LIPIDS 101 Ulrich K. Schubart JMCAECOM

Physiology of Lipids and Lipoproteins Lipoprotein Disorders

STEROID SYNTHESIS CELL MEMBRANES BILE ACIDS ENERGY STORAGE ENERGY PRODUCTION CHOLESTEROL TRIGLYCERIDE

Polar surface coat Non-polar Lipid Core Cholesterol

Chylomicrons VLDL LDL HDL COMPOSITION OF PLASMA LIPOPROTEINS Density g/ml Size (nM) Cholesterol/cholesteryl esters Protein Triglyceride Phospholipid Bilheimer. Textbook of Internal Medicine. 1989: Chylomicrons VLDL LDL HDL

Major apolipoproteins and their functions ApolipoproteinStructural Ligand Cofactor for Proteinfor: (+/-) apo A-I HDLLCAT (+) apo B-100 VLDL, IDL, LDL,Lp(a) LDL receptor apo B-48 Chylomicrons apo C-IILPL (+) apo C-IIILPL (-) apo E Chylo remnants, IDL Remnant receptor in liver apo (a)*Plasminogen (-)

Apo E Exogenous Pathway (Chylomicron metabolism) B48 CE Chylomicron Remnant Liver Intestines CE B48 CE TG LPL C-II Fatty acids TG Remnant Receptor

Endogenous Pathway (VLDL metabolism) Apo E B100 CE VLDL Remnant LDL (VLDL/IDL) Liver CE B100 CE TG Remnant Receptor LPL C-II Fatty acids TG B100 CE

Basic Pathways in LDL Regulation apo B-100 apo C apo E VLDL Remnant LDL Liver VLDL PRODUCTION LDL CLEARANCE LIPOLYSIS CONVERSION Other sites SHUNT PATHWAY

Rader et al JCI 2003

Nabel E NEJM 2003

Familial Hypercholesterolemia Autosomal Dominant Inheritance LDL Receptor Deficiency: -Heterozygous (1/500) -Homozygous (1/1,000,000) LDL Cholesterol Increased - Heterozygous 2 times (>250 mg/dl) -Homozygous 4-6 times elevated Familial Defective apoB is an exact phenocopy (note this is NOT Familial Combined HLD)

Familial Hypercholesterolemia Apo E apoB CE ChyloVLDL Remnants LDL Liver CE apoB CE TG LPL C-II Fatty acids TG B100 LDL-R

Familial Hypercholesterolemia: Clinical Manifestations Severe Hypercholesterolemia (LDL>250 mg/dl) -Atherosclerotic vascular disease Premature CHD Xanthelasma/ Corneal Arcus as young adults Tendon Xanthomas Arthritic type pains in joints Family History of premature CHD

Familial Hypercholesterolemia: Ligand Defective ApoB B100 LDL-R Apo E apoB CE ChyloVLDL Remnants LDL Liver CE apoB CE TG LPL C-II Fatty acids TG

Familial Combined Hyperlipidemia Common (1/100) Autosomal dominant pattern of inheritance Variable lipoprotein pattern in individual and family Multiple Phenotypes (IIa, IIb, IV, V) Pathophysiology: overproduction of apoB-100 particles CHD risk is increased

Familial Combined Hyperlipidemia (HyperapoB) Liver CE Apo E B100 CE TG LPL C-II Fatty acids Apo E B100 CE TG B100 VLDL Remnant LDL (VLDL/IDL) LDL-R CE

Familial (Type I) Hyperlipoproteinemia/Chylomicronemia Rare (1/1,000,000) Recessive inheritance Triglycerides > 1000 mg/dl with usual diet Presents in childhood, especially puberty in girls Pathophysiology: absence of lipoprotein lipase or apo C-II Complications: pancreatitis, xanthomatosis, hepatosplenomegaly

Familial (Type I) Hyperlipoproteinemia/Chylomicronemia Apo E apoB Chylo/VLDL Remnants LDL (VLDL/IDL) Liver CE apoB CE TG LPL C-II Fatty acids CE TG B100 LDL-R CE

Remnant Removal Disease Synonyms: Familial Dysbetalipoproteinemia, Type III hyperlipoproteinemia, Broad beta disease Uncommon: 1/1000 – 1/5000 Requires apo E2/E2 (1/100) + second defect for clinical expression Pathophysiology: impaired clearance of apoB/E remnant particles by the remnant receptor Chylomicron and VLDL (  -VLDL) remnants accumulate Diagnosis: VLDL-C/TG >0.3; broad  -band on EP CHD and peripheral vascular disease Palmar and tuberoeruptive xanthomata _

Remnant Removal Disease (Type III Hyperlipidemia) B100 LDL-R Apo EApo E2/E2 apoB CE ChyloVLDL Remnants LDL Liver CE apoB CE TG LPL C-II Fatty acids TG

Nabel E NEJM 2003

Primary Hypercholesterolemia: Clinical Classification Elevated LDL cholesterol (>160 mg/dl; 1/4 of all American Adults) -Familial Hypercholesterolemia (1/500) - Familial Combined Hyperlipidemia (1/100) -Polygenic Hypercholesterolemia (1/4)

Dietary Hyperlipidemia VLDL LDL Apo E Apo C apoB-100 LDL VLDL remnants Increased conversion to LDL X X Overproduction of VLDL TG Other sites Reduced activity of LDL receptors ( Saturated fat and cholesterol In the diet) Caloric intake

HDL

Reverse cholesterol transport A-I Liver CE FC LCAT FCFC Bile A-I ABCA1 Macrophage Mature HDL Nascent HDL FC CE

Reverse cholesterol transport : Role of CETP in HDL Metabolism CETP = cholesteryl ester transfer protein A-I Liver CE FC LCAT FC Bile SR-BI A-I ABCA1 Macrophage CE B LDLR VLDL/LDL CETP Mature HDL Nascent HDL CE SRA Oxidation CE TG

Rader D JCI Dec 06

Primary (Genetic) Causes of Low HDL-C ApoA-I –Complete apoA-I deficiency –ApoA-I mutations (eg, ApoA-I Milano ) LCAT –Complete LCAT deficiency –Partial LCAT deficiency (fish-eye disease) ABCA1 –Tangier disease HomozygousHeterozygous –Familial hypoalphalipoproteinemia (some families) Unknown genetic etiology –Familial hypoalphalipoproteinemia (most families) –Familial combined hyperlipidemia with low HDL-C –Metabolic syndrome

Tangier Disease Autosomal codominant disorder due to mutations in both alleles of ABCA1 gene Extremely marked reduction in HDL-C and apoA-I Markedly accelerated catabolism of apoA-I and apoA-II Cholesterol accumulation: –Enlarged orange tonsils –Hepatosplenomegaly –Peripheral neuropathy

Tangier Disease (Continued) Increased risk of premature atherosclerotic vascular disease Pathologic accumulation of cholesterol in macrophages and other cells of reticulo- endothelial system (orange tonsils) Heterozygotes have moderately reduced HDL-C and apoA-I levels and increased risk of premature atherosclerotic vascular disease, but no tonsillar enlargement or hepatosplenomegaly

HDL Metabolism in Tangier Disease A-I FC A-I ABCA1 Macrophage Rapid catabolism LCAT Nascent HDL CE

Familial Hypoalphalipoproteinemia Dominant disorder; due to mutations in one allele of ABCA1 gene in some families, and of unknown genetic etiology in other families Moderate reduction in HDL-C and apoA-I Increased risk of premature atherosclerotic vascular disease

Secondary Causes of Low HDL-C Smoking Obesity (visceral fat) Sedentary Lifestyle High carbohydrate or very-low-fat diet Hypertriglyceridemia (from any cause) Drugs –Beta-blockers –Androgenic steroids –Androgenic progestins

Cholesterol disorders associated with premature CAD Familial HypercholesterolemiaLow HDL Nephrotic Syndrome Lp(a) [ not ApoA]. Triglyceride Disorders associated with premature CAD (+) premature CAD(-) premature CAD Familial Combined HLDFamilial HTG Remnant Removal DzFamilial Chylomicronemia Central Obesity (metabolic syndrome)Estrogen DiabetesAlcohol Nephrotic syndrome/Uremia/dialysisBile Acid Resins HypothyroidismHigh Carbohydrate diet Cushing’s syndrome

New Concepts in Atherosclerosis Risk: Triglycerides, Small Dense LDL and the Metabolic Syndrome

Metabolic Syndrome HDL Atherogenic Dyslipidemia Insulin Resistance Procoagulant State BP

Atherosclerosis HDL VLDL IDL TG LDL Cigarette Smoking Hypertension Diabetes Pro Coagulant State Thrombosis CHD

HYPERTRIGLYCERIDEMIA Small, dense LDL HDL IDL VLDL remnants Chylomicron remnants Metabolic Consequences of Hypertriglyceridemia

Insulin Resistance and Dyslipidemia (lipoprotein or hepatic lipase) Fat Cells Insulin IR FFA Liver (CETP) CE TG Apo A-I (CETP)CETG VLDL HDL SD LDL TG Apo B VLDL Kidney v

Feingold KR et al. Arterioscler Thromb. 1992;12: Lamarche B et al. Circulation. 1997;95: Significance of Small, Dense LDL Low cholesterol content of LDL particles –  particle number for given LDL-C level Associated with  levels of TG variable LDL-C, and  levels of HDL 2 Marker for common genetic trait associated with  risk of coronary disease (LDL subclass pattern B) Possible mechanisms of  atherogenicity –greater arterial uptake –  uptake by macrophages –  oxidation susceptibility

Atherogenic Particles BB B E E C Small VLDL Remnant IDL LDL

Atherogenic Cholesterol VLDL + IDL + LDL = Total Cholesterol - HDL = non HDL cholesterol

Calculating LDL Cholesterol LDL-C = TC – HDL C – TG/5 Invalid when TG > 400 mg/dl Underestimates “atherogenic cholesterol” when TG >200 mg/dl nonHDL-C = TC - HDL C

Non-HDL Cholesterol Predictive of CV Events Rates in Prospective Clinical Trials Clinical Trials Useful when triglycerides > 200 mg/dl Allows use of NCEP LDL guidelines (+ 30 mg/dl) (+ 30 mg/dl) Flexible - Allows use of non fasting samples Flexible - Allows use of non fasting samples to assess lipid treatment goals to assess lipid treatment goals

ATP III: The Metabolic Syndrome* *Diagnosis is established when  3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is  BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: Risk FactorDefining Level Abdominal obesity † (Waist circumference ‡ ) Men Women >102 cm (>40 in) >88 cm (>35 in) TG  150 mg/dL HDL-C Men Women <40 mg/dL <50 mg/dL Blood pressure  130/  85 mm Hg Fasting glucose  110 mg/dL

ATP III: New Features of Guidelines— Focus on Multiple Risk Factors Persons with diabetes without CHD raised to level of CHD risk equivalent Framingham 10-year absolute CHD risk projections used to identify certain patients with  2 risk factors for more intensive treatment Persons with multiple metabolic risk factors (the metabolic syndrome) identified as candidates for intensified therapeutic lifestyle changes (TLC) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:

“It’s 11 PM….do you know what your Cholesterol is?