肝细胞特异性 ABCA1 转移可增加 HDL 胆固醇，但损害 HDL 功能并加速动脉粥样硬化。

Hepatocyte-specific ABCA1 transfer increases HDL cholesterol but impairs HDL function and accelerates atherosclerosis.

机构信息

Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

出版信息

Cardiovasc Res. 2010 Nov 1;88(2):376-85. doi: 10.1093/cvr/cvq204. Epub 2010 Jun 18.

DOI:10.1093/cvr/cvq204

PMID:20562425

Abstract

AIMS

The ATP-binding cassette transporter A1 (ABCA1) lipidates apolipoprotein (apo) A-I. The hypothesis that hepatocyte-specific ABCA1 overexpression results in high-density lipoprotein (HDL) dysfunction was evaluated by comparing the effects of murine ABCA1 (AdABCA1) and human apo A-I (AdA-I) transfer on lipoprotein profile, HDL function, and progression of atherosclerosis.

METHODS AND RESULTS

Gene transfer in male and female C57BL/6 apo E(-/-) mice was performed at the age of 3 months with E1E3E4-deleted adenoviral vectors containing hepatocyte-specific expression cassettes. Atherosclerosis was quantified at baseline and 56 days later in AdABCA1, AdA-I, and control mice. HDL cholesterol after AdA-I transfer was 1.7-fold (P < 0.001) and 1.8-fold (P < 0.001) higher in male and female mice, respectively, and potently inhibited atherosclerosis progression compared with respective controls. Notwithstanding a 1.4-fold (P < 0.01) and a 1.7-fold (P < 0.01) increase of HDL cholesterol in male and female mice, respectively, after AdABCA1 transfer, the intima was 2.2-fold (P < 0.001) larger in male and 1.3-fold (P = NS) larger in female mice compared with respective controls. HDL isolated from control and AdA-I mice but not from AdABCA1 mice enhanced endothelial progenitor cell (EPC) migration in vitro and reduced endothelial cell death in vitro after serum and growth factor withdrawal. Scavenger receptor class B type I (SR-BI) protein level in the liver was significantly lower in AdABCA1 mice than in control and AdA-I mice.

CONCLUSION

Hepatocyte-specific ABCA1 transfer decreases SR-BI protein level in the liver and abrogates beneficial effects of HDL on EPCs and endothelial cells. Decreased HDL function may underlie accelerated atherosclerosis in AdABCA1 apo E(-/-)mice.

摘要

目的

三磷酸腺苷结合盒转运子 A1（ABCA1）使载脂蛋白（apo）A-I 脂质化。通过比较鼠源 ABCA1（AdABCA1）和人源 apo A-I（AdA-I）转染对脂蛋白谱、高密度脂蛋白（HDL）功能和动脉粥样硬化进展的影响，评估了肝细胞特异性 ABCA1 过表达导致 HDL 功能障碍的假说。

方法和结果

在雄性和雌性 C57BL/6 apo E（-/-）小鼠 3 个月大时，用含有肝细胞特异性表达盒的 E1E3E4 缺失腺病毒载体进行基因转染。在 AdABCA1、AdA-I 和对照小鼠中，在基线和 56 天后定量测定动脉粥样硬化。AdA-I 转染后雄性和雌性小鼠的 HDL 胆固醇分别增加 1.7 倍（P < 0.001）和 1.8 倍（P < 0.001），并与各自的对照相比强力抑制动脉粥样硬化进展。尽管 AdABCA1 转染后雄性和雌性小鼠的 HDL 胆固醇分别增加 1.4 倍（P < 0.01）和 1.7 倍（P < 0.01），但雄性小鼠的内膜比各自的对照大 2.2 倍（P < 0.001），而雌性小鼠的内膜比各自的对照大 1.3 倍（P = NS）。与对照和 AdA-I 小鼠的 HDL 相比，从 AdABCA1 小鼠分离的 HDL 体外增强内皮祖细胞（EPC）迁移，并减少血清和生长因子耗尽后内皮细胞死亡。与对照和 AdA-I 小鼠相比，AdABCA1 小鼠肝脏中的清道夫受体 B 型 I（SR-BI）蛋白水平显著降低。