Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations
Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations
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DOI：
10.1194/jlr.m200414-jlr200
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发表时间：
2003-02-01
影响因子：
6.5
通讯作者：
Brewer, HB
中科院分区：
文献类型：
--
作者：
Basso, F;Freeman, L;Brewer, HB
目前的胆固醇逆向转运模型提出，HDL将主要来自外周细胞的过量胆固醇转运到肝脏进行清除。然而，最近在ABCA 1转基因小鼠中的研究表明，肝脏本身可能是HDL胆固醇（HDL-C）的主要来源。为了直接研究肝脏对血浆HDL-C水平的贡献，我们产生了将小鼠ABCA 1-GFP-β的体内表达靶向肝脏的腺病毒（rABCA 1-GFP-AdV）。与对照组相比，rABCA 1-GFP-AdV注射C57 B1/6小鼠后，肝脏中ABCA 1 mRNA和蛋白的表达均增加。在rABCA 1-GFP-AdV输注后1天分离的原代肝细胞中，ApoA-I依赖性胆固醇流出增加2.6倍。C57 B1/6小鼠（n = 15）肝脏ABCAI表达使TC、PL、FC、HDL-C、apoE和apoA-I的基线水平升高150-300%（P均< 0.05）。ABCA 1表达导致增加肝脏胆固醇的基因表达的显著代偿性变化，包括肝脏中的HMG-CoA还原酶（3.5倍）、LDLr（2.1倍）和LRP（5倍）。这些综合结果表明，ABCA 1在肝脏胆固醇流出中起关键作用，诱导调节肝脏胆固醇稳态的途径，并建立肝脏作为血浆HDI-C的主要来源。
The current model for reverse cholesterol transport proposes that HDL transports excess cholesterol derived primarily from peripheral cells to the liver for removal. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic contribution to plasma HDL-C levels, we generated an adenovirus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GF'P in vivo to the liver. Compared with mice injected with control AdV, infusion of rABCA1-GFP-AdV into C57B1/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepatocytes isolated I day after rABCA1-GFP-AdV infusion. Hepatic ABCAI expression in C57B1/6 mice (n = 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150-300% (P < 0.05 all). ABCA1 expression led to significant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reductase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver. These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing pathways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDI-C.