Review of Cholesterol and Lipoproteins

Objectives for Presentation: To review importance of Cholesterol and other lipids as a risk factor for heart disease To review the components of cholesterol and their relative importance To review cholesterol metabolism To understand the tests for total cholesterol and its different lipoprotein components

Cholesterol has important functions in the human body Necessary part of cell walls Precursor chemical for steroid compounds: -hydrocortisone, aldosterone, estrogens, etc. Formation of bile acids for digestion The Liver is the major organ for synthesis and metabolism of cholesterol. The body has developed an elaborate system of cholesterol transport

Serum Cholesterol and CHD in 361,662 U.S. Men 96DEC11 JH/FM/JH/FM Serum Cholesterol and CHD in 361,662 U.S. Men 18 16 14 12 10 8 6 4 2 6 Year CHD Death Rate per 1,000 Men 140 160 180 200 220 240 260 280 300 mg/dL Serum Cholesterol Martin M. Lancet 1986;11:933-936

Serum Cholesterol in the USA and CHD Death 96DEC03 JH/FM/KS Serum Cholesterol in the USA and CHD Death 18 16 14 12 10 8 6 4 2 100 MRFIT NHANES II 80 Above Cholesterol % U.S. Population Level 60 CHD Death /1000 /6 Year 40 20 140 160 180 200 220 240 260 280 300 mg/dL Serum Cholesterol Martin M. Lancet 1986;11:933-936

Lipids are packaged in the bloodstream into Lipoproteins Lipoproteins have different combinations of lipids and apoproteins Lipoproteins carry lipids from intestine Lipoproteins carry lipids to and from liver Each lipoprotein has a different function Lipoproteins are important in atherogenesis and the development of heart disease

Structure of HDL Particle A-I A-I CE TG Speaker’s Notes/Talking Points: The function of lipoproteins is to transport cholesterol and triglycerides (TGs) in the blood. The five major families of lipoproteins are: chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), intermediate-density lipoproteins (IDLs), and high-density lipoproteins (HDLs). HDL is the smallest lipoprotein and contains the least amount of lipid. This slide shows the structure of this lipoprotein particle. HDL contains a lipid core of cholesteryl esters (CEs) and TGs surrounded by phospholipids and specialized proteins known as apolipoproteins (apos). Apos are required for the structural integrity of lipoproteins and direct their metabolic interactions with enzymes, lipid transport proteins, and cell-surface receptors (as described in subsequent slides).1 ApoA-I is a major component of all HDL particles and is synthesized in the liver and intestine (see next slide).2 ApoA-II, the second most abundant apolipoprotein in HDL, is synthesized in the liver; its function is unclear.2   References Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1841–1851. Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:2031–2052. A-II A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides

Major Lipoproteins and their function Chylomicrons: Chylomicrons transport triglycerides from intestine Very Low Density Lipoproteins (VLDL) and Intermediate Density Lipoproteins (IDL) : VLDL produced in liver . Carry cholesterol and triglycerides Low Density Lipoproteins (LDL) LDL result from metabolism of VLDL and IDL and carry cholesterol. LDL are important cause of heart disease High Density Lipoproteins(HDL) HDL is “good” cholesterol. It removes cholesterol and protects against heart disease

Steps Involved in Cholesterol Absorption MTP

Net Cholesterol Balance in Humans

Plasma LCAT (lecithin cholesterol acyl transferase Exogenous Pathway Endogenous Pathway Dietary fat Bile acids and Cholesterol LDL ApoB -100 LDL-R Liver Endogenous Cholesterol LDL-R Extra Hepatic Tissue Intestine Dietary Cholesterol Remnant Receptor Chylomicrons Remnants VLDL IDL HDL ApoE B-100 ApoA-I A-II ApoE C-II B-48 ApoE B-48 ApoE C-II B-100 Plasma LCAT (lecithin cholesterol acyl transferase Lipoprotein lipase Lipoprotein lipase Free fatty acids Free fatty acids Adipose tissue, muscle Adipose tissue, muscle

LDL Levels in Populations With and Without CHD 96DEC03 JH/FM/KS LDL Levels in Populations With and Without CHD Frequency (%) LDL Cholesterol (mg/dL) Kannel W. Am J Cardiol 1995;76:69C-77C

Effect of Blocking Bile Acid Absorption

Inhibition of Cholesterol Absorption MTP (Inhibitors)

The Liver Regulates the Concentration of LDL-Cholesterol

Cholesterol Biosynthetic Pathway Squalene synthase HMG-CoA reductase Dolichol Acetyl CoA HMG- CoA Farnesyl pyrophosphate Mevalonate Squalene Cholesterol Ras protein Farnesyl- transferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones

Measurement of Cholesterol Total Cholesterol is the sum of cholesterol contained in the different lipoproteins Fasting not required Measured in millimoles per Liter (mmol/L) in Russia Measured in milligrams per deciliter in US 5.17 mmol/L = 200 mg/dL conversion factor 38.7

Complete Lipid Panel Requires 12 hour fast Total Cholesterol measured directly (mmol/L) HDL is measured directly (mmolL) Triglycerides are measured directly (mg/dL) Conversion factor to millimoles =88.6 LDL is usually calculated : LDL = Total Cholesterol - HDL- (Triglycerides/5) Calculation not accurate if Triglycerides > 400 mg/dL

Values for Cholesterol Total Cholesterol < 5.17 mmol/L = Good 5.17-6.19 = Borderline High > 6.20 = High

Values for Low Density Lipoprotein (LDL) < 2.58 = Good 2.58-3.33 = Near Normal 3.34- 4.12 = Borderline High 4.13-4.88 = High > 4.88 = Very High

Values for High Density Lipoprotein (HDL) < 1.03 mmol/L = LOW (Increased Risk) > 1.55 mmol/L = HIGH (Lower Risk)

Total Cholesterol/HDL Ratio or Coefficient of Atherogenicity No Longer Used in New Guidelines Reliance on LDL levels

Triglycerides Measured in mg/dL conversion to mmol/L = 88.6 Levels: < 150 mg/dL = normal 150-199 = borderline high 200-499 = high > 500 = very high

Disorders of Cholesterol and Lipoproteins in 3 Categories Specific Familial/Genetic Disorders These comprise a small minority of patients Secondary to other Diseases Diabetes, Hypothyroid, Nephrotic syndrome, Renal Failure, Lupus Dietary/Polygenic --(most common) This is the great majority of patients with elevated cholesterol/LDL