Lipoprotein Structure, Function, and Metabolism Lipid Transport Lipoprotein Structure, Function, and Metabolism

Objectives HDL: Function & structure. Mechanism of Cholesterol control and uptake. Atherosclerosis: Definition and mechanism.

Functions of HDL converts cholesterol to cholesterol esters via the LCAT reaction transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

Coordinate Control of Cholesterol Uptake and Synthesis Increased uptake of LDL-cholesterol results in: inhibition of HMG-CoA reductase reduced cholesterol synthesis stimulation of acyl CoA :cholesterol acyl transferase (ACAT) increased cholesterol storage decreased synthesis of LDL-receptors “down-regulation” decreased LDL uptake

Atherosclerosis hardening of the arteries due to the deposition of atheroma. heart disease is the leading cause of death caused by the deposition of cholesteryl esters on the walls of arteries. atherosclerosis is correlated with high LDL and low HDL.

Factors promoting elevated blood lipids age men >45 years of age; women > 55 years of age. family history of CAD ( coronary artery disease). Smoking. hypertension >90/ 140 mm Hg. low HDL cholesterol. obesity >30% overweight. diabetes mellitus. inactivity/ lack of exercise.

Low-Density Lipoproteins (LDLs) “Bad” cholesterol Delivers cholesterol to cells Can increase build-up of plaque High levels of LDL associated with increased risk for cardiovascular disease

High-Density Lipoproteins (HDLs) “Good” cholesterol Made by liver. Circulates in the blood to collect excess cholesterol from cells Returns cholesterol to liver for excretion in bile Highest protein content

Overview of Lipoproteins

Cardiovascular Disease (CVD) Main type of CVD is Atherosclerosis (AS) Endothelial dysfunction is one of earliest changes in AS Mechanical, chemical, inflammatory mediators can trigger endothelial dysfunction: High blood pressure Smoking (free radicals that oxidatively damage endothelium) Elevated homocysteine Inflammatory stimuli Hyperlipidemia

A Healthy Endothelium produces: á PGI2 á NO Maintaining an anti-coagulant, anti-thrombotic surface

â PGI2 â NO TNFa VCAM-1 A Dysfunctional Endothelium has decreased: Increased: pro-inflammatory molecules: MCP-1 TNFa VCAM-1 Shifting to a pro-coagulant, pro-thrombotic surface

Pro-Inflammatory Molecules Chemokines = monocyte chemoattractant protein 1 (MCP-1) Inflammatory cytokines = tumor necrosis factor  (TNF) Adhesion molecules = intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) Overexpression of all these inflammatory mediators is commonly seen in atherosclerotic lesions.

Endothelial Dysfunction ( endothelial activation, impaired endothelial-dependent vasodilation) â endothelial synthesis of PGI2 (prostacylcin), & NO (nitric oxide) PGI2 = vasodilator, âplatelet adhesion/aggregation NO = vasodilator, âplatelet & WBC (monocyte) adhesion á Adhesion of monocytes onto endothelium --> transmigration into subendothelial space (artery wall) --> change to macrophages Endothelial dysfunction --> increased flux of LDL into artery wall

Oxidation of LDL (oxLDL) Oxidation = process by which free radicals (oxidants) attack and damage target molecules / tissues Targets of free radical attack: DNA - carbohydrates Proteins - PUFA’s>>> MUFA’s>>>>> LDL can be oxidatively damaged: PUFA’s are oxidized and trigger oxidation of apoB100 protein --> oxLDL OxLDL is engulfed by macrophages in subendothelial space

Atherosclerotic Plaque Continued endothelial dysfunction (inflammatory response) Accumulation of oxLDL in macrophages (= foam cells) Migration and accumulation of: smooth muscle cells, additional WBC’s (macrophages, T-lymphocytes) Calcific deposits Change in extracellular proteins, fibrous tissue formation High risk = á VLDL (áTG) á LDL â HDL

Antioxidant Defense Systems 1. Prevent oxidation from being initiated 2. Repair oxidative damage

Antioxidant Mechanisms Antioxidant vitamins (vitamins C, E, carotenoids) Flavonoids and other phytochemicals Antioxidant enzyme systems Minerals required: Mn, Cu, Zn, Se

Factors Associated with CVD Genetic Variables Being male Being post-menopausal female Family history of heart disease before the age of 55 (some are associated with genetic defects in LDL receptors)

Factors Associated with CVD • Dietary 1. Elevated levels of LDL --More LDL around to potentially oxidize and accumulate in artery wall 2. Low levels of HDL --HDL carries cholesterol from artery walls back to the liver 3. Low levels of antioxidant vitamins --Vit. E, Vit. C, Beta-carotene 4. Low levels of other dietary antioxidants --Phenolics, flavanoids, red wine, grape juice, vegetables, fruits

Factors Associated with CVD High blood pressure • Damages the artery wall allowing LDL to enter the wall more readily Cigarette Smoking Cigarette smoke products are oxidants and can oxidize LDL Cigarette smoking compromises the body’s antioxidant vitamin status, especially Vit. C Damages the artery wall Activity Level Exercise is the most effective means of raising HDL levels Obesity

Homocysteine Levels Elevated levels cause damage to artery walls = increased the oxidation of LDL Elevated homocysteine levels are significantly correlated with increased risk to heart disease. Vitamins B6, B12, and Folic acid normalize homocysteine levels.

Diet Methionine (a.a.) Homocysteine SAM CH3 SAH cysteine sulfate Enzymes B12, Folate Homocysteine SAM 1. Norepinephrine 2. Guanidinoacetate 3. Serotonin 4. Serine Enzyme B6 cysteine CH3 1. Epinephrine 2. Creatine 3. Melatonin 4. Choline SAH sulfate

Know Your Lipid Profile Fasting Blood Level Ideal, Healthy Level Total Cholesterol < 200 mg/dl LDL-Cholesterol < 100 mg/dl HDL-Cholesterol ≥ 60 mg/dl Triglycerides < 150 mg/dl

Know Your Diabetes, Metabolic Risk Fasting Healthy Pre-Diabetes Diabetes (Metabolic Syndrome) Blood Glucose < 110 mg/dl 110-125 mg/dl ≥ 126 mg/dl 2 hr GTT < 140 mg/dl 140-200 mg/dl > 200 mg/dl Triglyceride < 150 mg/dl > 150 mg/dl Typically elevated HDL ≥ 60 mg/dl M < 40 mg/dl F < 50 mg/dl Typically low

The Metabolic Syndrome Abdominal Obesity Men Women > 40 inch waist > 35 inch waist Triglycerides ≥ 150 mg/dL HDL cholesterol < 40 mg/dL < 50 mg/dL Blood Pressure ≥ 130/ 85 mm Hg Fasting Blood Glucose 110-125 mg/dL

Know Your Blood Pressure Category Systolic (mm/Hg) Diastolic (mm/Hg) Normal 120 or less 80 or less High Normal 130-139 85-89 High Blood Pressure 140 or more 90 or more Strive for blood pressure of 120/80 or less

The following phrases is correctly describe “Atherosclerosis “Except……………. A. Hardening of Blood vessel wall. B. High HDL and Low LDL. C. Formation of atheroma plaque. D. Leads to heart diseases.