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BIOCHEMISTRY

LIPOPROTEINBY&
Dr.Liniyanti D.Oswari, MNS,
DYSLIPIDEMIA
MSc.

Learning Objectives

To understand the lipid & lipoprotein
metabolism in the body.
Recognize the significance of dyslipidemia in
Atherosclerosis on CVD & CHD, including the
role of HDL-C as a protective risk factor for
CVD &CHD
Recognize the relationship dyslipidemia with
central obesity & Insulin resistance
Examine recent clinical trials of dyslipidemia
as it relates to the prevention and treatment
of CVD & CHD

Lipoproteins

Clusters of lipids associated with
proteins that serve as transport vehicles
for lipids in the lymph and blood

Lipoproteins      Chylomicrons VLDL – Very low density lipoprotein IDL – Intermediate density lipoprotein LDL – Low density lipoprotein HDL – High density lipoprotein .

the lower the density The more protein. the higher the density .Lipoproteins   Distinguished by size and density Each contains different kinds and amounts of lipids and proteins   The more lipid.

E Lp (a) 25-30 CEs B-100 & glycoproteins .C-II.E VLDL 30-80 Endogenous TG B-100. E LDL 18-28 CEs B-100 HDL 5-15 CEs A.C-II.C-II.Lipoproteins Class Size (nm) Lipids Major Apoproteins Chylomicra 100-500 Dietary TG B-48.E IDL 25-50 CEs & TGs B-100.

Lipids (%) in Plasma Lipoproteins Chylomicro n VLDL IDL Cholesterol 9 22 35 47 19 Triglyceride 82 52 20 9 3 Phospholipi d 7 18 20 23 28 Lipid LDL HDL .

The Origins & Major Functions of Lipoproteins .

ApoC Deliver fatty acids via lipoprotein lipase . ApoB-48. ApoA-II.Functions of Chylomicrons    Made by intestinal cells Most of lipid is triglyceride Little protein   ApoA-I.

Chylomicron remnants  Lipoprotein particle that remains after a chylomicron has lost most of its fatty acids   Taken up by liver Contents reused or recycled .

Further Delivery of Lipids in Body  Liver    Synthesizes & metabolizes lipids “Central command center” for relation of lipid metabolism Makes additional lipoproteins .

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Exogenous Pathway of Lipid Metabolism Cholest AA FA P. glycerol Vessel wall .

Endogenous Pathway of Lipid Metabolism .

Hopfer U. In Harrison’s Principles of Internal Medicine. Biochemistry. Philadelphia: Lippincott Raven. New York: Wiley-Liss. 2002:728-777. New York: McGraw-Hill. 1994. Harvey RA. 1998:2138-2149.3(suppl E):E2-E5. Ginsberg HN. 5th ed. New York: Wiley-Liss. . In Textbook of Biochemistry with Clinical Correlations. 2002:1082-1150. Shepherd J Eur Heart J Suppl 2001.Endogenous & Exogenous Sources of Cholesterol Dietary cholesterol Exogenous Intestine (~300–700 mg/day) Biliary cholesterol Fecal bile acids and neutral sterols ~700 mg/day (~1000 mg/day) Liver Synthesis (~800 mg/day) Extrahepatic tissues Endogenous Adapted from Champe PC. 2nd ed. Goldberg IJ. Glew RH. In Textbook of Biochemistry with Clinical Correlations. 14th ed. 5th ed.

a reduction in the amount of dietary cholesterol leads to increased synthesis in the liver and intestine. approximately 1300 to 1700 mg of cholesterol per day passes through the intestines. 4 of which about 700 mg per day is absorbed. Thus. Exogenous cholesterol is absorbed by the intestine from dietary and biliary sources and transported to the liver. intestine.5 Because plasma cholesterol levels are maintained within a relatively narrow range in healthy individuals.2 .Endogenous & Exogenous Cholesterol  Cholesterol is obtained from endogenous and exogenous sources.2 In individuals eating a relatively low-cholesterol diet. Endogenous cholesterol is synthesized in all tissues. 3. 2 Depending on diet. the liver produces about 800 mg of cholesterol per day to replace bile salts and cholesterol lost in the feces. and reproductive tissues. adrenal cortex.1.4 Approximately 1000 mg of cholesterol is secreted by the liver into the bile. including the placenta. people typically consume 300 to 700 mg of cholesterol daily. but primarily the liver.

Cholesterol Absorption in the Intestine 1000 mg Inhibitors Resins Plant stanols NPC1L1 (Ezetimibe) .

There are several steps involved in the absorption of cholesterol from the intestinal Cholesterol that is absorbed from the intestinal lumen.     lumen comes from two sources: dietary cholesterol and biliary cholesterol (which is by far the greater of the two in quantity). the cholesterol is released from the lipid micelle and then enters the enterocyte. . Cholesterol is emulsified by bile acids and packaged in lipid micelles. These lipid micelles are transported to the brush border of jejunal enterocytes. At the brush border of the enterocyte.

ApoE .Very-Low-Density Lipoproteins (VLDL)      Made by liver Contains large amounts of triglyceride Delivers fatty acids to cells More dense than chylomicrons A bit more protein (8%)  ApoB-100. ApoC.

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Direct uptake by hepatocyte 4.Hydrolysis by LPL 3.Assembly and secretion 2.Flux of pathway into LDL 3 1 2 4 .VLDL life cycle 1.

Intermediate-Density Lipoproteins (IDL)    Lipoprotein that results from loss of fatty acids from VLDL Major lipid is cholesterol esters Proteins similar to VLDL but greater percentage (15%)    ApoB-100. ApoE Taken up by liver or remain in circulation Converted to low-density lipoproteins (LDL) . ApoC.

Low-Density Lipoproteins (LDL)   “Bad” cholesterol. causing them to be taken up & dismantled . major lipid in LDL Delivers cholesterol from liver to cells    Protein (21%)    Cell membranes Hormone production ApoB-100 Binds to specific LDL receptor LDL receptors  Membrane-bound proteins that bind LDL.

Effect of Diet on LDL Concentrations  Increase LDL      SFAs Trans fatty acids High cholesterol intake Lifestyle factors Genetics  Decrease LDL      High PUFA diet Ω-3 fatty acids Dietary fiber Lifestyle factors Genetics .

LDL Oxidation and Atherosclerosis .

Mechanism of Atherogenic Dyslipidemia Insulin resistance increased NEFA and glucose flux to liver Increased VLDL IR impairs LDLR Insulin resistance and decreased apoB degradation Insulin resistance and decreased LPL FCHL DM II Metabolic syndrome .

Increased Atherogenicity of Small Dense LDL  Direct Association      Longer residence time in plasma than normal sized LDL due to decreased recognition by receptors in liver Enhanced interaction with scavenger receptor promoting foam cell formation More susceptible to oxidation due to decreased antioxidants in the core Enter and attach more easily to arterial wall Endothelial cell dysfunction  Indirect Association    Inverse relationship with HDL Marker for atherogenic TG remnant accumulation Insulin resistance .

ApoE Reverse cholesterol transport   Salvage excess cholesterol from cells Transported back to liver . major lipid is phospholipid Lipoprotein made by liver that circulates in the blood to collect excess cholesterol from cells Lowest lipid-to-protein ratio  Protein (50%)   ApoA. ApoC.High-Density Lipoproteins (HDL)    “Good” cholesterol.

HDL Metabolism .

and LDL Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively .Key Enzymes and Cofactors in Lipid Metabolism         HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis (mainly liver and intestine) Lipoprotein Lipase.digests TG core of CMC and VLDL Hepatic Lipase-conversion of IDL to LDL CETP-transfers cholesteryl esters from HDL to other lipoproteins in exchange for TG LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol to cholesterol esters Apolipoprotein A-major protein of HDL activating many reactions Apo-B-major protein of VLDL. IDL.

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Why Does HDL-C Protect? Endothelial repair Protection against oxidation Antiinflammatory Anti-thrombotic Modulation of endothelial function HDL-C Cholesterol acceptor Cholesterylester donor Protection of the vessel wall Reverse Cholesterol Transport (RCT) .

Effects of Diet on HDL Concentration  What raises HDL?     Uncertain if low carbohydrate diets offer protection High MUFA intake Lifestyle factors ( Exercise) Genetic factors influence HDL .

High Density Lipoprotein & Atherosclerosis  Reverse cholesterol transport  Maintenance of endothelial function  Protection against thrombosis  With Apo A-I inhibits generation of calciuminduced procoagulant activity on erythrocytes by stabilizing cell membrane  Low blood viscosity via permitting red cell deformability  Anti-oxidant properties-may be related to enzymes called paraoxonase .

Dyslipidemia Characteristics      Elevated triglycerides Post-prandial lipemia Small dense LDL (type B) Elevated LDL Low HDL cholesterol Elevated Total Cholesterol Nature Medicine 2002 .

Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver FFA IR Insulin CE TG VLDL (CETP) HDL (hepatic lipase) Apo B TG VLDL Apo A-1 CE (CETP) TG LDL SD LDL (lipoprotein or hepatic lipase) Kidney .

Dyslipidemia in Diabetes Increased Decreased  Apo B  HDL  Triglycerides  Apo A-I  VLDL  LDL and Small Dense LDL .

Insulin Resistance: Associated Conditions .

Small dense LDL    VLDL1 gives rise to small dense LDL Increase TG/Chol content through CETP Increase delipidation by hepatic lipase .

larger with apo A. largest. with additional apo E.Low HDL-cholesterol    HDL-3. C-II. & C-III HDL-2. Best negative correlate CAD Other functions attributed to HDL: inhibits monocyte chemotaxis. LDL oxidation Tulenko 2002 J Nuclear Cardiology 9:638 .

Low HDL-cholesterol .

Low HDL-cholesterol Low HDL-cholesterol Increased catabolism of small dense HDL Low HDL cholesterol by both content and # particles CETP inhibitors .

    High triglycerides Post-prandial lipemia Small dense LDL (type B) Low HDL cholesterol Fibrate Niacin Statin CETP ABCA-1 .

Current Classifications      Familial Hypercholesterolemia – High LDL-C (Type IIA) Polygenic Familial Hypercholesterolemia Familial Combined Hyperlipidemia – High LDL-C and/or high TG levels Familial Dyslipidemias –High TG and low HDL Familial Dysbetalipoproteinemia (Type III) .

Tangier Disease   Genetic disorder resulting in production of faulty HDL particles that cannot take up cholesterol from cells High risk for developing cardiovascular disease .

strokecenter. it takes longer to develop a thrombus big enough to completely block the vessel… so you get warning signs (TIA. resulting in the production of fibrin strands which trap platelets. UA) of stroke and MI •This process happens everywhere (brain.org . heart) Image courtesy of the Internet Stroke Center at Washington University . red and white blood cells over the area = thrombus •In larger vessels.•Can see the platelet aggregation in response to the foam cell chemicals and tissue damage •The platelets will activate the coagulation cascade.www.

Image courtesy of the Internet Stroke Center at Washington University www.strokecenter.org .

CHD)   Cardio = heart Vascular = blood vessels .Cardiovascular disease (CVD)  General term for all diseases of the heart and blood vessels   Atherosclerosis is the main cause of CVD Atherosclerosis leads to blockage of blood supply to the heart. damage occurs (coronary heart disease.

Coronary Heart Disease  Athrogenesis [CHD] MVS 110: Lecture #11 .

Lipoproteins and cardiovascular disease (CVD)  LDL is positively associated with risk CVD  HDL is negatively associated with CVD .

MRI 3. IVUS. EBCT. Atherosclerosis Burden/End-organ Damage: Carotid IMT. 2. vWf . e-Selectin.A Plethora of Non-Lipid Markers of Risk 1. Vasodilatory Endothelial Dysfunction: Brachial Ultrasound Flow-Mediated Dilation. VCAM. advanced CT. General Inflammatory Marker: hs-C Reactive Protein 4. Markers of Inflamed Endothelium: ICAM. # plaques (based on carotid US).

105:1135-1143. Integrins VCAMLDLE-Selectin.Atherosclerosis Is an Inflammatory Disease L-Selectin. 1. Smooth Muscle Cell Migration . P-Selectin ICAM-1 Monocyt e MCP-1 OxLDL Intima M-CSF Other inflammato ry triggers Macrophage Activation & Division Media Libby et al. Circulation 2002.

There are several different types of adhesion molecules with specific functions in the endothelial–leukocyte interaction: The selectins tether and trap monocytes and other leukocytes. By activating the nuclear factor B (NFB) transcription factor. oxidized LDL (oxLDL) stimulates increased expression of cellular adhesion molecules. vascular cell adhesion molecules (VCAMs) and intercellular adhesion .Atherosclerosis Is an Inflammatory Disease Oxidation of low-density lipoprotein (LDL) initiates the atherosclerotic process in the vessel wall by acting as a potent stimulus for the induction of inflammatory gene products in vascular endothelial cells. Importantly.

MCP-1 mediates the attraction of monocytes and leukocytes and their diapedesis through the endothelium into the intima. M-CSF plays an important role in the transformation of monocytes to macrophage foam cells. Macrophages express scavenger receptors and take up and internalize oxLDL in their transformation into foam cells. Migration of smooth muscle cells (SMCs) from the intima into the media is another early event initiating .Atherosclerosis Is an Inflammatory Disease OxLDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage-colony stimulating factor (M-CSF).

1999.100:1148-1150. Endothelium and other cells IL-6 “Messenger” Cytokine CRP SAA Liver Circulation HSPs=heat shock proteins. IL-1. Circulation.The Acute-Phase Response Pathway Proinflammatory Risk Factors Primary Pro-inflamatory Cytokines (eg. SAA=serum amyloid-A. etc. . Adapted from Libby and Ridker. TNF-) ICAM-1 Selectins. HSPs.

LDL and atherosclerosis .

Recommended blood lipids Total cholesterol: <200 mg/dL  LDL cholesterol: <130 mg/dL  HDL cholesterol: >35 mg/dL  Triglycerides: <200 mg/dL  .

2-6mmol/L) Hypercholesterolemia > 240 mg/dl or > 6mmol/L) .Desirable Blood Cholesterol    Normal = < 200 mg/dl (5.2 mmol/L) Borderline = 200-239 mg/dl or (5.

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(HDL-C + .2TG)  HDL-C = (Past) >35 mg/dl (2001) > 40) HDL-C = > 60 mg/dl will negate one risk factor  .Desirable Levels LDL & HDL Continued  LDL-C = (Past) < 130 mg/dl (2001 < 100)  LDL-C=total cholesterol .

Desirable Levels Triglyceride Continued Normal TG = < 200 mg/dl  Borderline high = 200-400 mg/dl  High = 400-1000 mg/dl  Very High = > 1000 mg/dl  .

Life style is a Driver of CVD Life style intervention Physical inactivity Excessive food intake Stress Smoking Obesity Hypertension Risk factor modificatio n Diabetes Dyslipidaemia Atherosclerosis Chronic heart failure Atherosclerosis Arterial & venous thrombosis/ cardiac & cerebral events Arrhythmia .

Definition:(NCEP) National Cholesterol Education Program (2001) At least 3 of Abdominal obesity: waist circumference > 102 cm (M) > 88 cm (F) Hypertriglyceridemia > 150 mg/dl Low HDL cholesterol< 40 mg/dl (M) < 50 mg/dl (F) Hypertension (> 130/85 mm Hg) Impaired Fasting Glucose or Type 2 diabetes (> 100 mg/dl) (ATP III. JAMA 285:2486. 2001) .

Pathogenesis of the Metabolic
Syndrome

Central
obesity

Insulin
Resistan
ce

Type 2
Diabetes
Dyslipidemi
a
Hypertensio
n

Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease

Environmental factor

Genetic variation

Abdominal
Adipokines obesity
Adipocyte

Cytokines

Monocyte/
macrophag

Inflammatory markers
Insulin resistance
 Tg

Metabolic syndrome

 HDL

 BP

Atherosclerosis

Reilly & Rader
2003;
Eckel et al 2005

Plaque rupture/thrombosis

Cardiovascular events

Treatment

Treatment

NCEP ATP-III guidelines

Medications

Modification of lipids and major risk
factors
See Table 15.9
See Table 15.10

Procedures

Angioplasty
CABG

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pravastatin. simvastatin) Fibric Acid Derivatives (Clofibrate.Drugs      Nicotinic Acid (Niaspan) Bile Acid Sequestrants (cholestyramine and colestipol) HMG CoA Reductase Inhibitors (lovastatin. gemfibrozil) Probucol .

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11 for summary. cholesterol Rich in fruits.Treatment  Nutrition Therapy  Therapeutic Lifestyle Changes (TLC) developed as component of ATP-III      Modifications in fat. vegetables. complete guidelines in Appendix E9 . fiber Limit sodium to 2400 mg Include stanol esters See Table 15. grains.

* Increase Intake of Omega -3 essential Fatty Acids  . 15% of total calories  Limit Cholesterol intake <200 mg/day  Total calories Balance energy intake and expenditure to maintain desirable body weight/ prevent weight gain *Avoid Trans Fats.Nutrient Recommendations of TLC Diet Nutrient (TLC= Therapeutic lifestyle Recommended Intake Changes) Saturated fat < 7% of total calories  Polyunsaturated fat Up to 10% of total calories  Monounsaturated fat Up to 20% of total calories  Total fat 25-30% of total calories  Carbohydrates 50-60% of total calories  Fiber 20-30 grams/day  Protein Approx.

9 Regular physical activity .5-24. Nutrition Therapy .Other     Increase sources of soluble fiber Increase intake of plant sterols Weight loss – BMI 18.

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Medical Treatments  Coronary Angioplasty  Coronary Bypass Surgery (CABG) .

decreases in LDL observed Cholesterol-lowering Margarines Benecol and Take Control containing plant sterols and stanols  Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis  10-20% reduction in LDL and TC however no outcome studies  AHA recommends use only in hypercholesterolemia pts or those with a cardiac event requiring LDL treatment Other agents include soluble fiber. canola oil. green tea Overall a combination diet with multiple cholesterol-lowering agents causes much more significant LDL reductions   Salmon. flaxseed. walnuts).Diet Supplements  Fish Oil (source of omega-3 polyunsaturated fatty acids)          Soy  Source of phytoestrogens inhibiting LDL oxidation  25-50 grams/day reduce LDL by 4-8%  Effectiveness in postmenopausal women is questionable Garlic     Mixed results of clinical trials In combination with fish oil and large doses (900-7.2 grams/d). nuts (esp. soybean oil and nuts At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and apolipoprotein B Possibly decreases small LDL (by inhibiting CETP) Several studies have shown lower risk of coronary events 2 servings of fish/week recommended?? Pharmacologic use restricted to refractory hypertriglyceridemia Number of undesirable side effects (mainly GI) .

squash. Same ingredient in Lovastatin. strawberries. low fat. tomatoes. ginger. onion oil: lowers chol. okra. contain lecithin Phytosterols: sesame. 10-33% Omega 3 fish oils Red Yeast Rice: a natural substance that inhibits HMG-CoA reductase. increases HDL Carrots/Grapefruit: Fiber and pectin (whole fruits most beneficial) Avocado: monounsaturated fat Beans: High in fiber. spinach.Cholesterol Control With Foods and Herbs          Fiber: Decreases LDL. celery. . Shiitake mushrooms: contain lentinan (25% reduction in animal studies) Garlic. safflower.