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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
Lipoproteins
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
Lipoproteins
Size (nm) 100-500 30-80
Lipids
Dietary TG Endogenous TG
Major Apoproteins
B-48,C-II,E B-100,C-II,E
Chylomicra VLDL
IDL
LDL HDL Lp (a)
25-50
18-28 5-15 25-30
B-100, E
B-100 A,C-II,E B-100 & glycoproteins
VLDL 22 52
IDL 35 20
LDL 47 9
HDL 19 3
9 82
Phospholipid
18
20
23
28
Functions of Chylomicrons
Chylomicron remnants
Lipoprotein particle that remains after a chylomicron has lost most of its fatty acids
Liver
Synthesizes & metabolizes lipids Central command center for relation of lipid metabolism Makes additional lipoproteins
Cholest AA FA P, glycerol
Vessel wall
Exogenous Intestine
(~1000 mg/day)
(~300700 mg/day)
Biliary cholesterol
~700 mg/day
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 low-cholesterol 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)
There are several steps involved in the absorption of cholesterol from the intestinal lumen.
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%)
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%)
Bad cholesterol; major lipid in LDL Delivers cholesterol from liver to cells
Protein (21%)
LDL receptors
Membrane-bound proteins that bind LDL, causing them to be taken up & dismantled
Increase LDL
Decrease LDL
SFAs
High PUFA diet -3 fatty acids Dietary fiber Lifestyle factors Genetics
IR impairs LDLR
Insulin resistance and decreased apo-B degradation
Insulin resistance and decreased LPL
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%)
HDL 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, and LDL Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively
Uncertain if low carbohydrate diets offer protection High MUFA intake Moderate alcohol consumption Lifestyle factors
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
Dyslipidemia Characteristics
Elevated triglycerides Post-prandial lipemia Small dense LDL (type B) Low HDL cholesterol
Liver
Insulin
LDL
Kidney
Dyslipidemia in Diabetes
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
Low HDL-cholesterol
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
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
CETP ABCA-1
Tangier Disease
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
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)
Athrogenesis
LDL is positively associated with CVD HDL is negatively associated with CVD
MCP-1
OxLDL
M-CSF Other inflammator y triggers
Intima
Media
Libby et al. Circulation 2002;105:1135-1143.
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
Hypertension Dyslipidaemia
Diabetes
Atherosclerosis
Arrhythmia
Central obesity
Insulin Resistanc e
Type 2 Diabetes
Dyslipidemi a Hypertension
Abdominal obesity
Adipokines Cytokines
Inflammatory markers Insulin resistance Tg BP Atherosclerosis Metabolic syndrome HDL
Adipocyte
Monocyte/ macrophage
Plaque rupture/thrombosis
Cardiovascular events
Diet Supplements
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 cholesterol-lowering agents causes much more significant LDL reductions