Lipoprotein Formation, Structure and Metabolism: Cholesterol Balance and the Regulation of Plasma Lipid Levels
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1 Lipoprotein Formation, Structure and Metabolism: Balance and the Regulation of Plasma Lipid Levels David E. Cohen, MD, PhD Director of Hepatology, Gastroenterology Division, Brigham and Women s Hospital Director, Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology Associate Professor of Medicine and Health Sciences and Technology, Harvard Medical School
2 Multiple Studies Showed a Relationship Between LDL-C Reduction and CHD Relative Risk Nonfatal MI and CHD Death Relative Risk Reduction, % Š20 London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S WOSCOPS CARE LIPID AF/TexCAPS HPS ALERT PROSPER ASCOT-LLA CARDS LDL-C Reduction, %
3 ATP 2004 Update: LDL-C Therapy by Risk Categories Based on Recent Clinical Trial Evidence Risk Category High risk: CHD or CHD risk equivalents (10-year risk >20%) Very high risk Moderately high risk: 2 risk factors (10-year risk 10% 20%) Moderate risk: 2 risk factors (10-year risk <10%) Low risk: 1 risk factor LDL-C Goal <100 mg/dl Optional goal of <70 mg/dl <130 mg/dl (optional goal <100 mg/dl) <130 mg/dl <160 mg/dl Initiate Therapeutic Lifestyle Changes (TLC) 100 mg/dl 130 mg/dl 130 mg/dl 160 mg/dl Adapted from Grundy SM et al. Circulation. 2004;110: ; Consider Drug Therapy 100 mg/dl 130 mg/dl (consider drug options if LDL-C mg/dl) >160 mg/dl 190 mg/dl (consider drug options if LDL-C mg/dl)
4 Overview Digestive lipid metabolism balance Inhibitors of cholesterol synthesis and absorption Dual inhibition
5 Overview Digestive lipid metabolism balance Inhibitors of cholesterol synthesis and absorption Dual inhibition
6 Critical for membrane function Substrate for steroid hormone synthesis Synthesized by all cells in the body Toxic to cells when present in excess Broken down and eliminated by the liver only
7 - membranes HO Cholesteryl ester - transport/storage O O
8 Reverse Transport Excess BILE PERIPHERAL TISSUES BLOOD LIVER
9 Catabolism Into Bile Salts Liver Cell ONLY
10 Catabolism into Bile Salts Cholate OH COO _ HO 7α-hydroxylase HO OH
11 Bile Salts Breakdown products of cholesterol Amphipathic molecules Function to transport cholesterol in the digestive system
12 Structure of Biliary and Intestinal Micelles Bile Salt Phospholipid
13 Functions of Micelles Transport cholesterol from the liver into the intestine via the biliary tree Participate in fat digestion and absorption
14 Biliary Lipid Secretion BLOOD HEPATOCYTE BILE Sinusoidal Membrane ABCG5/G8 ABCB4 Phospholipid ABCB11 Bile Salt Canalicular Membrane
15 Biliary Lipids Lipid Class Daily secretion (g) Bile salts 24 Phospholipids 11 2
16 Biliary Lipid Transport Liver Duodenum Biliary Transport and Storage Jejunum Ileum Colon
17 Fat Digestion Liver Duodenum Biliary Transport and Storage Jejunum Ileum Colon
18 Dietary Fat Digestion
19 Dietary Fat Digestion
20 Fat Digestion Triglycerides Lipase Fatty Acids + Monoglycerides
21 Fat Digestion Triglycerides Lipase Fatty Acids + Monoglycerides
22 Lipid Absorption Liver Duodenum Biliary Transport and Storage Jejunum Ileum Colon
23 Absorption LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT? Cholesteryl Ester ABCG5/G8
24 Absorption LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
25 Triglyceride Absorption LYMPH ENTEROCYTE INTESTINAL LUMEN 2 Fatty Acid + Monoglyceride DGAT Triglyceride
26 Chylomicron Formation LYMPH ENTEROCYTE INTESTINAL LUMEN CM apob48 Triglyceride Cholesteryl Ester
27 Overview Digestive lipid metabolism balance Inhibitors of cholesterol synthesis and absorption Dual inhibition
28 Enterohepatic Circulation of Bile Salts Synthesis 0.4 g/d Secretion 24 g/d Biliary Transport and Storage Duodenum Jejunum Portal Venous Return (>95% of Biliary Secretion) Colon Ileum Fecal Excretion (0.4g/d)
29 Biliary Secretion Biliary (2 g/d) Duodenum Biliary Transport and Storage Jejunum Ileum Colon
30 Biliary and Dietary Dietary (0.4 g/d) Biliary (2 g/d) Duodenum Biliary Transport and Storage Jejunum Ileum Colon
31 Absorption Diet Low Fat/Low High Fat/Low High Fat/High Modified from Sehayek et al Absorption, %
32 Absorption Biliary (2 g/d) Dietary (0.4 g/d) Duodenum Biliary Transport and Storage Jejunum Ileum CM apob48 Absorption ~50% Colon
33 Fecal Excretion Biliary (2 g/d) Dietary (0.4 g/d) Biliary Transport and Storage Jejunum CM apob48 Absorption ~50% Colon Ileum Fecal Excretion (1.2 g/d)
34 Balance Synthesis (1.2 g/d) Loss (1.6 g/d) - Dietary (0.4 g/d) Bile salts Dietary (0.4 g/d) Loss (1.6 g/d) (1.2 g/d) + Bile Salts (0.4 g/d)
35 Overview Digestive lipid metabolism balance Inhibitors of cholesterol synthesis and absorption Dual inhibition
36 Inhibitors of Synthesis: Statins Inhibit synthesis of cholesterol by cells Lower LDL cholesterol Mechanism: Promote LDL clearance
37 Statins Acetate LDL Receptor HMG-CoA Reductase
38 Statins Acetate LDL Receptor HMG-CoA Reductase LDL
39 Absorption Inhibitors Inhibit absorption of dietary cholesterol Inhibit reabsorption of biliary cholesterol Lower LDL cholesterol Mechanism : Inhibit LDL formation
40 Absorption Inhibitors Inhibit absorption of dietary cholesterol Inhibit reabsorption of biliary cholesterol Lower LDL cholesterol Mechanism : Inhibit LDL formation
41 Absorption LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
42 Agents That Interfere With Absorption Plant sterols and stanols Ezetimibe
43 Agents That Interfere With Absorption Plant sterols and stanols Ezetimibe
44 Absorption LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
45 Plant Sterols and Stanols Dietary Sterol/Stanol
46 Plant Sterols and Stanols Dietary Sterol/Stanol
47 Plant Sterols and Stanols LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
48 Plant Sterols and Stanols LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
49 Plant Sterols and Stanols LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Cholesteryl Ester ABCG5/G8
50 Absorption Inhibitors Plant sterols and stanols Ezetimibe
51 Ezetimibe LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Ezetimibe X Cholesteryl Ester ABCG5/G8
52 Ezetimibe LYMPH ENTEROCYTE INTESTINAL LUMEN ACAT NPC1L1 Ezetimibe X Cholesteryl Ester ABCG5/G8
53 Mechanism of Ezetimibe Action: Role of NPC1L1 Absorption in NPC1L1 Knockout Mice % absorption * +/+ Wild type +/- Heterozygous -/- Homozygous * * 0 +/+ +/+ -/- EZE -/- EZE P<0.001 compared with wild-type mice (+/+) and heterozygous (+/-) mice. Altmann et al. Science. 2004;303:1201.
54 Absorption Inhibitors LYMPH ENTEROCYTE INTESTINAL LUMEN CM apob48 Triglyceride Cholesteryl Ester
55 Absorption Inhibitors LYMPH ENTEROCYTE INTESTINAL LUMEN CM apob48 Triglyceride Cholesteryl Ester
56 Absorption Inhibitors LYMPH ENTEROCYTE INTESTINAL LUMEN CM apob48 Triglyceride Cholesteryl Ester
57 Absorption Inhibitors LDL apob100 Liver Duodenum VLDL apob100 Ezetimibe X Jejunum Ileum CM Remnant apob48 CM apob48 Colon
58 Overview Digestive lipid metabolism balance Inhibitors of cholesterol synthesis and absorption Dual inhibition
59 Assembly and Secretion of VLDL Presence of Triglycerides ApoB Endoplasmic MTP MTP Reticulum
60 Assembly and Secretion of VLDL Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters Dietary/Biliary Synthesis
61 Effect of Ezetimibe Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary Synthesis
62 Effect of Ezetimibe Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary Synthesis
63 Compensatory Upregulation of Synthesis Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary Synthesis
64 Compensatory Upregulation of Synthesis Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary Synthesis
65 Addition of Statin Therapy Blocks the Compensatory Response Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary X Statin Synthesis
66 Addition of Statin Therapy Blocks the Compensatory Response Presence of Triglycerides ApoB MTP MTP Cholesteryl Esters X Ezetimibe Dietary/Biliary X Statin Synthesis
67 Absorption Inhibitors LDL apob100 Liver Duodenum VLDL apob100 Ezetimibe X Jejunum Ileum CM Remnant apob48 CM apob48 Colon
68 Dual Inhibition LDL apob100 Liver Duodenum X Statin VLDL apob100 Ezetimibe X Jejunum Ileum CM Remnant apob48 CM apob48 Colon
69 Dual Inhibition LDL apob100 Liver Duodenum X Statin VLDL apob100 Ezetimibe X Jejunum Ileum CM Remnant apob48 CM apob48 Colon
70 Benefits of Managing Dual Pathways balance is regulated by both synthesis and absorption Each pathway may compensate for changes in the other Optimal LDL lowering may best be achieved by inhibiting both pathways
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