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Lipoproteins
- 1. Lipoproteins Presented by: Farhad Jahanfar
- 2. Lecture Outline What are lipoproteins? What do they do Basic structure of lipoproteins Lipoprotein metabolism Cholesterol homeostasis Development of atherosclerosis Role of lipoproteins in atherosclerosis Role of diet in atherosclerosis prevention
- 4. What are lipoproteins? Lipoproteins are protein-lipid complexes.
- 5. The Players – Lipids Triacylglycerol Phospholipids Cholesterol Cholesteryl esters
- 6. What are lipoproteins? Hydrophobic lipids (TG, CE) in core; Hydrophilic lipids (UC, PL) on surface
- 7. The Players - Apolipoproteins Apo AI (liver, small intestine) Structural; activator of lecithin:cholesterol acyltransferase (LCAT) Apo AII (liver) Structural; inhibitor of hepatic lipase; component of ligand for HDL binding Apo A-IV (small intestine) Activator of LCAT; modulator of lipoprotein lipase (LPL) Apo A-V (liver) Direct functional role is unknown; regulates TG levels.
- 8. Apolipoproteins Apo B-100 (liver) Structural; synthesis of VLDL; ligand for LDL- receptor Apo B-48 (small intestine) Structural; synthesis of chylomicrons; derived from apo B-100 mRNA following specific mRNA editing Apo E (liver, macrophages, brain) Ligand for apoE receptor; mobilization of cellular cholesterol
- 9. Apolipoproteins Apo C-I (liver) Activator of LCAT, inhibitor of hepatic TGRL uptake Apo C-II (liver) Activator of LPL, inhibitor of hepatic TGRL uptake Apo C-III (liver) Inhibitor of LPL, inhibitor of hepatic TGRL uptake
- 10. What do lipoproteins do? Serve to transport lipid-soluble compounds between tissues Substrates for energy metabolism (TG) Essential components for cells (PL, UC) Precursors for hormones Precursors for eicosanoids Lipid soluble vitamins Precursors for bile acids
- 11. Lipoprotein Classes Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000; 149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. HDLHDLLDLLDLChylomicrons,Chylomicrons, VLDL, andVLDL, and their catabolictheir catabolic remnantsremnants > 30 nm> 30 nm 20–22 nm20–22 nm 9–15 nm9–15 nm D<1.006 g/ml D=1.019-1.063g/ml D=1.063-1.21 g/ml Lipids Online
- 12. Surface MonolayerSurface Monolayer Phospholipids (5%)Phospholipids (5%) Free Cholesterol (1%)Free Cholesterol (1%) Protein (1%)Protein (1%) Hydrophobic CoreHydrophobic Core Triglyceride (93%)Triglyceride (93%) Cholesteryl Esters (1%)Cholesteryl Esters (1%) TG Rich: Chylomicrons Cholesterol and Atherosclerosis, Grundy)
- 13. Surface MonolayerSurface Monolayer Phospholipids (12%)Phospholipids (12%) Free Cholesterol (14%)Free Cholesterol (14%) Protein (4%)Protein (4%) Hydrophobic CoreHydrophobic Core Triglyceride (65%)Triglyceride (65%) Cholesteryl Esters (8%)Cholesteryl Esters (8%) TG Rich: VLDL Cholesterol and Atherosclerosis, Grundy)
- 14. Surface MonolayerSurface Monolayer Phospholipids (25%)Phospholipids (25%) Free Cholesterol (15%)Free Cholesterol (15%) Protein (22%)Protein (22%) Hydrophobic CoreHydrophobic Core Triglyceride (5%)Triglyceride (5%) Cholesteryl Esters (35%)Cholesteryl Esters (35%) CE Rich: LDL Cholesterol and Atherosclerosis, Grundy)
- 15. Surface MonolayerSurface Monolayer Phospholipids (25%)Phospholipids (25%) Free Cholesterol (7%)Free Cholesterol (7%) Protein (45%)Protein (45%) Hydrophobic CoreHydrophobic Core Triglyceride (5%)Triglyceride (5%) Cholesteryl Esters (18%)Cholesteryl Esters (18%) CE Rich: HDL Cholesterol and Atherosclerosis, Grundy)
- 16. Chylomicron Metabolism Cholesterol and Atherosclerosis, Grundy) Long-chain fatty acids are re-esterified into triacylglycerols in the gut and transferred; chylomicrons which contain apoB48 are synthesized and secreted into the blood via the lymphatic circulation
- 17. Chylomicron Metabolism Cholesterol and Atherosclerosis, Grundy) ApoC’s, apoE and cholesteryl esters are acquired from HDL in circulation. ApoA-I and apoA-IV may be acquired from either the intestine or from HDL in circulation.
- 18. Chylomicron Metabolism Cholesterol and Atherosclerosis, Grundy) ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of triacylglycerols
- 19. Chylomicron Metabolism Cholesterol and Atherosclerosis, Grundy) Apolipoproteins are transferred back to HDL
- 20. Chylomicron Metabolism Cholesterol and Atherosclerosis, Grundy) The chylomicron remnant is taken up by the apoB48/remnant receptor in the liver
- 21. Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport
- 22. VLDL Biogenesis Cholesterol and Atherosclerosis, Grundy) Microsomal TG transfer protein (MTP) Facilitates the translocation, folding of apoB and addition of lipids to lipid binding domains TG and cholesterol are synthesized in the liver as VLDL which contains apoB- 100
- 23. VLDL Metabolism Cholesterol and Atherosclerosis, Grundy) Apo C’s and apoE and cholesteryl ester are acquired from HDL in circulation
- 24. Fatty Acid Transport Cholesterol and Atherosclerosis, Grundy) ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of TG
- 25. VLDL Metabolism Cholesterol and Atherosclerosis, Grundy) Apolipoproteins are transferred back to HDL The end product is a VLDL remnant (IDL)
- 26. VLDL Remnant Uptake Cholesterol and Atherosclerosis, Grundy) The remnant particle (IDL), if it contains apoE, can be taken up by the apoE/remanant receptor
- 27. VLDL Conversion to LDL Cholesterol and Atherosclerosis, Grundy) Further action on IDL by hepatic lipase loses additional apolipoproteins (apoE) becomes and is converted to LDL
- 28. LDL Metabolism Cholesterol and Atherosclerosis, Grundy) Hepatic Lipase Cholesteryl ester transfer protein LDL is removed by apoB100 receptors which are mainly expressed in the liver
- 29. LDL Uptake by Tissues Cholesterol and Atherosclerosis, Grundy) Defects in the LDL receptor leads to familial hypercholesterolemia X X
- 30. Corneal arcus
- 31. Tendon xanthoma
- 32. Tendon xanthoma
- 33. Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport
- 34. HDL Subpopulations Rye KA et al. Atherosclerosis 1999;145:227-238. Apolipoprotein CompositionApolipoprotein Composition A-I HDLA-I HDL A-I/A-IIA-I/A-II HDLHDL A-II HDLA-II HDL Particle ShapeParticle Shape DiscoidalDiscoidal SphericalSpherical Lipid CompositionLipid Composition TG, CE, and PLTG, CE, and PL Particle SizeParticle Size HDLHDL2b2b HDLHDL2a2a HDLHDL3a3a HDLHDL3b3b HDLHDL3c3c Lipids Online
- 35. HDL Maturation Cholesterol and Atherosclerosis, Grundy) HDL is secreted in a discoidal form from the liver and gut. As it acquires cholesterol from tissues in the circulation, it matures into a spherical form through the action of lecithin:cholesterol acyl transferase
- 36. HDL Metabolism Nascent HDL (lipid-poor apoA-I) is produced by the liver and intestine
- 37. HDL Metabolism Free cholesterol is acquired from peripheral tissues
- 38. HDL Metabolism LCAT converts free cholesterol to cholesteryl esters
- 39. HDL Metabolism A variety of enzymes interconvert HDL subspecies
- 42. HDL Metabolism Cholesteryl esters can be selectively taken up via SR-BI
- 43. HDL Metabolism HDL particles can be taken up by a receptor-mediated process
- 44. HDL Metabolism Lipid-poor apoA-I can be removed by the kidney
- 48. Hepatic Cholesterol Synthesis Cholesterol and Atherosaclerosis, Grundy) Rate Limiting Only pathway for cholesterol degradation Energetically expensive; prefer to conserve what is already made/acquired – LDL receptor pathway
- 49. LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy) LDL are taken up by the LDL Receptor into clathrin-coated pits
- 50. LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy) LDL dissociates from the receptor; the receptor recycles to the membrane
- 51. LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy) In the lysosome, lipids are deseterified; proteins are hydrolyzed
- 52. LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy) Increase in free cholesterol regulates decrease cholesterol synthesis and uptake; increase cholesterol esterification
- 53. ↓↓ X X X Sterol Regulatory Element Binding Proteins and Cellular Cholesterol Metabolism SREBP Cleavage Activating Protein
- 55. Intestinal Cholesterol Metabolism Schmitz et al, JLR 2001
- 56. Intestinal Cholesterol Metabolism Schmitz et al, JLR 2001 Lipids are absorbed from the intestine via a micellar transport process
- 57. Intestinal Cholesterol Metabolism Schmitz et al, JLR 2001 Liberated unesterified cholesterol and plant sterols are transported back into the lumen via ATP-binding cassette (ABC) proteins G5 and G8 (heterodimers) Defects in ABCG5 or ABCG8 leads to sitosterolemia
- 58. Role of LXR and FXR When cholesterol accumulates in cells, cholesterol is oxidized to create oxysterols
- 59. Role of LXR and FXR Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis
- 60. Role of LXR and FXR In the intestine, LXR also activates ABC-1 to remove cholesterol
- 61. Role of LXR and FXR In the intestine, FXR activates expression of I- BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion.
- 62. Role of LXR and FXR The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids.
- 65. Reverse Cholesterol Transport - Peripheral Cells Von Eckardstein et al, ATVB 2001 Aqueous Diffusion: Slow, unregulated, dictated by membrane composition
- 66. Reverse Cholesterol Transport - Peripheral Cells Von Eckardstein et al, ATVB 2001 SR-BI: Binding of HDL to SR- BI leads to reorganization of cholesterol within the plasma membrane and facilitates cholesterol efflux
- 67. Reverse Cholesterol Transport - Peripheral Cells Von Eckardstein et al, ATVB 2001 ABC1: Fast and involves the translocation of cholesterol from intracellular compartments to the plasma membrane via signal transduction processes
- 68. Reverse Cholesterol Transport - Intravascular and Liver TALL et al, ATVB 2000
- 70. Evolution and Progression of Coronary Atherosclerosis I ntimal I njury Fatty Streak Lipid- Rich Plaque Plaque Disruption Thrombus Lysis Response Fibromuscular O cclusion O cclusive Thrombus 0 20 40 50 60 Age (years ) Atherogenic Ris k Fac tors Thrombogenic Ris k Fac tors Adapted from Fuster, 1992
- 71. Endothelial Dysfunction Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin. Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc). Up-regulation of endothelial adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1). Migration of leukocytes into artery wall mediated by oxLDL, MCP-1, IL-8, PDGF, M-CSF. Ross, NEJM; 1999
- 72. Formation of Fatty Streak SMC migration stimulated by PDGF, FGF-2, TGF-B T-Cell activation mediated by TNF-a, IL-2, GM-CSF. Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M-CSF. Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF. Ross, NEJM; 1999
- 73. Formation of Advanced, Complicated Lesion Fibrous cap forms in response to injury to wall off lesion from lumen. Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core. Lesions expand at shoulders by means of continued leukocyte adhesion and entry. Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation. Ross, NEJM; 1999
- 74. Development of Unstable Fibrous Plaque Rupture or ulceration of fibrous cap rapidly leads to thrombosis. Occurs primarily at sites of thinning of the fibrous cap. Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes. These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation Ross, NEJM; 1999
- 75. Plaque Rupture with Thrombus Thrombus Fibrous cap 1 mm Lipid core Illustration courtesy of Frederick J. Schoen, M.D., Ph.D. Lipids Online
- 76. Growth Factors and Cytokines Involved in Atherosclerosis Growth Factor/Cytokine Abbr. Source Target Epidermal growth factor EGF P EC, SMC Acidic fibroblast growth factor aFGF EC ,M, SMC EC Basic fibroblast growth factor bFGF EC ,M, SMC EC, SMC Granulocyte macrophage colony stimulating factor GM-CSF EC ,M, SMC, T EC, M Heparin-binding EGF-like growth factor HB-EGF EC ,M, SMC SMC Insulin-like growth factor-I IGF-I EC ,M, SMC, P EC, SMC Interferon λ IFN-λ T, M SMC Interleukin–1 IL-1 P, EC, M, SMC, T EC, M, SMC Interleukin-2 IL-2 T EC, M, T Interleukin-8 IL-8 EC ,M, SMC, T EC, T Macrophage colony stimulating factor M-CSF EC ,M, SMC, T M Monocyte chemotactic protein-1 MCP-1 EC ,M, SMC M Platelet-derived growth factor PDGF EC ,M, SMC, P EC, M, SMC RANTES SIS T M, T Transforming growth factor-α TGF-α M EC Transforming growth factor-β TGF-β EC ,M, SMC, T, P M, SMC Tumor necrosis factor-α TNF-α EC ,M, SMC, T EC Tumor necrosis factor-β TNF-β T EC, M, SMC Vascular endotholelial growth factor VEGF EC ,M, SMC EC
- 77. Role of Lipoproteins in Atherosclerosis
- 78. CHD Mortality is Correlated with Plasma Cholesterol Levels LaRosa et al, 1990 140 160 180 200 220 240 260 280 300 Plasma Cholesterol (mg/dl) 0 2 4 6 8 10 12 14 16 18 CHDDeathRate/1000 Six Year CHD Mortality from MRFIT Desirable Borderline High HIGH
- 79. Role of LDL in Atherosclerosis Steinberg D et al. N Engl J Med 1989;320:915-924. EndotheliumEndothelium Vessel LumenVessel Lumen LDLLDL LDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be Modified LDLLDL IntimaIntima Modified LDLModified LDL Modified LDL are ProinflammatoryModified LDL are Proinflammatory Hydrolysis of PhosphatidylcholineHydrolysis of Phosphatidylcholine to Lysophosphatidylcholineto Lysophosphatidylcholine Other Chemical ModificationsOther Chemical Modifications Oxidation of LipidsOxidation of Lipids and ApoBand ApoB AggregationAggregation Lipids Online
- 80. Role of LDL in Atherosclerosis LDLLDL LDLLDL Navab M et al. J Clin Invest 1991;88:2039-2046. EndotheliumEndothelium Vessel LumenVessel Lumen IntimaIntima MonocyteMonocyte Modified LDLModified LDL MCP-1MCP-1 Lipids Online
- 81. Role of LDL in Atherosclerosis LDLLDL LDLLDL Steinberg D et al. N Engl J Med 1989;320:915-924. EndotheliumEndothelium Vessel LumenVessel Lumen IntimaIntima MonocyteMonocyte Modified LDLModified LDL Modified LDL PromoteModified LDL Promote Differentiation ofDifferentiation of Monocytes intoMonocytes into MacrophagesMacrophages MCP-1MCP-1 MacrophageMacrophage Lipids Online
- 82. Role of LDL in Atherosclerosis LDLLDL LDLLDL Nathan CF. J Clin Invest 1987;79:319-326. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines IntimaIntima Lipids Online
- 83. Role of LDL in Atherosclerosis LDLLDL LDLLDL EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules Steinberg D et al. N Engl J Med 1989;320:915-924. Foam CellFoam Cell Modified LDLModified LDL Taken up byTaken up by MacrophageMacrophage IntimaIntima Lipids Online
- 84. Role of LDL in Atherosclerosis EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte MacrophageMacrophage MCP-1MCP-1AdhesionAdhesion MoleculesMolecules Foam CellFoam Cell IntimaIntimaModifiedModified RemnantsRemnantsCytokinesCytokines Cell ProliferationCell Proliferation Matrix DegradationMatrix Degradation Doi H et al. Circulation 2000;102:670-676. Growth FactorsGrowth Factors MetalloproteinasesMetalloproteinases Remnant LipoproteinsRemnant Lipoproteins RemnantsRemnants Lipids Online
- 85. HDL is Protective 110 30 21 0 20 40 60 80 100 120 < 35 35–55 > 55 Incidence per1,000(in6years) HDL-C (mg/dL) Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993 186 events in 4,407 men (aged 40–65 y) Lipids Online
- 86. HDL Prevent Foam Cell Formation LDLLDL LDLLDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux FoamFoam CellCell Lipids Online
- 87. HDL Inhibits Oxidative Modification of LDL LDLLDL LDLLDL Mackness MI et al. Biochem J 1993;294:829-834. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines FoamFoam CellCell HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux IntimaIntima HDL InhibitHDL Inhibit OxidationOxidation of LDLof LDL Lipids Online
- 88. HDL Inhibits Expression of Adhesion Molecules LDLLDL LDLLDL Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. EndotheliumEndothelium Vessel LumenVessel Lumen MonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines IntimaIntima HDL InhibitHDL Inhibit OxidationOxidation of LDLof LDL HDL Inhibit Adhesion Molecule ExpressionHDL Inhibit Adhesion Molecule Expression FoamFoam CellCell HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux Lipids Online
- 89. Suggested Risk Factors for CVD LDL Oxidation LDL-C Anti-OxLDL OxLDL LDL Oxid. Lag Time Negative LDL HDL-C Paraoxonase PAF acetylhydrolase F2-Isoprostanes TBARS ORAC Breath Ethane Endothelial Injury Triglycerides/VLDL Non-HDL-C apoA-1/apoB HDL-2/HDL-3 LDL size Postprandial TG IDL Chylo. Remnants Blood Pressure Homocysteine Thrombi Formation Factor VII Fibrinogen PAI-1 Factor VII Tissue Plasminogen Activator D-Dimer Plasmin-Antiplasmin Complex Prothrombin Fragment 1+2 Platelet Activation Inflammatory Response C-Reactive Protein IL-6 Lp-PLA2 Endothelial Dysfunction von Willibrand’s Factor P-Selectin sICAM-1 sVCAM-2 Assymetric Dimethyl Arginine Nitrate/Nitrite Plaque Instability Plasma Metaloproteinase-9
- 90. Diet, Lipoproteins and CVD
- 91. Seven Countries Study: CHD Events are Correlated with Saturated Fat 0 5 10 15 20 % Calories from S aturated F at 0 1 2 3 4 5 CHDDeathsandMI/100 R = 0.84 V M C D G S W B Z U N E K Keys, 1970
- 92. Step 1 St ep 2 - 20 - 15 - 10 - 5 0 ³TC,mg/dl Total Cholesterol DAI RY DELTA Step 1 St ep 2 - 16 - 12 - 8 - 4 0 ³LDL-C,mg/dl LDL Cholesterol DAI RY DELTA Step 1 St ep 2 0 5 10 15 20 ³TG,mg/dl Triglycerides DAI RY DELTA Step 1 St ep 2 - 6 - 4 - 2 0 ³HDL-C,mg/dl HDL Cholesterol DAI RY DELTA Changes in Lipids with Step 1 and Step 2 Diets
- 93. Regression Equations Have Been Developed to Predict Average Lipid Responses to Dietary Changes Keys (1965) ∆TC = 1.35* (2*∆S - ∆P) + 1.52*∆Z Hegsted (1965) ∆TC = 2.16*∆S - 1.65*∆P + 0.067*∆C - 0.53 Mensink (1992) ∆TC = 1.51*∆S - 0.12*∆M - 0.60*∆P Hegsted (1993) ∆TC = 2.10*∆S - 1.16*∆P + 0.067*∆C Yu (1995) ∆TC = 2.02*∆c12:0-c16:0 - 0.03*∆c18:0 - 0.48*∆M - 0.96*∆P Howell (1997) ∆TC = 1.918*∆S - 0.900*∆P + 0.0222*∆C
- 94. Newer Equations Can Accurately Predict Population Response to Changes in Dietary Fat -8.7% Milkfat -13.1% Milkfat % Kcal Reduction in Milkfat 0 5 10 15 20 25 ³Cholesterol(mg/dl) Obs erve Howell Hegs ted Mens ink Keys
- 95. Dietary Mechanisms to Lower LDL Reduce cholesterol intake Increase ACAT activity (↓SFA) Inhibit cholesterol absorption (plant sterols) Inhibit bile acid uptake (soluble fibers) Inhibit HMGCoA-reductase (tocotrienols) Inhibit FXR activation (guggelsterone)
- 96. Fibrinogen: Upper tertile for fibrinogen associated with 2.3-fold increase in risk for myocardial infarction. Factor VII: 25% increase in factor VIIc is associated with a 55% increase in risk of a fatal CHD events within 5 years. Thrombogenic Risk Factors May be as Important as Lipid Risk Factors
- 97. Changes in Hemostasis Factors with Step 1 and Step 2 Diets Step 1 Step 2 -6 -4 -2 0 ³FactorVII,% Factor VII DAIRY DEL TA Step 1 Step 2 0 3 6 9 12 15 ³Fibrinogen,mg/dl Fibrinogen DAIRY DEL TA
- 98. Dietary Components and CHD Risk Summary of the Nurses’ Health Study Vit E (Supplement vs no Supplement) Margarine (<1 tsp/mo vs >4 tsp/d) Alcohol (1 drink/d vs none) Nuts (5 servings/wk vs almost never) Folic Acid (>545 ug/d vs <190 ug/d) Fiber (23g/d vs 12 g/d) Whole grains (>1.7 serv vs <0.25 serv) Eggs (<1/wk vs >1/d) Saturated Fat (10.7% vs 18.8%) Total Fat (29.1% vs 46.1%) -60 -50 -40 -30 -20 -10 0 10 20 Percent Change in CHDRis k Fruit (3.8 serv vs 0.6 serv) Vegetables (6.8 serv vs 1.5 serv)
- 99. Thanks
Editor's Notes
- Inner droplet of neutral (water-insoluble core lipids); primarily triglycerides and cholesteryl esters A solubilizing surface layer of phospholipids and unesterified cholesterol Specific proteins (apolipoproteins) attached to the outer lipid layer through their specific lipophilic domains
- Inner droplet of neutral (water-insoluble core lipids); primarily triglycerides and cholesteryl esters A solubilizing surface layer of phospholipids and unesterified cholesterol Specific proteins (apolipoproteins) attached to the outer lipid layer through their specific lipophilic domains
- Lipoproteins are classified into four groups which differ primarily in the amounts of cholesterol, trigyleride, phospholipids, and types of apolipoproteins they contain Original classification was a function of hydrated density.
- Chylomicrons are the largest lipoproteins and contain &gt;90% triglycerides Are synthesized by the intestine Transport dietary fat to peripheral tissues for metabolism or storage
- VLDL contain 60-70% triglycerides Produced by the liver Transport endogenously synthesized triglycerides to peripheral tissues
- Major cholesterol carrying lipoprotein 2/3 - 3/4 of serum cholesterol is carried by LDL 50% of mass is cholesterol Produced as a product of VLDL metabolism Delivers cholesterol to peripheral tissues for biosynthesis and steroid hormone production
- Smallest of the lipoproteins Synthesized by intestine and liver as nascent cholesterol-poor lipoprotein Accumulates cholesterol and cholesteryl esters through interactions with peripheral cells and other lipoproteins Participates in reverse cholesterol transport, removal of excess cholesterol from peripheral cells and delivery to the liver for metabolism
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Pathways involved in the generation and conversion of HDL. Mature HDL3 and HDL2 are generated from lipid-free apoA-I or lipid-poor pre-ß1-HDL as the precursors. These precursors are produced as nascent HDL by the liver or intestine or are released from lipolysed VLDL and chylomicrons or by interconversion of HDL3 and HDL2. ABC1-mediated lipid efflux from cells is important for initial lipidation; LCAT-mediated esterification of cholesterol generates spherical particles that continue to grow on ongoing cholesterol esterification and PLTP-mediated particle fusion and surface remnant transfer. Larger HDL2 particles are converted into smaller HDL3 particles on CETP-mediated export of cholesteryl esters from HDL onto apoB-containing lipoproteins, on SR-BI–mediated selective uptake of cholesteryl esters into liver and steroidogenic organs, and on HL- and EL-mediated hydrolysis of phospholipids. HDL lipids are catabolized either separately from HDL proteins (ie, by selective uptake or via CETP transfer) or together with HDL proteins (ie, via uptake through as-yet-unknown HDL receptors or apoE receptors). The conversion of HDL2 into HDL3 and the PLTP-mediated conversion of HDL3 into HDL2 liberated lipid-free or poorly lipidated apoA-I. A part of lipid-free apoA-I undergoes glomerular filtration in the kidney and tubular readsorption through cubilin. For further details, see text and Table 1 . Blue arrows represent lipid transfer processes, and red arrows represent protein transfer processes. TGRL indicates triglyceride-rich lipoproteins
- Sterol-regulatory element binding proteins (SREBPs) play a key role in transcriptional regulation of cholesterol metabolism in response to cholesterol levels in the cell. When cholesterol is abundant in the cell, the SREBPs are retained in the ER. When cholesterol levels decrease, SREBPs are cleaved and released to act as transcription factors, binding to the promoters of genes such as the LDL receptor and HMG CoA Synthase. Binding of SREBPs to the LDL receptor promoter increases the expression of LDL receptor on the cell surface and increases the internalization of LDL from plasma, increasing cellular cholesterol levels and lowering LDL cholesterol in the plasma. Upregulation of genes such as HMG CoA synthase increases the biosynthesis of cholesterol. The SREBP proteins are cleaved and activated by two proteases, S1P (Site 1 protease) and S2P (Site 2 protease). S1P cleaves SREBP region in the ER lumen and S2P cleaves in the transmembrane region of SREBPs. Regulation by sterols is provided by SCAP. SCAP activates S1P when sterols are low, inducing SREBP activation, and does not activate S1P when sterol levels increase. Drugs acting at various steps in this process can alter cholesterol metabolism and plasma cholesterol levels that contribute to coronary heart disease. The statins such as lovastatin are drugs that inhibit cholesterol biosynthesis, lowering intracellular cholesterol levels and activating SREBP cleavage to increase LDLR expression on the cell surface. Inhibition of S1P may provide another mechanism to alter plasma cholesterol levels, as suggested by the low cholesterol levels in mice lacking the S1P gene. Ligands that bind to SCAP also lower cholesterol levels through induction of LDLR expression
- Role of ABCG and ABCA proteins in intestinal sterol metabolism. ABCG5, ABCG8, and ABCA1 are sterol-induced members of the ABC transporter family. ABCG5 and ABCG8, which are mutated in sitosterolemia, form a heterodimer to mediate the export of absorbed plant sterols and cholesterol into the gut lumen. In contrast, ABCA1 expression and function are required for the uptake of sterols into intestinal epithelial cells. Implications for the intracellular location and vesicular trafficking of these proteins are presented. Abbreviations not defined in text: CE, cholesteryl ester; DAG, diacylglyceride; DGAT, acyl CoA:diacylglycerol transferase; HSP70, heat shock protein 70; L, lysosome; MAG, monoacylglyceride; Mic, micelle; MTP, microsomal transfer protein; Sit, sitosterol
- Role of ABCG and ABCA proteins in intestinal sterol metabolism. ABCG5, ABCG8, and ABCA1 are sterol-induced members of the ABC transporter family. ABCG5 and ABCG8, which are mutated in sitosterolemia, form a heterodimer to mediate the export of absorbed plant sterols and cholesterol into the gut lumen. In contrast, ABCA1 expression and function are required for the uptake of sterols into intestinal epithelial cells. Implications for the intracellular location and vesicular trafficking of these proteins are presented. Abbreviations not defined in text: CE, cholesteryl ester; DAG, diacylglyceride; DGAT, acyl CoA:diacylglycerol transferase; HSP70, heat shock protein 70; L, lysosome; MAG, monoacylglyceride; Mic, micelle; MTP, microsomal transfer protein; Sit, sitosterol
- Role of ABCG and ABCA proteins in intestinal sterol metabolism. ABCG5, ABCG8, and ABCA1 are sterol-induced members of the ABC transporter family. ABCG5 and ABCG8, which are mutated in sitosterolemia, form a heterodimer to mediate the export of absorbed plant sterols and cholesterol into the gut lumen. In contrast, ABCA1 expression and function are required for the uptake of sterols into intestinal epithelial cells. Implications for the intracellular location and vesicular trafficking of these proteins are presented. Abbreviations not defined in text: CE, cholesteryl ester; DAG, diacylglyceride; DGAT, acyl CoA:diacylglycerol transferase; HSP70, heat shock protein 70; L, lysosome; MAG, monoacylglyceride; Mic, micelle; MTP, microsomal transfer protein; Sit, sitosterol
- Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future.
- Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future.
- Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future.
- Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future.
- Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future.
- Regulation of cholesterol efflux from cells. Aqueous diffusion of unesterified cholesterol (UC) from the plasma membrane onto lipid-rich lipoproteins, albumin, phospholipid vesicles, or cyclodextrins is slow. Binding of HDL to SR-BI leads to reorganization of cholesterol within the plasma membrane and facilitates cholesterol efflux. ABC1-mediated efflux of UC and phospholipids (PL) onto lipid-free apolipoproteins or lipid-poor particles is fast and involves the translocation of cholesterol from intracellular compartments to the plasma membrane. This transport process appears to involve signal transduction processes, ie, the cAMP-mediated activation of a protein kinase A (PKA) and the degradation of phosphatidylcholine by phospholipase C (PC-PLC) and phospholipase D (PC-PLD). The products DAG and phosphatidic acid (PA) act as second messengers, which activate intracellular transporters either directly or indirectly by activation of a PKC.
- Regulation of cholesterol efflux from cells. Aqueous diffusion of unesterified cholesterol (UC) from the plasma membrane onto lipid-rich lipoproteins, albumin, phospholipid vesicles, or cyclodextrins is slow. Binding of HDL to SR-BI leads to reorganization of cholesterol within the plasma membrane and facilitates cholesterol efflux. ABC1-mediated efflux of UC and phospholipids (PL) onto lipid-free apolipoproteins or lipid-poor particles is fast and involves the translocation of cholesterol from intracellular compartments to the plasma membrane. This transport process appears to involve signal transduction processes, ie, the cAMP-mediated activation of a protein kinase A (PKA) and the degradation of phosphatidylcholine by phospholipase C (PC-PLC) and phospholipase D (PC-PLD). The products DAG and phosphatidic acid (PA) act as second messengers, which activate intracellular transporters either directly or indirectly by activation of a PKC.
- Regulation of cholesterol efflux from cells. Aqueous diffusion of unesterified cholesterol (UC) from the plasma membrane onto lipid-rich lipoproteins, albumin, phospholipid vesicles, or cyclodextrins is slow. Binding of HDL to SR-BI leads to reorganization of cholesterol within the plasma membrane and facilitates cholesterol efflux. ABC1-mediated efflux of UC and phospholipids (PL) onto lipid-free apolipoproteins or lipid-poor particles is fast and involves the translocation of cholesterol from intracellular compartments to the plasma membrane. This transport process appears to involve signal transduction processes, ie, the cAMP-mediated activation of a protein kinase A (PKA) and the degradation of phosphatidylcholine by phospholipase C (PC-PLC) and phospholipase D (PC-PLD). The products DAG and phosphatidic acid (PA) act as second messengers, which activate intracellular transporters either directly or indirectly by activation of a PKC.
- The role of HDL in reverse cholesterol transport. Free cholesterol (FC) undergoes efflux from peripheral cells into HDL. Subspecies of HDL, such as pre-ß particles, may be particularly important in mediating free cholesterol efflux from peripheral cells. Cholesterol efflux can occur by passive diffusion, or it may involve HDL or apoA-I receptors, such as scavenger receptor (SR) BI or ATP-binding cassette transporter 1. Subsequent activity of lecithin:cholesterol acyltransferase (LCAT) leads to formation of large, CE-rich HDL. HDL CEs may be returned to the liver by 3 pathways: (1) as part of a holo-HDL uptake mechanism, probably involving proteoglycans (PG), apoE, and possibly other factors; (2) via a process of selective uptake of CEs and free cholesterol–mediated hepatic SRBI and also by hepatic lipase (HL); and (3) by CETP-mediated transfer to TRLs, with subsequent uptake of TRL remnants in the liver, involving proteoglycans
- Role of LDL in inflammation LDL readily enters the artery wall by crossing the endothelial membrane. Once in the arterial wall, if LDL accumulates, it is subject to a variety of modifications. The best known of these is oxidation, both of the lipids and of the apo B. LDL is also subject to aggregation, and its phospholipids are subject to hydrolysis by phospholipases to form lysophosphatidylcholine. Several other chemical modifications have also been reported. The net effect of these changes is the production of a variety of modified LDL particles, and the evidence is now very strong that these modified LDL particles are proinflammatory. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- Modified LDL stimulate expression of MCP-1 in endothelial cells Modified LDL is involved in many stages of the inflammatory process that leads to the development of atherosclerosis. Modified LDL activates endothelial cells to express monocyte chemotactic protein 1 (MCP-1), which attracts monocytes from the vessel lumen and into the subendothelial space, in what is one of the very early stages in the inflammatory process leading to the development of atherosclerosis.
- Differentiation of monocytes into macrophages The modified LDL plays an important role in promoting the differentiation of monocytes into macrophages, a key step in the inflammatory process on the way to the development of atherosclerosis. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- Modified LDL induces macrophages to release cytokines that stimulate adhesion molecule expression in endothelial cells After modified LDL promotes the differentiation of monocytes into macrophages, the macrophages release a variety of chemicals, including cytokines. Of these cytokines, tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) activate endothelial cells to express adhesion molecules that bind monocytes, making them available for recruitment into the subendothelial space by MCP-1. Reference: Nathan CF. Secretory products of macrophages. J Clin Invest 1987;79:319-326.
- Macrophages express receptors that take up modified LDL The activated macrophages also express a variety of scavenger receptors, several of which recognize the different forms of modified LDL. The macrophages take up the LDL through these scavenger receptors, accumulate the lipid, and are converted into the lipid-rich foam cells that are the hallmark of atherosclerosis. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- The remnants of VLDL and chylomicrons are also pro-inflammatory VLDL remnants and chylomicron remnants behave in much the same way as LDL. They enter the subendothelial space, where they become modified, and the modified remnants stimulate MCP-1, promote the differentiation of monocytes into macrophages, and are taken up by the macrophages to form foam cells. Like LDL, the remnant lipoproteins are proinflammatory and proatherogenic. References: Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:670-676.
- HDL prevent formation of foam cells Perhaps the best-known function of HDL is the promotion of cholesterol efflux from cells. Efflux of cholesterol from foam cells leads to a reduction in foam cell formation; although the macrophages may accumulate, they are not converted into foam cells. As a result, the inflammatory process is arrested to a certain extent. Therefore, HDL is anti-inflammatory and also protects against the development of atherosclerosis.
- HDL inhibit the oxidative modification of LDL HDL has protective effects in addition to promoting cholesterol efflux. One of the best known of these is the ability to inhibit the oxidation of LDL. To the extent that LDL oxidation is an important step in the development of the inflammatory process, this property of HDL is clearly anti-inflammatory.
- Inhibition of adhesion molecules The cytokine-induced expression of adhesion molecules in endothelial cells has been shown in vitro and more recently in vivo to be inhibited by HDL, in a process that potentially blocks a very early inflammatory stage in the development of atherosclerosis.