BY Dr.Liniyanti D.Oswari, MNS, MSc.

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

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

Chylomicrons VLDL Very low density lipoprotein IDL Intermediate density lipoprotein LDL Low density lipoprotein HDL High density lipoprotein

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

Class Chylomicra VLDL

Size (nm) 100-500 30-80

Lipids
Dietary TG Endogenous TG

Major Apoproteins
B-48,C-II,E B-100,C-II,E

IDL
LDL HDL Lp (a)

25-50
18-28 5-15 25-30

CEs & TGs

CEs CEs CEs

B-100, E
B-100 A,C-II,E B-100 & glycoproteins

Lipid
Cholesterol Triglyceride

Chylomicron

VLDL 22 52

IDL 35 20

LDL 47 9

HDL 19 3

9 82

Phospholipid

18

20

23

28

Made by intestinal cells Most of lipid is triglyceride Little protein

ApoA-I, ApoA-II, ApoB-48, ApoC

Deliver fatty acids via lipoprotein lipase

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

Liver
Synthesizes & metabolizes lipids Central command center for relation of lipid metabolism Makes additional lipoproteins

12

13

Cholest AA FA P, glycerol

Vessel wall

(~300700 mg/day)

Dietary cholesterol

Exogenous Intestine
(~1000 mg/day)

Fecal bile acids and neutral sterols

Biliary cholesterol

~700 mg/day

Synthesis Extrahepatic tissues

Liver

(~800 mg/day)

Endogenous
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: WileyLiss, 2002:1082-1150.

Cholesterol is obtained from endogenous and exogenous sources. Endogenous cholesterol is synthesized in all tissues, but primarily the liver, intestine, adrenal cortex, and reproductive tissues, including the placenta. Exogenous cholesterol is absorbed by the intestine from dietary and biliary sources and transported to the liver.1,2 In individuals eating a relatively lowcholesterol diet, the liver produces about 800 mg of cholesterol per day to replace bile salts and cholesterol lost in the feces.2 Depending on diet, people typically consume 300 to 700 mg of cholesterol daily.3,4 Approximately 1000 mg of cholesterol is secreted by the liver into the bile. Thus, approximately 1300 to 1700 mg of cholesterol per day passes through the intestines,4 of which about 700 mg per day is absorbed.5 Because plasma cholesterol levels are maintained within a relatively narrow range in healthy individuals, a reduction in the amount of dietary cholesterol leads to increased synthesis in the liver and intestine.2

1000 mg

Inhibitors

Resins

Plant stanols

NPC1L1 (Ezetimibe)

Cholesterol that is absorbed from the intestinal lumen comes from two sources: dietary cholesterol and biliary cholesterol (which is by far the greater of the two in quantity). 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, the cholesterol is released from the lipid micelle and then enters the enterocyte.

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, ApoE

1- Assembly and secretion 2- Hydrolysis by LPL 3- Direct uptake by hepatocyte 4- Flux of pathway into LDL

3 1 2

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, ApoC, ApoE

Taken up by liver or remain in circulation Converted to low-density lipoproteins (LDL)

Bad cholesterol; major lipid in LDL Delivers cholesterol from liver to cells Protein (21%)
Cell membranes Hormone production

LDL receptors

ApoB-100 Binds to specific LDL receptor

Membrane-bound proteins that bind LDL, causing them to be taken up & dismantled

Increase LDL
SFAs Trans fatty acids High cholesterol intake Lifestyle factors Genetics

Decrease LDL
High PUFA diet -3 fatty acids Dietary fiber Lifestyle factors Genetics

Insulin resistance increased NEFA and glucose flux to liver

Increased VLDL

IR impairs LDLR
Insulin resistance and decreased apo-B degradation
Insulin resistance and decreased LPL

FCHL DM II Metabolic syndrome

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

Good cholesterol; 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, ApoE

Reverse cholesterol transport

Salvage excess cholesterol from cells Transported back to liver

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, and LDL Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively

Why Does HDL-C Protect?

Endothelial repair Anti-inflammatory

Protection against oxidation

Modulation of endothelial function

Anti-thrombotic

HDL-C

Cholesterol acceptor

Cholesterylester donor

Reverse Cholesterol Transport (RCT)

Protection of the vessel wall

What raises HDL?

Uncertain if low carbohydrate diets offer protection High MUFA intake Lifestyle factors ( Exercise)

Genetic factors influence HDL

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

Elevated triglycerides Post-prandial lipemia Small dense LDL (type B) Elevated LDL Low HDL cholesterol Elevated Total Cholesterol

Nature Medicine 2002

Fat Cells
FFA

Liver
CE

IR

TG VLDL (CETP) HDL (hepatic lipase) Apo B TG VLDL Apo A-1 CE (CETP) TG
SD LDL

Insulin

LDL

Kidney

(lipoprotein or hepatic lipase)

Increased Apo B Triglycerides VLDL LDL and Small Dense LDL

Decreased HDL Apo A-I

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

HDL-3, larger with apo A, C-II, & C-III HDL-2, largest, with additional apo E. Best negative correlate CAD Other functions attributed to HDL: inhibits monocyte chemotaxis, LDL oxidation

Tulenko 2002 J Nuclear Cardiology 9:638

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

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

Fredrickson-Levy-Lees Classification
Type I IIa Lipoprotein Elevation Chylomicrons LDL

IIb
III IV V

LDL + VLDL
IDL (LDL1) VLDL VLDL + Chylomicrons IDL, intermediate-density lipoprotein LDL, low-density lipoprotein VLDL, very-low-density lipoprotein

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

47

Lipid Phenotype

Plasma Lipid Levels [mmol/L (mg/dL)] Isolated hypercholesterolemia

Lipoprotein Phenotype Clinical Signs Elevated

IIa Usually develop xanthomas in adulthood and vascular disease at 3050 years Usually develop xanthomas in adulthood and vascular disease in childhood

Familial Heterozygotes TC = LDL hypercholesterolemi 713 (275500) a Homozygotes TC >13 (>500) LDL

IIa

Familial defective Apo B-100

Heterozygotes TC = LDL 713 (275500) LDL

IIa IIa Usually asymptomatic until vascular disease develops; no xanthomas

Polygenic TC = 6.59 (250 hypercholesterolemi 350) a Isolated hypertriglyceridemia

Asymptomatic; may be associated with increased risk of vascular disease Familial LPL TG >8.5 (750) Chylomicron I, V May be asymptomatic; deficiency s, VLDL may be associated with pancreatitis, abdominal pain, hepatosplenomegaly DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Familial Apo C-II TG >8.5 (>750) Chylomicron I, V As above 48 Edition: http://www.accesspharmacy.com

Familial TG = 2.88.5 (250 VLDL hypertriglyceridemia 750)

IV

Lipid Phenotype Plasma Lipid Levels [mmol/L (mg/dL)]

Lipoprotein Elevated

Phenotype Clinical Signs

Hypertriglyceridemia and hypercholesterolemia Combined hyperlipidemia TG = 2.88.5 (250 750); TC = 6.513 (250500) VLDL, LDL IIb Usually asymptomatic until vascular disease develops; familial form may present as isolated high TG or isolated high LDL cholesterol

Dysbetalipoproteinemia

TG = 2.88.5 (250 750); TC = 6.513 (250500)

VLDL, IDL; LDL normal

III

Usually asymptomatic until vascular disease develops; may have palmar or tuboeruptive xanthomas

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

49

Many genetic abnormalities & environmental factors lead to lipoprotein abnormalities Current laboratory values can not define underlying abnormality 2 hyperlipidemia should be initially managed by correcting underlying abnormality when possible

50 50

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

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

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

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

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

Age Men: 45 years Women: 55 years or premature menopause without estrogen replacement therapy Family history of premature CHD (definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative, or before age 65 years in mother or other female first-degree relative) Cigarette smoking Hypertension (140/90 mm Hg or taking antihypertensive medication) Low HDL cholesterol (<40 mg/dL)b
aDiabetes

regarded as coronary heart disease (CHD) risk equivalent. bHDL cholesterol >60 mg/dL counts as "negative" risk factor; its presence removes one risk factor from the total count.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com
55

Athrogenesis

MVS 110: Lecture #11

1. Vasodilatory Endothelial Dysfunction: Brachial Ultrasound Flow-Mediated Dilation. 2. Atherosclerosis Burden/End-organ Damage: Carotid IMT, # plaques (based on carotid US), IVUS, EBCT, advanced CT, MRI 3. General Inflammatory Marker: hs-C Reactive Protein 4. Markers of Inflamed Endothelium: ICAM, VCAM, e-Selectin, vWf 5. Other: Homocysteine

L-Selectin, Integrins VCAMLDL E-Selectin, 1, P-Selectin ICAM-1

Monocyte

MCP-1

OxLDL
M-CSF Other inflammator y triggers

Intima

Macrophage Activation & Division

Media
Libby et al. Circulation 2002;105:1135-1143.

Smooth Muscle Cell Migration

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. By activating the nuclear factor B (NFB) transcription factor, oxidized LDL (oxLDL) stimulates increased expression of cellular adhesion molecules. There are several different types of adhesion molecules with specific functions in the endothelialleukocyte interaction: The selectins tether and trap monocytes and other leukocytes. Importantly, vascular cell adhesion molecules (VCAMs) and intercellular adhesion molecules (ICAMs) mediate firm attachment of these leukocytes to the endothelial layer.

OxLDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophagecolony stimulating factor (M-CSF). 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 a sequence that leads to formation of a fibrous atheroma.

Proinflammatory Risk Factors

Primary Pro-inflamatory Cytokines (eg, IL-1, TNF-a)

ICAM-1 Selectins, HSPs, etc. Endothelium and other cells

IL-6 Messenger Cytokine

CRP SAA

Liver

Circulation
HSPs=heat shock proteins; SAA=serum amyloid-A. Adapted from Libby and Ridker. Circulation. 1999;100:1148-1150.

 Total

cholesterol: <200 mg/dL LDL cholesterol: <130 mg/dL HDL cholesterol: >35 mg/dL Triglycerides: <200 mg/dL Desirable Blood Cholesterol
Normal = < 200 mg/dl (5.2 mmol/L) Borderline = 200-239 mg/dl or (5.2-6mmol/L) Hypercholesterolemia>240 mg/dl or > 6mmol/L)

LDL-C = (Past) < 130 mg/dl (2001 < 100)

LDL-C=total cholesterol - (HDL-C + .2TG) HDL-C = (Past) >35 mg/dl (2001) > 40) HDL-C = > 60 mg/dl will negate one risk factor

 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 Smoking Obesity Excessive food intake Stress

Risk factor modification

Hypertension Dyslipidaemia

Diabetes

Atherosclerosis

Atherosclerosis Arrhythmia

Chronic heart failure

Arterial & venous thrombosis/ cardiac & cerebral events

At least 3 of

Abdominal obesity: waist circumference > 102 cm (M)

> 88 cm (F) Hypertriglyceridemia > 150 mg/dl < 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)

Low HDL cholesterol< 40 mg/dl (M)

Central obesity

Insulin Resistance

Type 2 Diabetes

Dyslipidemia
Hypertension

Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease

Genetic variation

Environmental factors

Abdominal obesity
Adipokines Cytokines Inflammatory markers Insulin resistance Tg BP Metabolic syndrome HDL

Adipocyte

Monocyte/ macrophage

Atherosclerosis

Plaque rupture/thrombosis
Reilly & Rader 2003; Eckel et al 2005

Cardiovascular events

Treatment
NCEP ATP-III guidelines
Modification of lipids and major risk factors See Table 15.9

Medications
See Table 15.10

Procedures
Angioplasty CABG

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

Nutrition Therapy
Therapeutic Lifestyle Changes (TLC) developed as component of ATP-III
Modifications in fat, cholesterol Rich in fruits, vegetables, grains, fiber Limit sodium to 2400 mg Include stanol esters See the next Table for summary

Nutrient Intake

Recommended
< 7% of total calories Up to 10% of total Up to 20% of total 25-30% of total calories 50-60% of total calories 20-30 grams/day Approx. 15% of total

Saturated fat Polyunsaturated fat calories Monounsaturated fat calories Total fat Carbohydrates Fiber Protein calories Limit Cholesterol intake Total calories

*Avoid Trans Fats.

<200 mg/day Balance energy intake and expenditure to maintain desirable body weight/ prevent weight gain

Nutrition Therapy - Other

Increase sources of soluble fiber Increase intake of plant sterols Weight loss BMI 18.5-24.9 Regular physical activity

Coronary Angioplasty Coronary Bypass Surgery (CABG)

Fish Oil (source of omega-3 polyunsaturated fatty acids)

Salmon, flaxseed, canola oil, 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) 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), 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, nuts (esp. walnuts), green tea Overall a combination diet with multiple cholesterollowering agents causes much more significant LDL reductions Fiber: Decreases LDL; increases HDL Carrots/Grapefruit: Fiber and pectin (whole fruits most beneficial) Avocado: monounsaturated fat Beans: High in fiber, low fat; contain lecithin Phytosterols: sesame, safflower, spinach, okra, strawberries, squash, tomatoes, celery, ginger. Shiitake mushrooms: contain lentinan (25% reduction in animal studies) Garlic, onion oil: lowers chol. 10-33% Omega 3 fish oils Red Yeast Rice: a natural substance that inhibits HMGCoA reductase. Same ingredient in Lovastatin.