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Familial Hypercholesterolemia

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Familial Hypercholesterolemia Advanced Lipoprotein Metabolism and Genetic Disorders Alan S. Brown, MD, FACC, FNLA Core Curriculum Map for Masters Course Lipid Metabolism 5. Lipoprotein metabolism * • 5.1. Intestinal lipid transport and chylomicron formation, secretion and catabolism * • 5.2. Hepatic lipid transport and VLDL formation, secretion and catabolism * • 5.3. LDL receptor expression, function and catabolism (PCSK9) * • 5.4. HDL synthesis, maturation, catabolism, role in peripheral / reverse cholesterol transport and non-ASCVD effects * • 5.5. Cholesterol and bile acid metabolism * • 5.6. Microbiome • 5.7. Intrahepatic gene regulation via nuclear receptor factors * • 5.7.1. LXR • 5.7.2. FXR • 5.7.3. PPAR • 5.7.4. SREBP) Core Curriculum Map for Genetic 10. Genetic dyslipidemias Dyslipidemia- Masters Course • 10.1. Physical findings • 10.1.1. Xanthomas • 10.1.2. Xanthelasma (including non-hyperlipidemic causes) • 10.1.3. Corneal arcus • 10.1.4. Lipemia retinalis • 10.1.5. “Test tube” blood appearance • 10.2. Hypolipidemias * • 10.2.1. Hypoalphalipoproteinemia syndromes (deficiencies in APOA1, apoA1milano, ABCA1 (Tangiers), ABCG1, LCAT (Fish Eye Disease) • 10.2.2. Abetalipoproteinemia (MTP deficiency) • 10.2.3. Hypobetalipoproteinemias • 10.2.4. PCSK9 loss of function • 10.2.5. ANGTL 3 loss of function • 10.3. Major lipid associated genes (GWAS studies) * • 10.3.1. LDL - LDLR, APOB, PCSK9, APOB, HMGCR, NPC1L1, LDLRAP1, SORT1, ABCG5/ABCG8, CYP27A1 • 10.3.2. Triglycerides - APOCIII, APOCII, APOA5, LPL, ANGPTL4, ANGPTL3, LMF1, GPIHBP1 • 10.3.3. HDL- ABCA1, ABCL1, ABCG1, LCAT, CETP, SR-B1 • 10.3.4. Lp(a) - LPA Core Curriculum Map (cont.) • 10.4. Hypertriglyceridemia * • 10.4.1. Polygenic • 10.4.2. Monogenic hypertriglyceridemia & familial hyperchylomicronemia syndromes (FCS) • 10.4.2.1. Lipoprotein lipase deficiency • 10.4.2.2. APOCII deficiency • 10.4.2.3. GPIHBP1 deficiency (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1) • 10.4.2.4. LMF1 deficiency (liase maturation factor) • 10.4.2.5. GPD1 deficiency (glycerol-3-phosphate dehydrogenase 1) • 10.4.3. Familial dysbetalipoproteinemia (ApoE II/II or other variants) • 10.5. Hypercholesterolemia • 10.5.1.1. Homozygous familial hypercholesterolemia • 10.5.1.2. Heterozygous familial hypercholesterolemia • 10.5.1.3. Polygenic hypercholesterolemia • 10.5.1.4. Sitosterolemia • 10.5.1.5. Autosomal recessive hypercholesterolemia • 10.5.1.6. Lysosomal acid lipase (LAL) deficiency • 10.6. Combined hyperlipidemia or mixed dyslipidemia • 10.6.1. Familial combined hyperlipidemia • 10.6.2. Non-familial combined hyperlipidemia Core Curriculum Map Masters Course- Genetic Dyslipidemias 11. Familial hypercholesterolemia • 11.1. Prevalence • 11.2. Genetics and genetic testing • 11.2.1. LDL receptor • 11.2.2. Defective apo B • 11.2.3. PCSK9 gain of function • 11.3. Diagnostic criteria • 11.4. Relevance of lipoprotein (a) • 11.5. Treatment Overview of Lipid Metabolism • Basics of Lipoprotein particles and their components • Endogenous and Exogenous Lipid Metabolism: “The 30,000 foot view • Focused discussion of each step in lipid metabolism to understand the details • LDL receptor activity and metabolism including role of PCSK9 • HDL metabolism and reverse cholesterol transport including the role of CETP • VLDL and Chylomicron production pathways and role of apoproteins • Summary and review Lipoprotein Structure TG CE Polar Surface Coat (Phospholipids, Apoprotein FC, Apoproteins) 3 Lipoprotein Structure Apoprotein Apoprotein POLAR SURFACE COAT NONPOLAR Phospholipid LIPID CORE Cholesterol Ester Free cholesterol Triglyceride Apoprotein 4 Adapted from Treatment of Heart Diseases:1992, Etiologies and Treatment of Hyperlipidemia-Scott Grundy, MD, PhD Lipoprotein Sub-Classes Chylomicron 0.95 VLDL VLDL Remnants 1.006 IDL Chylomicron Remnants 1.02 LDL Density(g/ml) 1.06 HDL2 Atherogenic Lp(a) (found in plaque) 1.10 HDL3DL3 pre-β2 HDL 1.20 pre-β1 HDL 1000 5 10 20 40 60 80 Particle Size (nm) Lipoprotein Composition and Function Lipoprotein Apolipoproteins Function Chylomicrons, B-48 (A-I, C-II, C-III, and E) Delivers TG & Chol (intestinal Chylo-remnants or exog. path) VLDL, IDL B-100 (C-II, C-III, E) Delivers TG & Chol (endogenous path) LDL B-100 Delivers Chol (endogenous path) Lp(a) B-100, apo (a) Delivers Chol (endogenous path) HDL A-I, A-II (C-II, C-III, E) RCT; Anti-athero; Major Apolipoproteins Apo Location Function Plasma Levels Athero A-I HDL (Chyl) Multi anti-athero High ↓↓↓ A-II HDL ?? Moderate ↓? B-48 Chyl Exog. TG & Ch transp Moderate (post-prandial ↑? only) B-100 VLDL, LDL Deliver endog. cholesterol High ↑↑↑ C-II VLDL, HDL ↑LPL activity Low ↓ C-III VLDL, HDL ↓LPL, plq rupt? Low ↑↑ E VLDL, HDL Remn Lp Catab, Chol Low ↑↑↑/↓? Efflux? (a) Lp(a) Ox FFA scaveng Low ↑↑↑ Overview of Secondary Causes of Dyslipidemia High cholesterol Secondary cause Low HDL-C High LDL-C Saturated fat caloric excess, Dietary Low-fat diet, high-sugar diet anorexia Diuretics, cyclosporine, Anabolic steroids, progestins, β- Drugs sirolimus, glucocorticoids, blockers, cigarettes, retinoic acid rosiglitazone, fibrates Disorders of metabolism Hypothyroidism, pregnancy, DM Obesity, type 2 DM Nephrotic syndrome, biliary Chronic renal failure, dialysis, Diseases obstruction (Lp-X), type 2 DM type 2 DM Adapted from Stone NJ, Blum CB. Management of Lipids in Clinical Practice. 2006. Lipid Metabolism Exogenous Endogenous B-100 Dietary Fat LDL Receptor Liver E Receptor LDL Remnant (LDLr) (LDLr) Receptor Intestine HTGL HDL LPL B-48 E C II E C II HDL C II Remnant B-48 LPL TG E Chylomicron ¯ E B-100 FFA LPL TG IDL B-100 ¯ VLDL FFA Apolipoproteins apoA-I HDL structural protein; LCAT(Lecithin cholesterol acyl transferase) activator;Enhances reverse cholesterol transport apoA-II Hepatic Lipase activation apoA-IV Triglyceride metabolism; LCAT activator; apoB-100 Structural protein of all Lipoproteins except HDL Binding to LDL receptor apoB-48 apoC-I Inhibit Lipoprotein binding to LDL Receptor; LCAT activator apoC-II Lipoprotein lipase (LpL) activator apoC-III LpL inhibitor; antagonizes apoE apoE B/E receptor ligand *E2:IDL; *E4: Diet Responsivity Lipid Metabolism Exogenous Endogenous B-100 Dietary Fat LDL Receptor Liver E Receptor LDL Remnant (LDLr) (LDLr) Receptor Intestine HTGL HDL LPL B-48 E C II E C II HDL C II Remnant B-48 LPL TG E Chylomicron ¯ E B-100 FFA LPL TG IDL VLDL B-100 ¯ FFA 11 Intestinal Absorption of Cholesterol and Bile Acids Influences Lipoprotein Metabolism Dietary Cholesterol Bile Liver Chol BA BA Ezetimibe Chol NPC1L1 LDLR CM CMR Bile acid iBAT sequestrants LDL VLDL BA Blood Rader DJ, Nature Medicine 2001; 7:1282-1284 Mechanism of Intestinal-Acting Agents Mutations in ABCG5 and ABCG8 Cause Sitosterolemia Hereditary Betasitosterolemia Clinical Summary: ABCG5 and ABCG8 • Mutations in ABCG5 (sterolin-1) and ABCG8 (sterolin-2) cause sitosterolemia • Affected individuals have high levels of plant sterols, but not always cholesterol • Tendon/tuberous xanthomas and accelerated atherosclerosis • Must play a key role in regulating dietary sterol absorption and excretion • ? Link between diet and atherosclerosis • Do sterolins prevent the entry of toxic bioactive sterols? FXR and LXR Regulation of Cholesterol Metabolism FXR activated by bile acids to reduce BA synthesis and increases I-BABP LXR activated by oxysterols to increase BA synthesis and ABCA1 activity http://www.biocarta.com/pathfiles/h_fxrPathway.asp#description FXR and LXR Regulation Pathways Regulation of transcription of cholesterol and genes by heterodimerisation of RXR and LXR for FXR A B (A)When nuclear receptors RXR and LXR heterodimerize, they bind to a recognition sequence (termed a DR-4 element, in which direct repeats of TGACCT, are separated by four base-pairs) in promoters of target genes (eg ABCA1). Interaction of ligands with binding domains on these receptors stimulated gene transcription, the effect being synergistic if both are bound simultaneously, RNA polymerase complex bound near the transcriptional start site (not shown) is then activated to produce multiple mRNA copies. (B)LXR ligands upregulate ABAC1 in peripheral cells, to increase cholesterol excretion onto lipid-poor apoA-1, and also in intestinal absorptive cells (or, if not ABCA1, another LXR target gene such as ABCG5/ABCG812), to reduce dietary uptake of cholesterol. FXR ligands downregulates 7 α-hydroxylase, to reduce the pool of bile acids and inhibit solubilization and absorption of intestinal cholesterol. RXR ligands activate both FXR and LXR regulated pathways and there is dual suppression of cholesterol absorption. In rodents, though not in human beings, LXR upregulates 7 α-hydroxylase but, since RXR/FXR repression of 7 α-hydroxylase dominates over RXR/LXR stimulation, RXR ligands still completely suppress cholesterol absorption. Wade, et al, Lancet. Volume 357, No. 9251, p161–163, 20 January 2001 SREBP and Cholesterol Homeostasis Pharmacologic Manipulation of ABCA1 and Macrophage Cholesterol Efflux Fibrates, TZDs, dual PPARs, new agents PPARα PPARγ A-I PPARδ FC LXR/RXR ABCA1 New agents ? New agents Effect of PPAR* α and Υ activation in VLDL, LDL and HDL metabolism PPAR α PPAR Υ Location of action: Liver, kidney, Location of action: Adipose tissue and heart, muscle. intestine. Ligands: fatty acids, fibrates Ligands: arachidonic acid, Glitazones Actions: Stimulate production Actions: increase expression of of apo A I, inhibit apo C III, ABC A-1, increase FFA synthesis Increase lipoprotein lipase, and uptake by adipocytes, increase increase expression of ABC insulin sensitivity
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