lipoprotein metabolism

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  • 1. Lecture 5: Lipoprotein Metabolism (pg 62-77)I. Digestive lipid metabolism A. Digestive System 1) Small intestine: digestion and absorption of lipids occur a. Break covalent bonds from polymer to monomer 2) Liver: houses and produces bile a. Bile- substance aiding in digesting fat i. Bile acid ii. Cholesterol iii. Bilirubin – byproduct of RBC destruction iv. Lecithin – transports fat in small intestine b. Gall bladder- stores bile B. Bile Salt 1) Cholesterol catabolism into bile salt a. Cholesterol (hydrophobic)  cholate or bile salt (amphipatic) i. Enzyme: cholesterol 7 -hydroxylase b. Bile salt can travel in small intestine (aqueous solution) 2) Functions a. Break down products of cholesterol and transport cholesterol in digestive system b. Lipid emulsification: Break down fat globules into smaller particles i. Packaging fat globules into micelles (amphipatic) to travel in lumen of SI ii. Allow pancreatic lipase to breakdown dietary fat within micelle c. Function of micelles i. Transport cholesterol from liver to intestine ii. Participate in fat digestion and absorption C. Cholesterol Absorption- only 50% get absorbed in bloodstream 1) Cholesterol transferred into enterocyte from lumen a. Enzyme: NPC1L (Niemann –Pick C1 Like) 2) In enterocyte, cholesterol converted into cholesteryl ester (more hydrophobic) a. Enzyme: ACAT (acetyl-coenzyme A acetyltransferase) b. CE combines with TG in enterocyte to form chylomicron c. Chylomicron absorbed into lymph system 3) Cholesterol can be pumped back out into lumen from enterocytes a. ABCG5- adenosine triphosphate binding cassette – ATP pump D. Triglyceride Digestion and Absorption 1) In lumen, pancreatic lipase breaks down TG  FA and monoglycerides (MG) w/in micelle a. Triglyceride = 3 FA + glycerol 2) FA/MG diffuse easily through lumen into enterocyte 3) W/in enterocyte, 2 FA + Monoglyceride converted into TG a. Enzyme: DGAT (diglycerol acyltransferase) b. This prevents FA from leaking back into lumen or circulation 4) Package TG and CE into chylomicrons which leaves by exocytosis a. Into interstitial space, then into lymph system, BV, liver E. Enterocyte Functions 1) Convert FA and MG into triglycerides 2) Convert free cholesterol into CEII. Cholesterol Balance A. Enterohepatic Circulation of Bile Salts 1) Liver makes 0.4 grams/day, releases 24 grams/day 2) Fecal excretion = 0.4 grams/day 3) >95% of biliary secretion- portal venous return to liver B. Biliary and Dietary Cholesterol 1) Liver secretes 2 grams/day 2) Dietary intake – 0.4 grams/day 3) Fetal excretion- 1.2 grams/day 4) Absorption is 50%, returns to liver C. Balance 1) Body loses 1.2 gram chol and 0.4 gram bile acid PER DAY a. Total loss=1.6 grams/day 2) Liver cholesterol synthesis: 1.6 grams – 0.4 grams (dietary cholesterol) = 1.2 grams/day
  • 2. III. Lipid and Lipoprotein Metabolism A. Chylomicrons- packages of dietary fat 1) Vehicles for transporting dietary lipids in plasma to body tissues 2) Originate in enterocytes, formed from exogenous TG a. Enter lymph system, thoracic duct, heart, coronary vessels 3) Contain: a. TG, cholesterol ester, phospholipids (PL) b. ApoB-48, ApoAI AI, ApoAII 4) Metabolism a. Nascent CM (inside enterocytes) i. Receives ApoC, ApoE, and cholesterol from HDL-2 ii. Gives ApoAI, ApoAII, and PL to HDL-2 iii. HDL function: donor and recipient of ApoC and ApoE to facilitate CMs b. CM (with ApoC and ApoE) unloads to i. Muscle (skeletal and cardiac) FA broken down for energy ii. Adipose tissue FA stored iii. Both use LPL (lipoprotein lipase) Bound to endothelial cells Breakdown TG into FA iv. ApoC: activates LDL v. ApoE: facilitates binding to inner wall of endo cells c. CM (with ApoC and ApoE) – after unloading TG i. Gives ApoC and ApoE back to HDL-2 d. CM remnant i. Liver uptakes via LRP (LDL Receptor like Protein) B. Very Low-Density Lipoproteins (VLDL) 1) Produced by the liver and made of endogenous TG a. Occurs within hepatocyte 2) Transport endogenous lipids to peripheral tissues 3) Contain: a. TG, free cholesterol, PL b. ApoB-100, ApoE, ApoAI, ApoAII 4) How its made in hepatocyte a. 2 Fatty Acid + Monoglyceride -> Triglyceride i. Enzyme: DGAT b. Free cholesterol -> Cholesterol ester (CE) i. Enzyme: ACAT ii. Free cholesterol (slight hydrophilic) – can bind to PL on membrane iii. CE- completely hydrophobic- can be locked inside lipoprotein c. TG + CE -> VLDL 5) Metabolism a. Nascent VLDL (from liver) i. Receives ApoC and ApoE from HDL-2 ii. Gives ApoAI, ApoAII and PL to HDL-2 b. Functional VLDL (with ApoC and ApoE) unloads TG to i. Muscle (skeletal and cardiac) ii. Adipose tissue iii. Both use LPL c. IDL (with ApoC and ApoE) – mostly cholesterol i. Gives ApoC, ApoE, and TG to HDL-2 ii. Receives CE via CETP from HDL-2 CETP (CE transfer protein) d. IDL i. IDL unloads more TG to liver Breakdown TG into FA with HTG1 (hepatic triglyceride lipase) e. LDL (mostly cholesterol because TG unloaded)- formed in blood i. Uptaken by liver via LDLR (LDL receptors) ii. Transports cholesterol to body tissue C. High Density Lipoprotein (HDL) 1) Made in liver and released into blood a. Moves in blood and picks up cholesterol
  • 3. b. HDL-3: functional HDL that collects cholesterol from tissue 2) Primary function is to retrieve and transport surplus chol from tissue back to liver a. Reverse transport pathway- counteracts and protects against atherosclerosis 3) Serves as a donor and acceptor for ApoE and ApoC for nascent and remnant chylomicrons and VLDL 4) Principal Lipoproteins: ApoAI and ApoAII a. Produced by liver/intestine and secreted with CM and VLDL b. Dissociate from CM/VLDL as phospholipids complex c. Combine to form nascent HDL 5) Metabolism a. Nascent HDL (with ApoAI and ApoAII) b. HDL-3 (ApoAI, ApoAII, ApoC, and ApoE) i. Receives FC and PL from tissue ABCA-1- Apolipoprotein binding cassette A1 c. HDL-3 (all Apos plus FC) i. LCAT- enzyme that converts FC into CE that will be locked inside HDL ii. Ensures constant unloading d. HDL-2 (all Apos) i. Exchange of ApoC and ApoE with VLDL or CM ii. Unloads CE and TG into liver SRB-1 (Scavenger receptor B1) ApoAI helps binding Hepatic lipase (HL) ApoAII activates HL so TG can be taken into liverIV. HDL and Coronary Artery Disease A. HDL 1) Structure: a. Surface monolayer of PL and free cholesterol (FC) b. Hydrophobic Core of TG and CE c. ApoAI and ApoAII 2) Heterogeneity a. Particle shape i. Discoidal ii. Spherical b. Apolipoprotein Composition i. A-I HDL ii. A-I/A-II HDL iii. A-II HDL c. Particle Size i. HDL2b, HDL2a ii. HDL3a, HDL3b, HDL3c d. Lipid Composition i. TG, CE and PL 3) HDL is a major factor in predicating CAD/CHD a. Increase in HDL decreases incidence of CHD b. Low HDL levels increase CHD Risk even if total C normal (Framingham) c. High total C/HDL ratio increases risk of CHD (Framingham) d. Low HDL levels independent predictor of CHD even when LDL low 4) Summary a. Low HDL (<40) occur in 40-60% of CHD patients i. CDH risk even if total C is below 200 when HDL < 40 b. Hypertriglyceridemia/elevated LDL level increase CHD risk in low HDL patients c. Smoking, hypertension and diabetes increase CDH risk in low HDL patients B. HDL and Atherosclerosis 1) HDL Characteristics – antioxidant effect a. Decrease LDL oxidation (plaque formation) b. Decrease Endothelial VCAM-1 production, HDL3>HDL2 (anti-inflammatory) c. Decrease platelet aggregation (or clotting), HDL3 d. Increase cholesterol efflux and reverse transport i. Takes cholesterol from LDL e. Decrease endothelial apoptosis (natural cell death) f. Decrease LDL uptake in subendothelial space
  • 4. g. Enzymes in HDL: (both antioxidants) i. Platelet-activating factor acetylhydrolase (PAF-AH) ii. Paraoxanase (PON) 2) HDL prevents formation of foam cells by promoting cholesterol efflux a. HDL decreases binding of monocytes b. Acute phase HDL- HDL overwhelmed by too much LDL i. No effect on monocyte binding 3) HDL inhibits oxidative modification of LDL: Role of PON a. PON is transported in plasma as component of HDL b. Accounts for proportion of antioxidant properties of HDL 4) HDL Apolipoproteins Remove Oxidized Lipids from LDL a. Oxidized lipids in HDL reduced by HDL apoLP (repair cholesterol) b. Liver takes up reduced lipids from HDL more rapidly than from LDL i. Easier for liver to uptake reduced cholesterol 5) HDL inhibit adhesion molecule expression (VCAM-1): effect of HDL Composition a. Unaffected by replacing ApoAI with ApoAII b. Unaffected by varying cholesterol ester or TG content of HDL c. Affected by varying HDL phospholipids 6) HDL Anti-inflammatory Properties a. HDL binds and neutralizes proinfl. lipopolysaccharides b. SAA (serum amyloid A)- acute phase reactant (inflammatory) binds to plasma HDL with possibly neutralizes SAA effectsC. Studies 1) Treatments that reduce LDL reduce C-reactive protein and soluble adhesion molecules 2) Normal Levels of HDL not protective in patients with CAD a. HDL less effective in patients with CAD b. Deficient in PON c. Doesn’t protect LDL From oxidation d. Doesn’t inhibit biological activity of oxidized PL e. Doesn’t prevent foam cell formation 3) Quality of HDL important a. HDL inflammatory when added to LDL b. Inflammatory /anti-inflam properties of HDL better predictor than HDL level 4) Summary a. LDL subject to pro-infl modifications so contribute to AS b. HDL have anti-infl properties that help protect against ASD. Conclusions 1) Strategies reducing pro-inflammatory modifications to LDL may reduce AS 2) Strategies increasing anti-inflammatory properties of HDL may reduce AS 3) Need more research to see if pharmacological increase in HDL is anti-infl and reduce ASE. HDL Metabolism as a Therapeutic Target: Potential Strategies 1) Increase ApoAI production by Liver and Intestine a. ApoAI reverses cholesterol pathway b. Increased ApoAI reduces AS in animals i. Reduced initiation and progression of AS ii. Regression of preexisting AS 2) Promote reverse cholesterol transport a. Overexpression of LCAT prevents development of AS 3) Other mechanisms a. Antioxidant effects b. Inhibition of adhesion molecule expression c. Inhibition of platelet activation d. Prostacyclin stabilization e. Promotion of NO production 4) Genes involved in HDL metabolism a. HDL associated apoLP i. ApoAI b. HDL modifying plasma enzymes and transfer proteins i. LCAT ii. LPL iii. CETP iv. HL- hepatic lipase c. Cellular and cell-surface proteins that influence HDL metabolism i. SR-B1
  • 5. 5) Delay Catabolism of HDL a. Hepatic lipase- convert IDL to LDL i. Deficiency leads to elevated HDL levels b. CETP- Cholesteryl ester transfer protein i. Plasma protein that collects TG from VLDL or LDL and exchanges them for CE from HDL and vice versa ii. Pharmacological inhibition of CETP is being studied as a method of improving HDL levels iii. Decreases catabolism of HDL 6) Summary a. HDL metabolism is complex b. HDL and ApoAI levels determined by production and catabolic rates c. Rates of reverse cholesterol transport can’t be determined solely by HDL and ApoAI levels d. Effect of genetic defects or interventions that alter HDL metabolism on AS depend on specific metabolic effects on HDL i. Genes and proteins involved in HDL metabolism are potential targets for therapiesV. Lipid Lowering Treatments A. Atherogenic Particles 1) ApoB 2) Non HDL Cholesterol B. Treatment categories: LDL Goals and Cut points 1) More than 2 risk factors: a. 10yr risk: 10-20% i. LDL goal: <130 ii. Drug therapy: >130 b. 10yr risk: less than 10% i. LDL goal: <130 ii. Drug therapy: >160 2) Less than 2 risk factors i. LDL goal: <160 ii. Drug therapy: >190 C. Drug Therapy: 4 Major Types 1) Bile acid sequesterants: a. Bind to bile and both are excreted, so less chol is reabsorbed b. Reduces liver cholesterol pool b/c make more bile c. Ex: Cholestipol (side effects: bloating, GI distress) 2) HMG-CoA reductase inhibitors a. Inhibits liver’s production of cholesterol b. Liver increases production of LDL-Receptor and more cholesterol is removed from blood c. Ex: statins (lovastatin) 3) Nicotinic Acid (Niacin) a. Inhibit liver production of VLDL (source of LDL)  LDL decreases b. Increases HDL and decreases TG 4) Fibric acid derivatives a. Increase peripheral lipolysis (breakdown of fat) b. Decreases hepatic TG production c. Affects LPL and ApoC-III (inhibits LDL) i. enhances catabolism of TG rich lipoproteins d. Increase in FA oxidation decreases formation of VLDL-TG D. Statins: Inhibitors of Cholesterol Synthesis 1) Mechanism a. Decreases hepatic cholesterol synthesis  lowers intracellular cholesterol b. Stimulates up-regulation of LDL receptor and uptakes of non-HDL particles from systemic circulation (LDL receptor synthesis) c. Decreases production of cholesterol by inhibiting HMG-CoA Reductase 2) Effects a. Increases LDL receptor mediated hepatic uptake of LDL and VLDL remnants b. Decreases serum LDL, VLDL remnants and IDL c. Promotes LDL clearance 3) Studies- a. Statin causes decreases in total chol, TG, LDL, increases HDL b. Decrease major coronary events and call cause mortality E. Bile Acid Resins
  • 6. 1) Mechanism: a. Increase Bile Acid excretion- decreases reabsorption of BA b. Increases LDL receptors in liver i. Increases VLDL and LDL removal c. Increases cholesterol 7- hydroxylase and conversion of cholesterol to BA i. Increases BA secretion d. NET EFFECT: decrease LDLF. Nicotinic Acid 1) Mechanism a. Mobilization of free fatty acids b. Decreases TG synthesis in liver and VLDL secretion c. Decreased serum VLDL  reduced lipolysis to LDL  decreases serum LDL d. Increases HDL in systemic circulation and decreases TG 2) NET EFFECT: decreases hepatic production of VLDL and ApoB