Cholesterol And Sterol Metabolism PowerPoint Presentation

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Cholesterol And Sterol Metabolism

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Cholesterol Functions Membrane component Precurser to Bile acids Vitamin D Steroid hormones

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Central Role of the Liver in Cholesterol Balance:Sources of hepatic cholesterol Dietary cholesterol From chylomicron remnants Cholesterol from extra-hepatic tissues Reverse cholesterol transport via HDL Chylomicron remnants IDL De novo synthesis

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Central Role of the Liver in Cholesterol Balance:Fate of hepatic cholesterol VLDL -> LDL Transport to extra-hepatic tissues Direct excretion into bile Gallstones commonly are precipitates of cholesterol Occurs when bile becomes supersaturated with cholesterol Obesity, biliary stasis, infections Bile acid synthesis and excretion into bile

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De novo Synthesis of Cholesterol Primary site: liver (~1g/d) Secondary sites: adrenal cortex, ovaries, testes Overall equation:

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De novo Synthesis of Cholesterol:four stages Formation of HMG CoA (cyto) Analogous to KB synthesis (mito) Conversion of HMG CoA to activated isoprenoids

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De novo Synthesis of Cholesterol:four stages Condensation of isoprenoids to squalene Six isoprenoids condense to form 30-C molecue

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De novo Synthesis of Cholesterol:four stages Conversion of Squalene to Cholesterol

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De novo Synthesis of Cholesterol:What do you need to know? All carbons from acetyl-CoA Requires NADPH, ATP, & O2 Stages One: forms HMG CoA Two: forms activated 5 carbon intermediates (isoprenoids) Three: six isoprenoids form squalene Four: squalene + O2 form cholesterol

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Smith-Lemli-Opitz (SLO) syndrome(MAAG, chap 32, p 72) 3rd most common inborn error of metabolism in US Cystic fibrosis & PKU 1/30 Americans of N. European descent are carriers (heterozygous advantage??) Prevalence of SLO is 1:20-60,000 Predicted prevalence: 1:5-18,000 Spontaneous abortion Underdiagnosed ? “multiple congenital abnormality syndrome of unknown aetiology” Deficiency of delta-7-dehydrocholesterol reductase 7-dehydrocholesterol ->desmosterol -> cholesterol

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Smith-Lemli-Opitz (SLO) syndrome multiple congenital anomalies/mental retardation Spontaneous abortions/still births Multiorgan failure shortly after birth Congenital heart disease: cyanosis or congestive heart failure Vomiting, feeding problems, failure to thrive Visual and hearing loss Pathophysiology Very low plasma cholesterol Inability to synthesize cholesterol Membranes, precursers for steroid hormones & bile acids, myelin component

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The following characteristics have been seen in more than 50% of patients: Microcephaly Blepharoptosis (drooping of the upper eyelids) Cleft palate Postnatal growth retardation Syndactyly of toes (webbing between toes) Mental retardation Hypospadias (developmental anomaly involving the urethra) Hypotonia Inner epicanthal folds Low-set ears Small, upturned nose Small tongue Undescended testicles Micrognathia (small jaw) Broad maxillary alveolar ridges

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Regulation of Cholesterol Synthesis Cellular cholesterol content exerts transcriptional control HMG-CoA reductase Half life = 2 hours LDL-receptor synthesis Nutrigenomics: interactions between environment and individual genes and how these interactions affect clinical outcomes

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Regulation of Cholesterol Synthesis Covalent Modification of HMG-CoA Reductase Insulin induces protein phosphatase Activates HMG-CoA reductase Feeding promotes cholesterol synthesis Activates reg. enzyme Provides substrate: acetyl CoA Provides NADPH

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Regulation of Cholesterol Synthesis Covalent Modification of HMG-CoA Reductase Glucagon stimulates adenyl cyclase producing cAMP cAMP activates protein kinase A Inactivates HMG-CoA reductase Fasting inhibits cholesterol synthesis

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Cholesterol and Bile Acid/Salt Metabolism Major excretory form of cholesterol Steroid ring is not degraded in humans Occurs in liver Bile acid/salts involved in dietary lipid digestion as emulsifiers

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Types of Bile Acids/Salts Primary bile acids Good emulsifying agents All OH groups on same side pKa = 6 (partially ionized) Conjugated bile salts Amide bonds with glycine or taurine Very good emulsifier pKa lower than bile acids

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Synthesis of Bile Salts Hydroxylation Cytochrome P-450/mixed function oxidase system Side chain cleavage Conjugation Secondary bile acids Intestinal bacterial modification Deconjugation Dehydroxylation Deoxycholic acid Lithocholic acid

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Recycling of Bile Acids Enterohepatic circulation 98% recycling of bile acids Cholestyramine Treatment Resin binds bile acids Prevents recycling Increased uptake of LDL-C for bile acid synthesis

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Reducing intake of dietary saturated fat to < 7% of calories Proposed mechanism: High saturated fat intake reduces activity of LDL-receptors Higher unsaturated fat intake increases activity of LDL-receptors Side effects: none

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Reduce intake of dietary cholesterol to less than 200mg/day Proposed mechanism: Reducing exogenous source of cholesterol reduces intracellular cholesterol pool and up-regulates LDL-receptors Side effects: none

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Increase consumption of viscous soluble dietary fiber (10-25g/d) Proposed mechanisms: Impairs absorption of dietary cholesterol Impairs reabsorption of bile acids Bacterial fermentation of soluble fibers results in short chain fatty acids that may inhibit cholesterol synthesis Side effects: minimal (laxative)

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Consume therapeutic doses of plant sterols and stanols (2g/d) Functional foods Benecol, Take Control Proposed mechanism Inhibit absorption of dietary cholesterol Inhibit re-absorption of cholesterol in bile Side effects: none

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Plant sterols Different side chains Plant stanols No double bond on B ring

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III HMG-CoA Reductase Inhibitors Statins 18-55% reduction in LDL-C Increases in HDL and decreases in TG Proposed mechanism of action Inhibition of cholesterol synthesis reduces intracellular cholesterol pool and up-regulates LDL-receptors Side effects: myopathy, increased serum hepatic enzymes

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Structures of Common statin drugs

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Statin drugs are structural analogs of HMG-CoA

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Bile acid sequestrants Reduces LDL by 15-30% Mechanism of action Binds and prevents reabsorption of bile acids Increases hepatic synthesis of bile acids, reduces cholesterol pool, up-regulates LDL-receptors Side effects: GI distress, constipation, decreased absorption of other drugs

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Pharmacological doses of niacin 5-25% reduction in LDL Increases HDL, decreases LDL Proposed mechanism Reduces VLDL synthesis Decreases lipolysis in adipose Increases LPL activity Decreases esterification of TG in liver Side effects: flushing, GI distress, hyperglycemia, hyperuricemia, hepatotoxicity

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Nutritional and Pharmaceutical Means for Treating HypercholesterolemiaNCEP-ATP III Fibric Acids Decreases LDL by 5-20% Larger decreases in TG (20-50%), increases HDL Mechanism of action: increases LPL activity Side effects: dyspepsia, myopathy, gallstones

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Case Studychapter 19 – familial hypercholesterolemia 8 yo girl Admitted for heart/liver transplant History CHD in family 2 yo xanthomas appear on legs 4 yo xanthomas appear on elbows 7 yo admitted w/ MI symptoms [TC] = 1240 mg/dl [TG] = 350 mg/dl [TC]father = 355 mg/dl [TC]mother = 310 mg/dl 2 wks after MI had coronary bypass surgery Past year severe angina & second bypass Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000 mg/dl

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Xanthomas Raised, waxy appearing, often yellow skin lesions (shown here on knee) Associated with hyperlipidemia Tendon xanthomas common on Achilles and hand extensor tendons

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Xanthomasraised lesions related to hyperlipidemia Eruptive Xanthomas -generally associated with hypertriglyceridemia Xanthomas of the eyelid -generally associated with hypercholesterolemia

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Did Da Vinci’s Mona Lisa have hyper-cholesterolemia?

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Familial Hypercholesterolemia LDL receptor deficiency Gene for LDL-receptor on chromosome 19 No gender difference Mutation is recessive Heterozygous FH 1/500 French Canadians (1/270), Christian Lebanese (1/170), South African Afrikaners (1/100), Ashkenazi Jews (1/67, Jews descended from families from eastern Europe, comprise 80% of all Jews, higher risk for several diseases including breast, ovarian, colon cancers). Hypercholesterolemia and premature CAD

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Familial Hypercholesterolemia Homozygous FH 1/1,000,000 Extremely high LDL-cholesterol Xanthomas common Very early symptomatic CHD

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Familial Hypercholesterolemia LDL-receptor deficiency 420 different mutations identified (dominant trait) LDL-receptor activity: 0-25% of normal Classes of LDL-receptor mutations 1 – no receptors 2 – blockage of receptor from ER to Golgi Apparatus 3 – receptor does not bind LDL normally 4 – receptor does not accumulate in cathrin-coated pit 5 – receptor fails to release LDL after internalization and does not recycle to cell surface

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Treatment of FH Heterozygous FH Dietary interventions, weight loss, exercise Alone only moderately successful Cholesterol lowering-drugs In combination with diet will cause up-regulation of LDL-receptors Most powerful statins at highest dosage will result in ~60% reduction in LDL-C

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Medications Bile Acid Sequestrants (Resins) Anion exchange resins Prevents reabsorption of bile salts Effects additive when used with statins May inhibit absorption of fat soluble vitamins (use multi-vitamin supplement) Cholestryramine (Questran) Cholestipol (Cholestid) Cholesavelem (Welchol) Newest resin, better tolerated than traditional resins

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Medications HMG-CoA Reductase Inhibitors (statins) Most potent LDL-C lowering drug Modest TG lowering and HDL-C increasing effects Atorvastatin (Lipitor) Simvastatin (Zochor)

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Treatment of FH Homozygous FH Diet, exercise, weight loss, drugs Small to no effect on LDL-C Dependent on activity of LDL-receptor

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Treatment of homozygous FH LDL-apheresis Selective binding of apo B lipoproteins LDL, VLDL, IDL, LP(a) Dextran sulfate cellulose beads Reduces LDL-C by ~80% Used every 2 weeks FDA approved 1997 $3000/treatment Insurance coverage?

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Treatment of homozygous FH Liver transplantation ~70% of LDL-receptors in liver High risk, long-term immuno-suppression, high cost Success rate (Columbia Univ) 1yr – 92%, 5 yr – 88%

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Resolution of Clinical Case Patient is homozygous for FH Parents appear to be heterozygous FH Early appearance of xanthomas Cholestyramine and lovastatin treatment ineffective Early symptomatic CHD Combined liver and heart transplant Liver has ~ 70% of total LDL-receptors Heart in FH often with significant CAD Transplantation was successful !!! Good hepatic and cardiac function TC = 26 mg/dl, regression of xanthomas

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Steroid Hormone Metabolism:Adrenal Steroid Hormones Aldosterone C21 derivative of cholesterol Promotes renal Sodium retention Potassium excretion Glucocorticoids (cortisol) Starvation Hepatic gluconeogenesis Muscle protein degradation Adipose lipolysis Adrenal androgens Dehydroepiandroterone (DHEA) Precurser to potent androgens in extra-adrenal tissues