Ning Yanxia, Xu Leyuan, Ren Shunlin, Pandak William M, Chen Sifeng, Yin Lianhua
Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, PO Box 224, 138 Yixueyuan Road, 200032, Shanghai, People's Republic China.
Lipids. 2009 Jun;44(6):511-9. doi: 10.1007/s11745-009-3299-1. Epub 2009 Apr 17.
Cholesterol metabolism as initiated by mitochondrial sterol 27-hydroxylase (CYP27A1) is a ubiquitous pathway capable of synthesizing multiple key regulatory oxysterols involved in lipid homeostasis. Previously we have shown that the regulation of its activities within hepatocytes is highly controlled by the rate of mitochondrial cholesterol delivery. In the present study, we hypothesized that increasing expression of the mitochondrial cholesterol delivery protein, steroidogenic acute regulatory protein (StAR), is able to lower lipid accumulation in liver, aortic wall, as well as in serum in a well-documented animal model, apolipoprotein E-deficient (apoE(-/-)) mice. ApoE(-/-) mice, characterized by increased serum, liver, and endothelial cholesterol and triglyceride levels by 3 months of age, were infected with recombinant cytomegalovirus (CMV)-StAR adenovirus to increase StAR protein expression. Six days following infection, serum total cholesterol and triglycerides had decreased 19 and 30% (P < 0.01), respectively, with a compensatory 40% (P < 0.01) increase in serum HDL-cholesterol in increased StAR expressing mice as compared to controls (no or control virus). Histologic and biochemical analysis of the liver demonstrated not only a dramatic decrease in cholesterol ( downward arrow25%; P < 0.01), but an even more marked decrease in triglyceride ( downward arrow56%; P < 0.01) content. En bloc Sudan IV staining of the aorta revealed a >80% (P < 0.01) decrease in neutral lipid staining. This study demonstrates for the first time a possible therapeutic role of the CYP27A1-initiated pathway in the treatment of dyslipidemias.
由线粒体固醇27-羟化酶（CYP27A1）启动的胆固醇代谢是一条普遍存在的途径，能够合成多种参与脂质稳态的关键调节性氧化固醇。此前我们已经表明，其在肝细胞内的活性调节受到线粒体胆固醇递送速率的高度控制。在本研究中，我们假设在一个有充分记录的动物模型——载脂蛋白E缺陷（apoE(-/-)）小鼠中，增加线粒体胆固醇递送蛋白——类固醇生成急性调节蛋白（StAR）的表达能够降低肝脏、主动脉壁以及血清中的脂质积累。3月龄时，apoE(-/-)小鼠的特征是血清、肝脏和内皮胆固醇及甘油三酯水平升高，用重组巨细胞病毒（CMV）-StAR腺病毒感染以增加StAR蛋白表达。感染后6天，与对照组（无病毒或对照病毒）相比，StAR表达增加的小鼠血清总胆固醇和甘油三酯分别降低了19%和30%（P<0.01），血清高密度脂蛋白胆固醇代偿性增加了40%（P<0.01）。肝脏的组织学和生化分析表明，不仅胆固醇显著降低（下降25%；P<0.01），而且甘油三酯含量下降更为明显（下降56%；P<0.01）。主动脉的整体苏丹IV染色显示中性脂质染色减少>80%（P<0.01）。本研究首次证明了CYP27A1启动的途径在治疗血脂异常方面可能具有治疗作用。
