HDL代谢的生理学和病理学意义
HDL and Coronary Heart Disease
Physiology and Pathophysiology of HDL Metabolism
Structure of HDL Particle
A-I
A-I
A-II
A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides
CE
TG
Production of HDL by Liver and Intestine
A-I
A-I
A-II
A-I, A-II = apolipoprotein A-I, A-II
Liver
Intestine
HDL
HDL
HDL Metabolism and Reverse Cholesterol Transport
A-I
Liver
CE
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
A-I
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
ABC1
Macrophage
Mature HDL
Nascent HDL
Role of CETP in HDL Metabolism
A-I
Liver
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
A-I
ABC1
Macrophage
CE
B
CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein
LDLR
VLDL/LDL
CETP
Mature HDL
Nascent HDL
CE
SRA
Oxidation
Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism
CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride
B
Kidney
Endothelium
B
TG
CMR/IDL
C-II
CM/VLDL
HL
LPL
A-I
CE TG
HDL2
PL
A-I
CE
HDL3
PL
Phospholipids and apolipoproteins
Primary (Genetic) Causes of Low HDL-C
ApoA-I
Complete apoA-I deficiency
ApoA-I mutations (eg, ApoA-IMilano)
LCAT
Complete LCAT deficiency
Partial LCAT deficiency (fish-eye disease)
ABC1
Tangier disease
Homozygous
Heterozygous
Familial hypoalphalipoproteinemia (some families)
Unknown genetic etiology
Familial hypoalphalipoproteinemia (most families)
Familial combined hyperlipidemia with low HDL-C
Metabolic syndrome
Complete ApoA-I Deficiency
Markedly reduced HDL-C levels and absent apoA-I
Cutaneous xanthomas (some patients)
Premature atherosclerotic vascular disease (some patients)
ApoA-I Mutations
Modest to marked reduction in HDL-C and apoA-I
Rapid catabolism of apoA-I
Systemic amyloidosis
Premature atherosclerotic disease (rare)
LCAT Deficiency and Fish-eye Disease
Both due to mutations in LCAT gene:
LCAT deficiency – complete
Fish-eye disease – partial
Common to both types of LCAT deficiency:
Markedly reduced HDL-C and apoA-I levels
Rapid catabolism of apoA-I and apoA-II
Corneal arcus
Premature atherosclerotic vascular disease (rare)
Unique to complete LCAT deficiency:
Proteinuria and progressive renal insufficiency
HDL Metabolism in LCAT Deficiency
A-I
FC
FC
LCAT
A-I
ABC1
Macrophage
Rapid catabolism
Nascent HDL
CE
Tangier Disease
Autosomal codominant disorder due to mutations in both alleles of ABC1 gene
Extremely marked reduction in HDL-C and apoA-I
Markedly accelerated catabolism of apoA-I and apoA-II
Cholesterol accumulation:
Enlarged orange tonsils
Hepatosplenomegaly
Peripheral neuropathy
Tangier Disease (Continued)
Increased risk of premature atherosclerotic vascular disease
Pathologic accumulation of cholesterol in macrophages and other cells of reticulo-endothelial system
Heterozygotes have moderately reduced HDL-C and apoA-I levels and increased risk of premature atherosclerotic vascular disease, but no tonsillar enlargement or hepatosplenomegaly
HDL Metabolism in Tangier Disease
A-I
FC
FC
A-I
ABC1
Macrophage
Rapid catabolism
LCAT
Nascent HDL
CE
Familial Hypoalphalipoproteinemia
Dominant disorder; due to mutations in one allele of ABC1 gene in some families, and of unknown genetic etiology in other families
Moderate reduction in HDL-C and apoA-I
Increased risk of premature atherosclerotic vascular disease
Secondary Causes of Low HDL-C
Smoking
Obesity (visceral fat)
Very-low-fat diet
Hypertriglyceridemia
Drugs
Beta-blockers
Androgenic steroids
Androgenic progestins
Primary (Genetic) Causes of High HDL-C
CETP
CETP deficiency
Hepatic lipase
Hepatic lipase deficiency
Unknown genetic etiology
Familial hyperalphalipoproteinemia
CETP Deficiency
Autosomal co-dominant; due to mutations in both alleles of CETP gene
Markedly elevated levels of HDL-C and apoA-I
Delayed catabolism of HDL cholesteryl ester and apoA-I
HDL particles enlarged and enriched in cholesteryl ester
No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease
HDL Metabolism in CETP Deficiency
A-I
CE
FC
FC
LCAT
A-I
Macrophage
B
Delayed catabolism
CETP
ABC1
HDL
VLDL/LDL
Nascent HDL
CE
Hepatic Lipase Deficiency
Autosomal recessive, due to mutations in both alleles of hepatic lipase gene
Modestly elevated levels of HDL-C and apoA-I
Variable elevations in total cholesterol, triglycerides, and lipoprotein remnant particles
No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease
HDL Metabolism in Hepatic Lipase Deficiency
A-I
Liver
A-I
CE TG
CE
HL
Delayed catabolism
HDL2
HDL3
Familial Hyperalphalipoproteinemia
Autosomal dominant; molecular etiology unknown
Modest to marked elevations in HDL-C and apoA-I
Selective increased synthesis of apoA-I in some families
Associated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies
Secondary Causes of Increased HDL-C
Extensive regular aerobic exercise
Very-high-fat diet
Regular substantial alcohol intake
Estrogen replacement therapy
Drugs
Phenytoin
Genes Involved in HDL Metabolism Potential Targets for Development of Novel Therapies for Atherosclerosis
HDL-associated apolipoproteins
— ApoA-I — ApoE
— ApoA-IV
HDL-modifying plasma enzymes and transfer proteins
— LCAT — Lipoprotein lipase
— CETP — Hepatic lipase
— PLTP — Endothelial lipase
Cellular and cell-surface proteins that influence HDL metabolism
— ABC1 — SR-BI
Gene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis in LDLR–/– Mice
0
1
2
3
4
5
Baseline
Adnull
Aortic lesion (%)
AdhapoA-I
*
* P ? 0.05
Tangirala R et al. Circulation 1999;100:1816–1822
Overexpression of LCAT Prevents Development of Atherosclerosis in Transgenic Rabbits
* P < 0.003
LCAT = lecithin-cholesterol acyltransferase; Tg = transgenic
Hoeg JM et al. Proc Natl Acad Sci U S A. 1996;93:11448–11453
Copyright ?1996 National Academy of Sciences, USA.
0
10
20
30
40
50
Control
LCAT Tg
Atherosclerotic surface area (%)
*
Summary
HDL metabolism is complex
HDL-C and apoA-I levels are determined by both production and catabolic rates
Rates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and apoA-I
Effect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL
Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis