Lipoprotein Structures, Function and Metabolism (2)

Lipoproteins in plasma Density Mobility Component CM CM TG rich VLDL Pre-b-lipoprotein TG rich LDL b-lipoprotein Cholesterol rich HDL a-lipoprotein Cholesterol/protein rich

Chylomicron Transport dietary lipids from the intestine to the peripheral tissues

VLDL – IDL - LDL VLDL function: Deliver TG from liver to peripheral tissue cells LDL function: Deliver Cholesterol from live to peripheral tissue cells

Metabolism of VLDL and LDL

LDL Cholesterol rich Can be taken up either by the peripheral tissues or by the liver LDL is taken up by LDL receptor through apoB100/LDL receptor interaction. After internazation, the LDL is digested by lysosomal enzymes. The cholesterol is released and the receptor recycles back to the membrane. LDL function: Deliver cholesterol from liver to peripheral tissue cells.

LDL receptor (839 aa) extracellular domain is responsible for apoB100/apoE binding intracellular domain is responsible for clustering of LDL receptors into clathrin- coated pit region of plasma membrane LDL receptors exist in most peripheral tissues and in the liver.

Michael S. Brown and Joseph L. Goldstein discovered LDL-receptor. 1985 Nobel prize in Medicine

LDL cholesterol levels are positively related to risk of cardiovascular disease Therefore, cholesterol in LDL has been called “bad cholesterol” Defects in the LDL receptor leads to familial hypercholesterolemia

Familial Hypercholesterolemia LDL-receptor deficiency 420 different mutations identified 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 clathrin-coated pit 5 – receptor fails to release LDL after internalization and does not recycle to cell surface

Metabolism of HDL

HDL HDL are synthesized in the liver and intestine as a small disc-like particle. Proteins on the surface of HDL: apoAs, apoCs, apoE, CETP，LCAT. Nascent HDL acquires cholesterol in peripheral tissues.

HDL The cholesterol is esterificated by LCAT (lecithin cholesterol acyltransferase) associated with the particle. This reaction is activated by apoA-I The cholesterol ester move to the hydrophobic core of the particle and particle becomes spherical.

HDL HDL particles bind to SRB1 receptors (scavenger receptor type B1) on the liver and are taken into the cells. HDL particles are also a reservoir for apolipoproteins (especially apoE & apoCII） Some of the CE in HDL is transferred from HDL to other lipoproteins by cholesterol ester transfer protein （CETP）

HDL HDL salvage excess cholesterol from cells and reverse-transport cholesterol from peripheral cells to the liver for excretion HDL cholesterol levels are inversely related to risk of cardiovascular disease Therefore, cholesterol in HDL has been called “good cholesterol”

Main Functions of Lipoproteins CM: transfer exogenous lipids (dietary fat) from intestine to peripheral tissues. VLDL-LDL: transfer endogenous lipids from liver to peripheral tissues. HDL: reverse cholesterol transport from peripheral tissues to liver.

Lipoproteins (a) Another kind of atherogenic lipoprotein. Consist of LDL and a protein designated as apo(a) The apo(a) is covalently linked to apoB-100 by a disulfide linkage High risk association with premature coronary artery disease and stroke.

Hyperlipoproteinemia

Fredrickson classification of hyperlipoproteinemia Type I (hyperchylomironemia): Increased CM Type II-A (hyper-b-lipoproteinemia): Increased LDL Receptor deficiency or polygenic disorder. Type II-B: Increased VLDL + LDL Increased production of VLDL and impaired LDL catabolism Type III: (broad-b-lipoproteinemia) Increased IDL, elevated cholesterol and triglycerides

Fredrickson classification Type IV: (hyper-pre-b-lipoproteinemia) Increased VLDL Impaired VLDL catabolism Type V: Increased CM + VLDL Reduced lipoprotein lipase

Where do we get cholesterol? Our bodies make all the cholesterol we need. We also get cholesterol from foods we eat. 22

Blood cholesterol levels increase by eating these products Beef poultry, fish milk, eggs, cheese, yogurt, etc. 23

Why worry about cholesterol? Blood cholesterol can stick to the sides of arteries. Blockages can form. It can lead to serious medical problems: Heart attack and Stroke. 24

What does my total cholesterol mean? Normal Less than 200 mg/dL Borderline High High 240 mg/dL or higher 200-239 mg/dL 25

HDL Cholesterol 26 Optimal: 60+ mg/dL for both males and females At Risk for Heart Disease: Women: less than 50 mg/dL Men: less than 40 mg/dL 26

LDL Cholesterol Optimal Less than 100 mg/dL Near or above Optimal 100-129 mg/dL Borderline High 130-159 mg/dL High 160-189 mg/dL Very High 190+ mg/dL Now let’s examine where we want LDL cholesterol levels to be for both men and women. Remember, LDL cholesterol is considered the bad cholesterol, so we want it as low as possible. Any level below 100mg/dL is optimal, and levels between 100-129mg/dL are near or above optimal. Levels between 130-159mg/dL are considered borderline high. Levels between 160-189 mg/dL are considered high, and levels above 190 mg/dL are considered very high. There are many things you can do to reduce your LDL cholesterol levels if they fall in any of the high categories. 27

Triglycerides Now let’s discuss triglyceride levels. Normal Less than 150 mg/dL Borderline High 150-199 mg/dL High 200-499 mg/dL Very High 500+ mg/dL Now let’s discuss triglyceride levels. Less than 150 mg/dL is normal and where you want to be. Between 150-199 mg/dL is borderline high; 200-499 mg/dL is high; and 500+ mg/dL is very high. Remember, triglycerides are fats, and the lower the better! 28