胆固醇代谢与双重抑制
Cholesterol Metabolism and the Concept of Dual Inhibition David E. Cohen, MD, PhD
Overview
Digestive lipid metabolism
Cholesterol balance
Inhibitors of cholesterol synthesis and absorption
Dual inhibition
Digestive Lipid Metabolism
Reverse Cholesterol Transport
Blood
Peripheral Tissues
Liver
Bile
Excess Cholesterol
Cholesterol Catabolism into Bile Salts
Cholate
Cholesterol
Cholesterol 7?-hydroxylase
HO
Bile Salts
Breakdown products of cholesterol
Amphipathic molecules
Function to transport cholesterol in the digestive system
Structure of Biliary and Intestinal Micelles
Cholesterol
Bile Salt
Phospholipid
Functions of Micelles
Transport cholesterol from the liver into the intestine via the biliary tree
Participate in fat digestion and absorption
Biliary Lipid Secretion
Sinusoidal Membrane
Blood
Hepatocyte
Canalicular Membrane
Bile Salt
ABCG5/G8
Cholesterol
ABCB4
Phospholipid
ABCB11
Bile
Biliary Lipids
Daily Secretion (g)
Lipid Class
Bile salts
Phospholipids
Cholesterol
24
11
2
Biliary Lipid Transport
Duodenum
Jejunum
Ileum
Colon
Biliary Transport and Storage
Liver
Fat Digestion
Duodenum
Jejunum
Ileum
Colon
Biliary Transport and Storage
Liver
Fat Digestion
Triglycerides
Dietary Cholesterol
Fatty Acids + Monoglycerides
Fat Absorption
Duodenum
Jejunum
Ileum
Biliary Transport and Storage
Colon
Liver
Lymph
Enterocyte
Intestinal Lumen
Cholesterol Absorption
Cholesterol
NPC1L1
Cholesteryl Ester
ABCG5/G8
ACAT
Lymph
Enterocyte
Intestinal Lumen
Triglyceride Absorption
2 Fatty Acid
+
Monoglyceride
DGAT
Triglyceride
Lymph
Enterocyte
Intestinal Lumen
Chylomicron Formation
Cholesteryl Ester
CM
apoB48
Triglyceride
Cholesterol Balance
Duodenum
Jejunum
Ileum
Colon
Portal Venous Return (>95% of Biliary Secretion)
Fecal excretion (0.4 g/d)
Biliary Transport and Storage
Liver
Synthesis 0.4 g/d
Secretion 24 g/d
Enterohepatic Circulation of Bile Salts
Duodenum
Jejunum
Ileum
Colon
Biliary Transport and Storage
Fecal excretion (1.2 g/d)
Dietary Cholesterol (0.4 g/d)
Absorption ~50%
CM
apoB48
Liver
Biliary Cholesterol (2 g/d)
Biliary and Dietary Cholesterol
Cholesterol Balance
Duodenum
Jejunum
Ileum
Colon
Biliary Transport and Storage
Cholesterol
Cholesterol (1.2 g/d) + Bile Salts (0.4 g/d)
Dietary Cholesterol (0.4 g/d)
Loss (1.6 g/d)
Bile salts
Loss (1.6 g/d) — Dietary Cholesterol (0.4 g/d)
Synthesis (1.2 g/d)
Liver
Inhibitors of Cholesterol Synthesis and Absorption
Inhibitors of Cholesterol Synthesis: Statins
Inhibit synthesis of cholesterol by cells
Lower LDL cholesterol
LDL Receptor
Statins
Acetate
LDL
HMG-CoA Reductase
Cholesterol
Cholesterol Absorption Inhibitors
Inhibit absorption of dietary cholesterol
Inhibit reabsorption of biliary cholesterol
Lower LDL cholesterol
Plant Sterols and Stanols
Sterol/Stanol
Dietary Cholesterol
Lymph
Enterocyte
Intestinal Lumen
Plant Sterols and Stanols
Cholesterol
Cholesteryl Ester
ABCG5/G8
ACAT
NPC1L1
Lymph
Enterocyte
Intestinal Lumen
Ezetimibe
Cholesterol
NPC1L1
Cholesteryl Ester
ABCG5/G8
ACAT
Ezetimibe
X
Lymph
Enterocyte
Intestinal Lumen
Cholesterol Absorption Inhibitors
Cholesteryl Ester
CM
apoB48
Triglyceride
Cholesterol Absorption Inhibitors
Duodenum
Jejunum
Ileum
CM
apoB48
Liver
CM Remnant apoB48
VLDL apoB100
LDL apoB100
Colon
Dual Inhibition
Assembly and Secretion of VLDL
Presence of Triglycerides
ApoB
MTP
MTP
Cholesteryl Esters
Cholesterol
Dietary/Biliary
Synthesis
Effect of Cholesterol Absorption Inhibitor
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary
Synthesis
Ezetimibe
X
MTP
MTP
Cholesteryl Esters
Adding a Statin Blocks Compensatory Increase in Synthesis
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary
Synthesis
Ezetimibe
X
X
Statin
MTP
MTP
Cholesteryl Esters
Dual Inhibition
Duodenum
Jejunum
Ileum
CM
apoB48
Liver
CM Remnant apoB48
VLDL apoB100
LDL apoB100
X
Statin
Colon
Conclusions
Cholesterol balance is regulated by both synthesis and absorption
Inhibition of cholesterol absorption may be compensated by increases in synthesis
Optimal LDL lowering may best be achieved by inhibiting both pathways