rafts components was abolished.. In addition, lipid raft disruptors MβCD and filipin decreased malondialdehyde expression levels. Density gradient centrifugation coupled to label‑free quantitative proteomic analysis identified 1,449 individual proteins, of which 203 were significantly upregulated following native‑LDL stimulation. Functional classification of the proteins identified in the lipid rafts revealed that the expression levels of translocation proteins were upregulated. In conclusion, the results of the present study indicated that native‑LDL induced lipid raft clustering in macrophages, and the expression levels of several proteins were altered in the stimulated macrophages, which provided novel insights into the mechanism underlying LDL oxidation.

  16. Fully mechanized latex immunoassay for serum lipoprotein(a).

    Science.gov (United States)

    Abe, A; Yoshimura, Y; Sekine, T; Maeda, S; Yamashita, S; Noma, A

    1994-03-01

    We have developed a fully automated system to quantify lipoprotein(a) (Lp(a)) in human serum, based on the latex-enhanced turbidimetric immunoassay by application of the Immuno Chemistry Analyzer 501X. This assay was carried out with undiluted serum and was able to detect at Lp(a) levels higher than 4.0 mg/l. When judged to be out of range of the calibration (> 600 mg/l), the sample was automatically re-tested after automatic 10-fold dilution. Within-run C.V.s ranged from 1.9 to 2.1% and between-run C.V.s from 2.7 to 3.9%. Results by the present method were in good agreement with those by the in-house ELISA (r = 0.978) and the commercial ELISA (r = 0.990). The distribution of Lp(a) levels in sera from 508 healthy donors was highly skewed; the mean and median were 158 mg/l and 105 mg/l, respectively.

  17. Stability of discoidal high-density lipoprotein particles

    Science.gov (United States)

    Maleki, Mohsen; Fried, Eliot

    Motivated by experimental and numerical studies revealing that discoidal high-density lipoprotein (HDL) particles may adopt flat elliptical and nonplanar saddle-like configurations, it is hypothesized that these might represent stabilized configurations of initially unstable flat circular particles. A variational description is developed to explore the stability of a flat circular discoidal HDL particle. While the lipid bilayer is modeled as two-dimensional fluid film endowed with surface tension and bending elasticity, the apoA-I belt is modeled as one-dimensional inextensible twist-free chain endowed with bending elasticity. Stability is investigated using the second variation of the underlying energy functional. Various planar and nonplanar instability modes are predicted and corresponding nondimensional critical values of salient dimensionless parameters are obtained. The results predict that the first planar and nonplanar unstable modes occur due to in-plane elliptical and transverse saddle-like perturbations. Based on available data, detailed stability diagrams indicate the range of input parameters for which a flat circular discoidal HDL particle is linearly stable or unstable.

  18. A novel lipoprotein nanoparticle system for membrane proteins

    Science.gov (United States)

    Frauenfeld, Jens; Löving, Robin; Armache, Jean-Paul; Sonnen, Andreas; Guettou, Fatma; Moberg, Per; Zhu, Lin; Jegerschöld, Caroline; Flayhan, Ali; Briggs, John A.G.; Garoff, Henrik; Löw, Christian; Cheng, Yifan; Nordlund, Pär

    2016-01-01

    Membrane proteins are of outstanding importance in biology, drug discovery and vaccination. A common limiting factor in research and applications involving membrane proteins is the ability to solubilize and stabilize membrane proteins. Although detergents represent the major means for solubilizing membrane proteins, they are often associated with protein instability and poor applicability in structural and biophysical studies. Here, we present a novel lipoprotein nanoparticle system that allows for the reconstitution of membrane proteins into a lipid environment that is stabilized by a scaffold of Saposin proteins. We showcase the applicability of the method on two purified membrane protein complexes as well as the direct solubilization and nanoparticle-incorporation of a viral membrane protein complex from the virus membrane. We also demonstrate that this lipid nanoparticle methodology facilitates high-resolution structural studies of membrane proteins in a lipid environment by single-particle electron cryo-microscopy (cryo-EM) and allows for the stabilization of the HIV-envelope glycoprotein in a functional state. PMID:26950744

  19. Inhibitory effect of morinda citrifolia L. On lipoprotein lipase activity.

    Science.gov (United States)

    Pak-Dek, M S; Abdul-Hamid, A; Osman, A; Soh, C S

    2008-10-01

    Efficacy of Morinda citrifolia L. leaf (MLE) and fruit extracts (MFE) in inhibiting lipoprotein lipase (LPL) was determined in vitro. The result of the study showed that the highest inhibition on the LPL activity was exhibited by MLE (66%+/- 2.1%), which is significantly higher than that demonstrated by MFE (54.5%+/- 2.5%), green tea extract (GTE) (54.5%+/- 2.6%), and catechin (43.6%+/- 6.1%). Percent of LPL inhibition increase with concentration of the extracts. Quantitative analysis of the extracts revealed the presence of high levels of (+)-catechin at 63.5 +/- 17 and 53.7 +/- 5.7 mg/g in MLE and MFE, respectively, although not as high as that found in GTE (530.6 +/- 42 mg/g). Appreciable amount of epicatechin was found in all extracts tested, while rutin was only found in MLE and MFE. The study suggested that both leaf and fruit of M. citrifolia may be used as antiobesity agents in body weight management.

  20. Lipoprotein(a) accelerates atherosclerosis in uremic mice

    DEFF Research Database (Denmark)

    Pedersen, Tanja X; McCormick, Sally P; Tsimikas, Sotirios

    2010-01-01

    lipoprotein-associated OxPL. Thus, Lp(a) may be particularly atherogenic in a uremic setting. We therefore investigated whether transgenic (Tg) expression of human Lp(a) increases atherosclerosis in uremic mice. Moderate uremia was induced by 5/6 nephrectomy (NX) in Tg mice with expression of human apo(a) (n...... = 19), human apoB-100 (n = 20), or human apo(a) + human apoB [Lp(a)] (n = 15), and in wild-type (WT) controls (n = 21). The uremic mice received a high-fat diet, and aortic atherosclerosis was examined 35 weeks later. LDL-cholesterol was increased in apoB-Tg and Lp(a)-Tg mice, but it was normal in apo...... with both apo(a) and Lp(a). In conclusion, expression of apo(a) or Lp(a) increased uremia-induced atherosclerosis. Binding of OxPL on apo(a) and Lp(a) may contribute to the atherogenicity of Lp(a) in uremia....

  1. Escherichia coli lipoprotein binds human plasminogen via an intramolecular domain

    Directory of Open Access Journals (Sweden)

    Tammy eGonzalez

    2015-10-01

    Full Text Available Escherichia coli lipoprotein (Lpp is a major cellular component that exists in two distinct states, bound-form and free-form. Bound-form Lpp is known to interact with the periplasmic bacterial cell wall, while free-form Lpp is localized to the bacterial cell surface. A function for surface-exposed Lpp has yet to be determined. We hypothesized that the presence of C-terminal lysines in the surface-exposed region of Lpp would facilitate binding to the host zymogen plasminogen, a protease commandeered by a number of clinically important bacteria. Recombinant Lpp was synthesized and the binding of Lpp to plasminogen, the effect of various inhibitors on this binding, and the effects of various mutations of Lpp on Lpp-plasminogen interactions were examined. Additionally, the ability of Lpp-bound plasminogen to be converted to active plasmin was analyzed. We determined that Lpp binds plasminogen via an atypical domain located near the center of mature Lpp that may not be exposed on the surface of intact E. coli according to the current localization model. Finally, we found that plasminogen bound by Lpp can be converted to active plasmin. While the consequences of Lpp binding plasminogen are unclear, these results prompt further investigation of the ability of surface exposed Lpp to interact with host molecules such as extracellular matrix components and complement regulators, and the role of these interactions in infections caused by E. coli and other bacteria.

  2. Tiliroside and gnaphaliin inhibit human low density lipoprotein oxidation.

    Science.gov (United States)

    Schinella, Guillermo R; Tournier, Horacio A; Máñez, Salvador; de Buschiazzo, Perla M; Del Carmen Recio, María; Ríos, José Luis

    2007-01-01

    Two flavonoids, gnaphaliin and tiliroside, isolated from Helichrysum italicum, were studied in vitro for their capacity to inhibit Cu(2+)-induced human low density lipoprotein (LDL) and diluted plasma oxidation. LDL oxidation was monitored by conjugated diene, thiobarbituric acid-reactive substances (TBARS) formation and electrophoretic mobility on agarose gel. Gnaphaliin and tiliroside increased the lag-phase for diene conjugate production in a dose-dependent manner. The reduction of TBARS production confirmed the antioxidant activity of gnaphaliin and tiliroside with 50% inhibitory concentration (IC(50)) values of 8.0+/-3.9 microM and 7.0+/-2.6 microM respectively. Furthermore, the flavonoids negated the Cu(2+)-induced increase in electrophoretic mobility of LDL. Antioxidant activity of gnaphaliin and tiliroside was significantly different when diluted plasma was oxidised by adding 1 mM CuSO(4). Although both flavonoids again reduced the TBARS production, tiliroside showed higher activity than gnaphaliin (IC(50)=10.6+/-2.5 microM vs. IC(50)>50 microM). In conclusion, tiliroside and gnaphaliin are antioxidants against in vitro Cu(2+)-induced LDL oxidation in the same order of magnitude compared to that of the reference drug, probucol.

  3. Probucol alleviates atherosclerosis and improves high density lipoprotein function

    Directory of Open Access Journals (Sweden)

    Zhong Jian-Kai

    2011-11-01

    Full Text Available Abstract Background Probucol is a unique hypolipidemic agent that decreases high density lipoprotein cholesterol (HDL-C. However, it is not definite that whether probucol hinders the progression of atherosclerosis by improving HDL function. Methods Eighteen New Zealand White rabbits were randomly divided into the control, atherosclerosis and probucol groups. Control group were fed a regular diet; the atherosclerosis group received a high fat diet, and the probucol group received the high fat diet plus probucol. Hepatocytes and peritoneal macrophages were isolated for [3H] labeled cholesterol efflux rates and expression of ABCA1 and SR-B1 at gene and protein levels; venous blood was collected for serum paraoxonase 1, myeloperoxidase activity and lipid analysis. Aorta were prepared for morphologic and immunohistochemical analysis after 12 weeks. Results Compared to the atherosclerosis group, the paraoxonase 1 activity, cholesterol efflux rates, expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages, and the level of ABCA1 and SR-BI in aortic lesions were remarkably improved in the probucol group, But the serum HDL cholesterol concentration, myeloperoxidase activity, the IMT and the percentage plaque area of aorta were significantly decreased. Conclusion Probucol alleviated atherosclerosis by improving HDL function. The mechanisms include accelerating the process of reverse cholesterol transport, improving the anti-inflammatory and anti-oxidant functions.

  4. Lipoprotein(a) and risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Mora, Samia; Kamstrup, Pia R; Rifai, Nader;

    2010-01-01

    (a) concentrations and incident type 2 diabetes (n = 1670) for a follow-up period of 13 years. We confirmed our findings in 9652 Danish men and women with prevalent diabetes (n = 419). Analyses were adjusted for risk factors that included age, race, smoking, hormone use, family history, blood pressure, body mass......BACKGROUND: Previous studies have demonstrated that cardiovascular risk is higher with increased lipoprotein (a) [Lp(a)]. Whether Lp(a) concentration is related to type 2 diabetes is unclear. METHODS: In 26 746 healthy US women (mean age 54.6 years), we prospectively examined baseline Lp...... index, hemoglobin A(1c) (Hb A(1c)), C-reactive protein, and lipids. RESULTS: Lp(a) was inversely associated with incident diabetes, with fully adjusted hazard ratios (HRs) and 95% CIs for quintiles 2-5 vs quintile 1 of 0.87 (0.75-1.01), 0.80 (0.68-0.93), 0.88 (0.76-1.02), and 0.78 (0.67-0.91); P...

  5. Fast protein chromatofocusing of human very-low-density lipoproteins.

    Science.gov (United States)

    Weisweiler, P; Friedl, C; Schwandt, P

    1986-01-03

    Using fast protein chromatofocusing, a high-efficiency column chromatography method with a self-generated pH gradient and focusing effects, soluble human very-low-density lipoprotein (VLDL) apolipoproteins were fractionated between pH 6.3 and 4.0. In the presence of 6 mol/l urea and with a flow rate of 1 ml/min, one run (up to 10 mg of protein) took 30 min. VLDL apolipoproteins were separated in seven peaks. As revealed by SDS-polyacrylamide gel electrophoresis, isoelectric focusing and double-immunodiffusion against mono-specific antisera, fractions corresponded to the following proteins: apolipoprotein C-I, albumin, apolipoproteins A-I, E, C-II plus C-III0, C-III1 and C-III2, respectively. Apolipoproteins were eluted in sharp, well-resolved peaks. The recovery of proteins was 78% of the starting material. With fast protein chromatofocusing, an efficient isolation of single apolipoproteins is possible from small amounts of VLDL apolipoprotein preparations. This technique is superior to the commonly used, time-consuming methods for apolipoprotein isolation.

  6. Nonpharmacological approaches for reducing serum low-density lipoprotein cholesterol.

    Science.gov (United States)

    Griffin, Bruce A

    2014-07-01

    To reinforce the key role of diet and lifestyle modification as the first-line treatment for the reduction of raised serum low-density lipoprotein cholesterol (LDL-C) and prevention of cardiovascular disease. Also, to counter recent claims that the current dietary guidelines for the treatment of cardiovascular disease have misplaced emphasis on the importance of removing dietary saturated fat instead of sugar. This review provides new insight into the effects of diet and lifestyle factors with established efficacy in lowering serum LDL-C. This includes energy-restricted weight loss and new findings on the effects of alternative day fasting; novel metabolic and molecular effects of replacing palmitic acid with oleic acid; evidence for a dose-response relationship between the intake of dietary stanols and LDL-C; and identification of a unique metabolic pathway for the excretion of cholesterol. The review reports new evidence for the efficacy of alternate day fasting, reassurance that the current dietary guidelines are not misguided by recommending removal of saturated fat, that a high intake of dietary stanols can achieve a reduction in LDL-C of up to 18%, and describes a pathway of cholesterol excretion that may help to explain variation in the response of serum LDL-C to dietary fat and cholesterol.

  7. [Effects of antihypertensive agents on lipoproteins and thrombocyte function].

    Science.gov (United States)

    Birkebaek, N H

    1990-09-24

    This article is a review of the literature concerning the effects of antihypertensive agents on the lipid status and thrombocyte function. Many investigations have revealed that thiazide diuretics, non-selective beta-blockers and beta-1 selective beta-blockers have resulted in alteration of lipids in a potentially atherogenic direction. Only thiazide diruetics have caused increase in low density lipoprotein, which is causally connected with increased tendency to atheroschlerosis. In some investigations, alpha-1 blockers have had a favourable effect on lipids in an atherogenic direction. Other antihypertensive agents appear, by and large, to be lipid neutral even although isolated investigations have demonstrated displacement of lipids both in positive and negative directions. Non-selective beta-blockers appear to alter thrombocyte function towards a greater tendency to aggregation while beta-1 selective beta-blockers are neutral. Ca-antagonists, angiotensin converting enzyme inhibitors and ketanserin have, theoretically, anti-aggregatory effects on the thrombocytes but only few ex vivo and in vivo experiments have confirmed this effect. Monitoring of lipids is recommended before and after antihypertensive treatment. Finally, the effect on thrombocyte function should be considered in the choice of hypertensive agent.

  8. Acrolein impairs the cholesterol transport functions of high density lipoproteins.

    Science.gov (United States)

    Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang; Thomas, Michael J; Sorci-Thomas, Mary G; Silverstein, Roy L; Pritchard, Kirkwood A; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.

  9. Postprandial lipoproteins and the molecular regulation of vascular homeostasis.

    Science.gov (United States)

    Botham, Kathleen M; Wheeler-Jones, Caroline P D

    2013-10-01

    Blood levels of triglyceride-rich lipoproteins (TRL) increase postprandially, and a delay in their clearance results in postprandial hyperlipidemia, an important risk factor in atherosclerosis development. Atherosclerosis is a multifactorial inflammatory disease, and its initiation involves endothelial dysfunction, invasion of the artery wall by leukocytes and subsequent formation of foam cells. TRL are implicated in several of these inflammatory processes, including the formation of damaging free radicals, leukocyte activation, endothelial dysfunction and foam cell formation. Recent studies have provided insights into the mechanisms of uptake and the signal transduction pathways mediating the interactions of TRL with leukocytes and vascular cells, and how they are modified by dietary lipids. Multiple receptor and non-receptor mediated pathways function in macrophage uptake of TRL. TRL also induce expression of adhesion molecules, cyclooxygenase-2 and heme-oxygenase-1 in endothelial cells, and activate intracellular signaling pathways involving mitogen-activated protein kinases, NF-κB and Nrf2. Many of these effects are strongly influenced by dietary components carried in TRL. There is extensive evidence indicating that raised postprandial TRL levels are a risk factor for atherosclerosis, but the molecular mechanisms involved are only now becoming appreciated. Here, we review current understanding of the mechanisms by which TRL influence vascular cell function. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Simulated lipoprotein transport in the wall of branched arteries.

    Science.gov (United States)

    Darbeau, M Z; Lutz, R J; Collins, W E

    2000-01-01

    Study of arterial blood flow dynamics improves our understanding of the development of cardiovascular diseases such as atherosclerosis. The transport and accumulation of macromolecules in the arterial wall can be influenced by local fluid mechanics. We used numeric simulations to investigate such transport in a T-junction model. Presumably an in vitro experiment would consist of gel segments inserted in the walls of a mechanical flow T-junction model near branch points where separation and recirculation zones are expected. The transport of low density lipoprotein (LDL) was investigated theoretically at these sites in a two dimensional numeric T-branch model. In the numeric model, the hydraulic conductivity of the porous gel wall segments was varied for a fixed species diffusivity to provide simulations with wall transmural Peclet numbers ranging from 0.3 to 30. Steady state flow patterns in the lumen of the two dimensional T-branch were simulated at Reynolds numbers of 250 and 500, using the software package FIDAP 7.61 to implement the finite element method. The simulations demonstrated that wall Peclet numbers greater than 1.0 were needed to achieve species concentration gradients within the wall that varied in the axial direction, thereby reflecting the influence of disturbed flow and pressure patterns in the lumen. As expected, the transmural concentration gradients were steeper when convection predominated. Blood flow in the lumen can influence the distribution of macromolecules in the arterial wall and needs to be investigated for the relevance to atherosclerosis.

  11. High Density Lipoprotein: A Therapeutic Target in Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Philip J. Barter

    2013-09-01

    Full Text Available High density lipoproteins (HDLs have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic β cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions.

  12. Adropin induction of lipoprotein lipase expression in tilapia hepatocytes.

    Science.gov (United States)

    Lian, Anji; Wu, Keqiang; Liu, Tianqiang; Jiang, Nan; Jiang, Quan

    2016-01-01

    The peptide hormone adropin plays a role in energy homeostasis. However, biological actions of adropin in non-mammalian species are still lacking. Using tilapia as a model, we examined the role of adropin in lipoprotein lipase (LPL) regulation in hepatocytes. To this end, the structural identity of tilapia adropin was established by 5'/3'-rapid amplification of cDNA ends (RACE). The transcripts of tilapia adropin were ubiquitously expressed in various tissues with the highest levels in the liver and hypothalamus. The prolonged fasting could elevate tilapia hepatic adropin gene expression, whereas no effect of fasting was observed on hypothalamic adropin gene levels. In primary cultures of tilapia hepatocytes, synthetic adropin was effective in stimulating LPL release, cellular LPL content, and total LPL production. The increase in LPL production also occurred with parallel rises in LPL gene levels. In parallel experiments, adropin could elevate cAMP production and up-regulate protein kinase A (PKA) and PKC activities. Using a pharmacological approach, cAMP/PKA and PLC/inositol trisphosphate (IP3)/PKC cascades were shown to be involved in adropin-stimulated LPL gene expression. Parallel inhibition of p38MAPK and Erk1/2, however, were not effective in these regards. Our findings provide, for the first time, evidence that adropin could stimulate LPL gene expression via direct actions in tilapia hepatocytes through the activation of multiple signaling mechanisms.

  13. High-density lipoprotein endocytosis in endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Stefanie; Fruhwürth; Margit; Pavelka; Robert; Bittman; Werner; J; Kovacs; Katharina; M; Walter; Clemens; Rhrl; Herbert; Stangl

    2013-01-01

    AIM: To describe the way stations of high-density lipoprotein(HDL) uptake and its lipid exchange in endothelial cells in vitro and in vivo. METHODS: A combination of fluorescence microscopy using novel fluorescent cholesterol surrogates and electron microscopy was used to analyze HDL endocytosis in great detail in primary human endothelial cells. Further, HDL uptake was quantified using radio-labeled HDL particles. To validate the in vitro findings mice were injected with fluorescently labeled HDL and particle uptake in the liver was analyzed using fluorescencemicroscopy. RESULTS: HDL uptake occurred via clathrin-coated pits, tubular endosomes and multivesicular bodies in human umbilical vein endothelial cells. During uptake and resecretion, HDL-derived cholesterol was exchanged at a faster rate than cholesteryl oleate, resembling the HDL particle pathway seen in hepatic cells. In addition, lysosomes were not involved in this process and thus HDL degradation was not detectable. In vivo, we found HDL mainly localized in mouse hepatic endothelial cells. HDL was not detected in parenchymal liver cells, indicating that lipid transfer from HDL to hepatocytes occurs primarily via scavenger receptor, class B, type Ⅰ mediated selective uptake without concomitant HDL endocytosis. CONCLUSION: HDL endocytosis occurs via clathrincoated pits, tubular endosomes and multivesicular bodies in human endothelial cells. Mouse endothelial cells showed a similar HDL uptake pattern in vivo indicating that the endothelium is one major site of HDL endocytosis and transcytosis.

  14. Lipoprotein(a: Cellular Effects and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Kirsten Riches

    2012-01-01

    Full Text Available Lipoprotein(a (Lp(a is an independent risk factor for the development of cardiovascular disease (CVD. Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a apart from plasma apheresis, which is costly and labour intensive. The Lp(a molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a (apo(a, both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC and endothelial cells (EC. Therefore, it is of key importance to determine the molecular pathways by which Lp(a exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

  15. Low fasting low high-density lipoprotein and postprandial lipemia

    Directory of Open Access Journals (Sweden)

    Sorodila Konstandina

    2004-07-01

    Full Text Available Abstract Background Low levels of high density lipoprotein (HDL cholesterol and disturbed postprandial lipemia are associated with coronary heart disease. In the present study, we evaluated the variation of triglyceride (TG postprandially in respect to serum HDL cholesterol levels. Results Fifty two Greek men were divided into 2 main groups: a the low HDL group (HDL p = 0.002. The low HDL group had significantly higher TG at 4, 6 and 8 h postprandially compared to the controls (p = 0.006, p = 0.002, and p p = 0.017 compared to the matched-control group. ROC analysis showed that fasting TG ≥ 121 mg/dl have 100% sensitivity and 81% specificity for an abnormal TG response (auc = 0.962, p Conclusions The delayed TG clearance postprandially seems to result in low HDL cholesterol even in subjects with low fasting TG. The fasting TG > 121 mg/dl are predictable for abnormal response to fatty meal.

  16. Lipoprotein(a) and risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Mora, S.; Kamstrup, Pia R; Rifai, N.;

    2010-01-01

    BACKGROUND: Previous studies have demonstrated that cardiovascular risk is higher with increased lipoprotein (a) [Lp(a)]. Whether Lp(a) concentration is related to type 2 diabetes is unclear. METHODS: In 26 746 healthy US women (mean age 54.6 years), we prospectively examined baseline Lp......(a) concentrations and incident type 2 diabetes (n = 1670) for a follow-up period of 13 years. We confirmed our findings in 9652 Danish men and women with prevalent diabetes (n = 419). Analyses were adjusted for risk factors that included age, race, smoking, hormone use, family history, blood pressure, body mass...... index, hemoglobin A(1c) (Hb A(1c)), C-reactive protein, and lipids. RESULTS: Lp(a) was inversely associated with incident diabetes, with fully adjusted hazard ratios (HRs) and 95% CIs for quintiles 2-5 vs quintile 1 of 0.87 (0.75-1.01), 0.80 (0.68-0.93), 0.88 (0.76-1.02), and 0.78 (0.67-0.91); P...

  17. High-density lipoprotein (HDL) metabolism and bone mass.

    Science.gov (United States)

    Papachristou, Nicholaos I; Blair, Harry C; Kypreos, Kyriakos E; Papachristou, Dionysios J

    2017-05-01

    It is well appreciated that high-density lipoprotein (HDL) and bone physiology and pathology are tightly linked. Studies, primarily in mouse models, have shown that dysfunctional and/or disturbed HDL can affect bone mass through many different ways. Specifically, reduced HDL levels have been associated with the development of an inflammatory microenvironment that affects the differentiation and function of osteoblasts. In addition, perturbation in metabolic pathways of HDL favors adipoblastic differentiation and restrains osteoblastic differentiation through, among others, the modification of specific bone-related chemokines and signaling cascades. Increased bone marrow adiposity also deteriorates bone osteoblastic function and thus bone synthesis, leading to reduced bone mass. In this review, we present the current knowledge and the future directions with regard to the HDL-bone mass connection. Unraveling the molecular phenomena that underline this connection will promote the deeper understanding of the pathophysiology of bone-related pathologies, such as osteoporosis or bone metastasis, and pave the way toward the development of novel and more effective therapies against these conditions. © 2017 Society for Endocrinology.

  18. Serum lipoproteins of patients with glycogen storage disease.

    Science.gov (United States)

    Rosenfeld, E L; Chibisov, I V; Karmansky, I M; Tabolin, V A; Chistova, L V; Leontiev, A F

    1980-03-14

    Seventeen patients with different types of glycogen storage disease (GSD) were under observation. The type of the disease was defined from glucaemic and lactotaemic curves obtained in glucose, galactose and adrenaline tolerance tests and by biochemical analysis of liver biopsy specimens. Seven patients were found to have Type I; five patients, Type III; one patient, Type VI; and four patients, the Type IX (or X) of GSD. The serum lipoprotein (LP) content was determined in all patients using analytical ultracentrifugation. Hyperlipoproteinaemia (HLP) was found in virtually all patients. Patients with Type I of GSD were found to have Types 2b and 4 of HLP; and patients with Type III of GSD, 2b Type of HLP. 2a Type of HLP was diagnosed in patients with GSD of VI and IX (X) Types. Patients with Type III GSD, in contrast to those with GSD of other types, had enhanced levels of Sf 12-20 LP. The levels of Sf 100-400 and Sf 20-100 LP were greatly increased only in patients with Type I GSD.

  19. [Plasma lipoproteins as drug carriers. Effect of phospholipid formulations].

    Science.gov (United States)

    Torkhovskaia, T I; Ipatova, O M; Medvedeva, N V; Ivanov, V S; Ivanova, L I

    2010-01-01

    The extensive development of nanotechnologies in the last two decades has brought about new understanding of plasma lipoproteins (LP) as natural drug nanocarriers that escape interaction with immune and reticuloendothelial systems. Drugs bound to LP (especially LDL) can more actively penetrate into cells of many cancer and inflammation tissues with enhanced expression or/and dysregulation of B,E receptors or possibly scavenger SR-BI receptors. Relevant studies are focused on the development of new dosage forms by conjugating lipophilic drugs either with isolated plasma LP or with their model formulations, such as nanoemulsions, mimetics, lipid nanospheres, etc. Some authors include in these particles serum or recombinant apoproteins, peptides, and modified polymer products. As shown recently, protein-free lipid nanoemulsions in plasma take up free apoA and apoE. Complexes with various LP also form after direct administration of lypophilic drugs into blood especially those enclosed in phospholipid formulations, e.g. liposomes. Results of evaluation of some lipophilic dugs (mainly cytostatics, amphotericin B, cyclosporine A, etc.) are discussed. Original data are presented on the influence of phospholipid formulations on the distribution of doxorubicin and indomethacin between LP classes after in vitro incubation in plasma. On the whole, the review illustrates the importance of research on LP and phospholi pid forms as drug nanocarriers to be used to enhance effect of therapy.

  20. Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

    Science.gov (United States)

    Arnadottir, M; Nilsson-Ehle, P

    1994-01-01

    The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions.