Prof. Dr. Sarma VSN Rachakonda M.D., M.Sc., (Canada), FCGP, FICP, FIMSA, FRCP (G), FCCP (USA) Visiting Professor of Internal Medicine, SBMC, FLL, iDRF Sr. Consultant Physician& Cardio-metabolic Specialist website: www.drsarma.in YouTube: drsarmaji channel 1 Consensus DevelopmentConference in July 2009 2 www.lipidsonline.org www.ccmdweb.org www.ncbi.nlm.nih.gov www.univbaylor.orgwww.hypertensiononline.org www.drsarma.in 3 LDL CMR Statins Optimization NHDL control Non Lipid Effects 2 1 4 3 4 DM MS HT Lipids CVD DM HT Lipids CVD 5 CMR CAD Stroke PAD CKD CADStroke CKDPAD 6 1 2 3 COST 75 % 25 % EVENTS 7 REGRESS Target organ damage Asymptomatic Target organ damage Symptomatic Death CVD New risk factors Risk factors Cardiometabolic risk Atherosclerosis CVD 8 REGRESS Target organ damage Asymptomatic CVD New risk factors Risk factors Cardiometabolic risk Target organ damage Symptomatic Death Atherosclerosis CVD 9 1. Ester.Cholesterol (EC) 2. Triglycerides (TG) What are the important components (two) oflipids in the plasma ? What are the other two components in lipids in their outer layer ? 1. Free Cholesterol (FC) 2. Phospholipids (PL) What are Apoproteins ? Why are they needed in the lipid molecules ? 1. The outer protein coat is made of Apoproteins 2. To make lipids soluble and thus help transport 10 Free fatty acids (FFA)to Triglyceride (TG) Source of energy to the tissues Stored as TG; Metabolized to CO2 and H2O Exogenous (diet) and De novo synthesis Free Cholesterol (FC) to Esterified (EC) Cell membrane integrity Bile acids synthesis Steroid hormones synthesis; Vitamin D in skin Can not be broken down Exogenous (diet) and De novo synthesis 11 TG, EC PhospholipidsFree Cholesterol (Hydrophilic) Apolipoproteins A, B, C, E, (a) (Amphiphatic) Lipids or Fats (Hydrophobic) Size < RBC 12 ECTG Apoprotein boat 1. Make the lipids soluble and transportable 2. Structural Integrity of the lipoprotein 3. Act as ligands for cell receptors 4. Activate enzymes such as LPL, LCAT as cofactors 13 Apolipoprotein B Non-HDL-C Measurements TG-rich lipoproteins VLDLVLDLrIDLLDLSLDL The smaller the particle The greater is the danger Lp(a)CM 14 A-I A-I A-II A-I, A-II = Apo lipoprotein A-I, A-II;CE = cholesterol ester; TG = triglycerides CE TG 15 CE A-I CE A-I CE A-IIA-II HDL 1HDL 2HDL 3 APO A I ProtectiveAlcohol increases 16 Synthesized HDL VLDL Lp(a) Chylomicrons Generated LDL IDL (VLDL R) Chylomicron R 17 Duodenum Jejunum Ileum Colon Biliary Transport and Storage Fecal excretion (1.6 g/d) Dietary Cholesterol (0.4 g/d) Absorption ~50% CM apoB48 Liver Biliary Cholesterol (2.4 g/d) 18 Synthesis (1.2 g/d) Cholesterol (1.2 g/d) + Bile Salts (0.4 g/d) Bays H et al. Expert Opin Pharmacother 2003;4:779-790. Intestinalepithelial cell Biliary cholesterol Dietary cholesterol Luminal cholesterol Micellar cholesterol Bile acid Cholesteryl esters Free cholesterol excretion uptake ACAT ABCG5 ABCG8 (esterification) MTP CM Through lymphatic system to the liver NPC1L1 19 Free Cholesterol NPC1L1 Cholesterol Ester ABCG5/G8 ACAT Ezetimibe Avasimibe Pancreatic Esterase 20 Sterol/StanolDietary Cholesterol 21 LymphEnterocyte Intestinal Lumen Cholesterol Cholesteryl Ester ABCG5/G8 ACAT NPC1L1 22 23 Similar LDL-C Larger LDL (phenotype A) More cholesterol/particle 24 LymphEnterocyteIntestinal Lumen 2 Fatty Acids + Mono glyceride DGAT Triglyceride Intestinal Lipase APO B48 Chylomicrons 25 LymphEnterocyteIntestinal Lumen Cholesteryl Ester CM apoB48 Triglyceride 26 27 Sinusoidal Membrane BloodHepatocyte Canalicular Membrane Bile Salt ABCG5/G8 Cholesterol ABCB4 Phospholipid ABCB11 Bile 28 29 30 Intestine Peripheral Cells Kidney PLTP LCAT ABC1 Particle Uptake Liver TGRL Selective Uptake Surface Remnants Cubilin apo A1 HDL3 HDL2 Pre-|- HDL CETP SR-BI HL, EL LPL Reprinted from von Eckardstein A, Assmann G. Curr Opin Lipidol. 2000;11:627637, with permission from Lippincott Williams & Wilkins. Nascent HDL (lipid-poor apo lipoprotein A1 is produced by the liver and intestine 31 LIVER MF in Vascular Endothelium Free Cholesterol L CAT Enzyme UEC EC HDL 32 Liver ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I;CE = cholesteryl ester; FC = free cholesterol;LCAT = lecithin:cholesterol acyltransferase;SR-BI = scavenger receptor class BI Mature HDL CE A-I CE CE FC FC LCAT FC Bile SR-BI A-I ABC1 Macrophage NascentHDL 33 B SRA Mature HDL A-I Liver CE CE FC FC LCAT FC Bile SR-BI A-I ABC1 Macrophage CE CETP = cholesteryl ester transfer protein LDL = low-density lipoproteinLDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein LDLR VLDL/LDL CETP Nascent HDL CE Torcitrapib X 34 Lipoprotein Lipase : LPL Capillary endothelium muscle, heart, adipose tissue, TG hydrolysis to FFA & Glycerol Converts CM and VLDL to their remnants Apo CII is the cofactor, Insulin stimulates LPL Hepatic Lipase : HL Present in hepatic sinusoids Hydrolysis of TG to FFA and glycerol IDL converted to LDL HDL converted to small lipid poor HDL 35 Endothelial Lipase : EL Member of LPL family Made by endothelial cells Hydrolyses the phospholipid in HDL Lecithin Cholesterol Acyl Transferase : LCAT Produced in the liver In the plasma catalyzes FC to EC in HDL Cholesterol Ester Transfer Protein : CETP Plasma protein bound to HDL, from the liver Transfers EC to CM, VLDL, IDL, LDL from HDL Transfers TG from CM, VLDL, IDL , LDL to HDL 36 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Foam Cell Intima ModifiedLDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1 37 LDL, IDLNot normally taken up by the vessel wallROS Freeradicals and Pro-oxidants Oxidized LDL, IDL Freely enters the vessel wallScavenger pathway EndotheliumMacrophages Foam CellsCytokines, GF Atherosclerosis 38 LIPIDS ESTIMATED TOTAL CHOLESTEROL (TC)TRIGLYCERIDES (TG) HDLcLDLcVLDLcChylomicronsVLDL PPFasting 39 A.Isolated High LDL32.90% B.Isolated low HDL21.35% C.Isolated high TG10.45% IHJ, 2000, 52: 173-177 Am J Med, 1998, vol 105(1A), 48S-56S LDL HDL TG The Triad 40 IHJ, 2000, 52: 173-177 Am J Med, 1998, vol 105(1A), 48S-56S Lp(a) HDL TG The Indian Triad 41 Low HDL39.2% High TG 32.5% Lp(a) excess 28.6% High LDL10.8% Normal Lipids23.5% Am J C 2001;88(suppl) 9N-13N; 22N 42 NHDL 75% HDL 25% Total Cholesterol LDL 120 mg TG/5 30 mg HDL 50 mg Total Cholesterol = 200 mg 43 Total Cholesterol HDL = N-HDL LDL + (TG/5) = N-HDL N-HDL goal is 30 mg above the LDL goal Because TG should be kept at 150 (150/5 = 30) Significance of N-HDL It includes all known atherogenic particles Correlates closely with visceral adiposity, obesity It is a stronger predictor of CVD than LDLc 44 LDL NHDL HDL100 mg 130 mg 50+ mg 45 Level of RiskLDL CholesterolNHDL CholesterolApo B 100 Highest