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D- Dyslipidemias

D- Dyslipidemias. SCHEME FOR LIPID TRANSPORT. Production / Catabolism = Number. # Over- production Very common (? Cause). $ Decreased Catabolism Defective Receptor in FH (RARE). Cell receptors. Endogenous transport. Lipoprotein lipase. Hepatic lipase. LDL receptor. VLDL.

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D- Dyslipidemias

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  1. D-Dyslipidemias

  2. SCHEME FOR LIPID TRANSPORT Production / Catabolism = Number # Over- production Very common (? Cause) $ Decreased Catabolism Defective Receptor in FH (RARE) Cell receptors Endogenous transport Lipoprotein lipase Hepatic lipase LDL receptor VLDL IDL LDL Lipoprotein lipase Exogenous transport chylomicrons remnants gut Remnant receptor Free cholesterol + phospholipids + C-apolipoproteins Nascent HDL Mature HDL Lecithin: cholesterol acyltransferase # [circulating LDL] $ # risk for atherosclerosis

  3. GENETIC DYSLIPIDEMIAS I ApoB: II HDL III Lipoprotein Modifying Enzymes

  4. GENETIC/METABOLIC CLASSIFICATION OF PRIMARY HYPERLIPIDAEMIAS

  5. GENETIC/METABOLIC CAUSES OF PRIMARY HYPERLIPIDAEMIAS

  6. Chylo ↑ ↓ ↓

  7. Familial Lipoprotein Lipase Deficiency APO C-II DEFICIENCY LIPOPROTEIN LIPASE DEFICIENCY CHYLOMICRON CHYLOMICRON CHYLOMICRON NORMAL APO C-II APO C-II LIPOPROTEIN LIPASE LIPOPROTEIN LIPASE FFA FFA

  8. Xanthomas

  9. CLINICAL FINDINGS IN Familial Lipoprotein Lipase Deficiency RECURRENT ACUTE PANCREATITIS ERUPTIVE XANTHOMAS RETINAL LIPEMIA HEPATOSPLENOMEGALY AUTOSOMAL RECESSIVE INHERITANCE (CONSANGUINITY COMMON)

  10. ↑↑

  11. DISORDERS OF LDL RECEPTORS: RARE • Familial hypercholesterolemia • (defective receptor) • Familial defective B100 • (defective ligand)

  12. B B B B B B B B B B B B FH CE CE CE CE CE CE CE CE CE CE CE CE B Tg B Tg VLDL LDL LDL Clearance

  13. HTGL LDL LDL IDL IDL Free Cholesterol Free Cholesterol Lysis Lysis B-100 Receptor B-100 Receptor PERIPHERAL CELLS LIVER

  14.                                                                      <>

  15. Collagen Rich Plaque

  16. → → ↑ ↑ ↑

  17. Familial Combined Hyperlipidemia/ HyperapoB

  18. PRODUCTION BREAKDOWN

  19. Features of HyperapoB • Increased LDL particle number due • primarily to increased secretion of • hepatic B100 lipoprotein particles. • Often, but not always, many of the • LDL particles are smaller and denser • than normal.

  20. HETEROGENEITY OF LDL B CE NORMAL FC CE Tg FC Tg PL B FC B CE FC CE Tg FH Tg PL B B CE CE FC Tg HYPERAPO B Tg FC PL PL

  21. CII FH Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg CI CIII CE CE CE CE CE CE CE CE CE CE CE CE CE CE CE CE CE CE CE Tg E

  22. E E CII CII HyperapoB Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg Tg CI CI CIII CIII CE CE CE CE CE CE CE CE CE CE CE Tg Tg CE CE CE CE Tg CE Tg CE E E

  23. Interaction of apoB and LDL size as Determinants of CAD Risk 6.2 (p < 0.001) apoB Odds ratios for IHD 2.0 1.0 1.0 LDL peak particle diameter

  24. HYPERAPO B IS • ASSOCIATED WITH: • SMOKING • MALE SEX • ABDOMINAL OBESITY • HYPERINSULINEMIA • OFFSPRING OF PARENTS WITH CAD

  25. Principle I: VLDL synthesis and secretion is substrate driven.

  26. Effect of Fatty Acid on Liver Cholesterol Synthesis 4HR pmol/min/mg

  27. Direct Correlation between Cholesterol Synthesis and Hepatic Secretion of apoB 100 in Normolipidemic Subjects 15 10 5 Hepatic secretion ratio to VLDL apoB (mg/kg/day) 0 2 4 6 8 10 Plasma mevalonate concentration (ng/ml)

  28. Principle II: What comes out depends on what went in. FA CHO

  29. HDL ← ↓ ↑ ↑

  30. COMMON GENETIC CAUSES OF HDL DEFICIENCY SECONDARY: 1. Familial Hypertriglyceridemia with Hypoalphalipoproteinemia (low apo A1) 2. Familial Combined Hyperlipidemia (Hyperapo B) with Hypoalphalipoproteinemia PRIMARY: Familial Hypoalphalipoproteinemia

  31. HDL HDL FUNCTIONS OF HDL NASCENT VLDL VLDL VLDL CHOLESTEROL ESTERS LCAT LCAT CHOLESTEROL LIVER PERIPHERAL CELLS NASCENT CHYLOMICRON CHYLOMICRON CHYLOMICRON

  32. RARE GENETIC CAUSES OF HDL DEFICIENCY Name Premature CAD Tangier disease + Apo A1, Clll, AlV deficiency ++ Apo A1, Cll deficiency +++ Apo A1 deficiency UK Apo A1 variants UK LCAT deficiency +

  33. SECONDARY CAUSES OF DECREASED HDL • Hypertriglyceridemia • Obesity • Diabetes Mellitus • Cigarette smoking • Beta blockers • Liver cirrhosis

  34. SECONDARY DYSLIPIDEMIAS AND DRUG EFFECTS ON LIPIDS

  35. DISEASES CAUSING SECONDARY HYPERLIPIDAEMIA

  36. LIPID ABNORMALITIES IN LIVER DISEASE

  37. LIPID ABNORMALITIES IN RENAL DISEASE

  38. DRUGS THAT CAN CAUSE SECONDARY HYPERLIPIDAEMIA DIURETICS BETA BLOCKERS ESTROGENS PROGESTERONE RETINOIDS CORTICOSTEROIDS MICROSOMAL ENZYME INDUCERS egPHENYTOIN

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