Stanford BIO 118 - Genes Regulating Cholesterol Metabolism

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GENES REGULATING CHOLESTEROL METABOLISM Chau Vu Bio 118FUNCTIONS OF CHOLESTEROL  Maintain membrane fluidity, facilitate trafficking and signaling of membrane-associated proteins  Precursor for important metabolites  LDL = low density lipoprotein  HDL = high density lipoprotein  High LDL  atherosclerosisSYNTHESIS OF CHOLESTEROL  Occurs in cytoplasm and microsomes  acetyl-CoA – starting material  Less than half from biosynthesis de novo  liver 10%  intestines 15%  5 major stepsSYNTHESIS OF CHOLESTEROLREGULATION OF CHOLESTEROL  Synthesis and dietary intake:  Normal Adult: produce1g/day; consume 0.3g/day  Pathway 1: LDL binds to receptors; receptor-ligand complex absorbed by endocytosis  Pathway 2: cholesterol synthesized when intra-cellular levels are low  Pathway 3: reduce HMG CoA reductase activity; excess cholesterol transported to the liver  Involve many transcription factors, binding proteins, enzymes and receptorsREGULATION OF CHOLESTEROL SYNTHESISGAPS IN OUR UNDERSTANDING OF CHOLESTEROL METABOLISM  Heritability of human plasma cholesterol levels ~ 50% to 70%.  Known common genetic factors linked to cholesterol explain 5 to 7% of heritability  common polymorphisms that modulate plasma cholesterol levels account for small portionSTUDY 1: CHANGES IN THE EXPRESSION OF CHOLESTEROL METABOLISM-ASSOCIATED GENES IN HCV-INFECTED LIVER  real time PCR  Results  (SREBP)-2 expression unchanged  transcription protein, induces production of sterols; negative feedback loop  low density lipoprotein receptor expression reduced by 90% in HCV infected liver  mediates endocytosis of LDL(cholesterol)STUDY 1: CHANGES IN THE EXPRESSION OF CHOLESTEROL METABOLISM-ASSOCIATED GENES IN HCV-INFECTED LIVER  Expression of apolipoprotein B100, microsomal triglyceride transfer protein and ABC G5 transporter significantly increased  Apolipoprotein B100 - protein the binds to LDL; carry LDL to tissues  Microsomal Triglyceride transfer protein - helps produce beta-lipoproteins  ATP-binding cassette G5; proteins limits intestinal absorption and promotes biliary excretion of sterolsSTUDY 1: CHANGES IN THE EXPRESSION OF CHOLESTEROL METABOLISM-ASSOCIATED GENES IN HCV-INFECTED LIVER  Up-regulation of HMG-CoA reductase, HMG-CoA synthase and squalene synthase  HMG-CoA reductase- rate controlling enzyme for the mevalonate pathway  HMG-CoA synthase - enzyme that catalyzes production of HMG-CoA  Squalene synthase - enzyme for sterol synthesis  Confirmed enhanced de novo cholesterol synthesisSTUDY 1: CHANGES IN THE EXPRESSION OF CHOLESTEROL METABOLISM-ASSOCIATED GENES IN HCV-INFECTED LIVER  Expression of cholesterol 7alpha-hydroxylase and farnesoid X receptor enhanced  bile salt export pump expression was unchanged.  Cholesterol 7 alpha-hydroxylase – enzyme in rate limiting step of bile acids, converts cholesterol to 7-alpha-hydroxycholesterol  Farnesoid X receptor- suppression of cholesterol 7alpha-hydroxylase (CYP7A1), rate-limiting enzyme in bile acid synthesis cholesterol.STUDY 1: CHANGES IN THE EXPRESSION OF CHOLESTEROL METABOLISM-ASSOCIATED GENES IN HCV-INFECTED LIVER  Conclusions:  regulation of lipid metabolism impaired  cholesterol and fatty acid synthesis increase without negative feedbackGWAS STUDIES  Six new loci associated with blood LDL, HDL or triglycerides in humans  large sample sizes, multiple cohorts  common SNPs at 18 loci associated with concentrations LDL, HDL, and/or triglycerides.  Six of the 18 loci are new  Two LDL (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4)  one HDL cholesterol (1q42 in GALNT2)  five triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3).GWAS STUDY  Common variants at 30 loci contribute to polygenic dyslipidemia  The 11 newly defined loci  LDL near ABCG8, MAFB, HNF1A and TIMD4  HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B  triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP.  proportion of individuals with high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to allelic dosage score  cumulative effect; contributes to polygenic dyslipidemiaHOW THESE FINDINGS WILL AFFECT THE TREATMENT OF CVD: THE CASE OF FH  caused by mutations in LDLR gene  apolipoprotein B-100 gene (APOB)  proprotein convertase subtilisin/kexin type 9 gene (PCSK9)  over 700 variants  reduced number of functional LDL receptors  severe elevation of plasma LDL cholesterol levels  FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk  new factor identified  potential new target for therapyNOVEL THERAPY: UPDATE ON PATENTED CHOLESTEROL ABSORPTION INHIBITOR  Statins: block the rate determining step in the biosynthesis of cholesterol  Ezetimibe: inhibit cholesterol absorption  Combination therapy of ezetimibe and statins  Newer analogues under clinical trials, among which darapladib, FM-VP4 and A-002BIBLIOGRAPHY  Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008, 40:189-197!  Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. !  Nakamuta, M. "Changes in the expression of cholesterol metabolism-associated genes in HCV-infected liver: a novel target for therapy?" International Journal Of Molecular Medicine 24.


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Stanford BIO 118 - Genes Regulating Cholesterol Metabolism

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