OVEREXPRESSION OF HUMAN LECITHIN CHOLESTERYL ACYLTRANSFERASE IN TRANSGENIC MICE

转基因小鼠中人卵磷脂胆固醇酰基转移酶的过度表达

• 批准号: 6162693
• 负责人: S SANTAMARINA-FOJO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162693
• 关键词: Adenoviridae; atherosclerosis; blood lipoprotein metabolism; cholesterol; enzyme activity; gene expression; genetically modified animals; hepatic lipase; high density lipoproteins; laboratory mouse; phosphatidylcholine sterol acyltransferase; transfection

Despite increased plasma concentrations of HDL and apoA-I, LCAT transgenic (L-Tg) mice have enhance diet-induced atherosclerosis. In contrast, expression of the same transgene in NZW rabbits results in reduced aortic atherosclerosis. One of the major differences in the HDL metabolism between these two transgenic animal models is a deficiency of cholesteryl ester transfer protein (CETP) in mice. To evaluate whether CETP deficiency modulates the development of atherosclerosis in L-Tg mice we crossed CETP-Tg x L-Tg mice. Compared to L-Tg mice, CETP x L-Tg mice had reduced plasma concentrations of cholesterol, cholesteryl esters, HDL-C and apoE (-44%,-68%, -49% and -57% that of L-Tg; p<0.05). FPLC analysis revealed a marked reduction of apoE-rich HDL1. Despite decreased plasma concentrations of HDL-C, CETP x L-Tg mice had reduced diet-induced aortic atherosclerosis (40% that of L-Tg; p<0.001). Thus, CETP expression reduces HDL heterogeneity and concentrations in L-Tg mice. CETP-mediated transfer of CE from HDL to apoB-containing lipoproteins may normalize L-Tg mouse HDL composition and function, thereby reducing LCAT induced atherosclerosis in mice.

尽管HDL和apoA-I的血浆浓度增加，LCAT 转基因（L-Tg）小鼠增强了饮食诱导动脉粥样硬化。在 相反，在NZW兔中表达相同的转基因导致 减少主动脉粥样硬化。HDL的主要区别之一是 这两种转基因动物模型之间的代谢是一个缺陷， 胆固醇酯转移蛋白（CETP）。评价 CETP缺乏是否调节动脉粥样硬化的发展， 我们将CETP-Tg × L-Tg小鼠杂交。与L-Tg小鼠相比，CETP x L-Tg小鼠具有降低的胆固醇血浆浓度， 胆固醇酯、HDL-C和apoE（分别为对照组的-44%、-68%、-49%和-57 L-Tg; p<0.05）。FPLC分析显示，富含apoE的 HDL 1。 尽管HDL-C血浆浓度降低，CETP x L-Tg 小鼠具有减少的饮食诱导的主动脉粥样硬化（L-Tg的40%; p<0.001）。因此，CETP表达降低HDL异质性， L-Tg小鼠中的浓度。CETP介导的CE从HDL转移到 含载脂蛋白B的脂蛋白可使L-Tg小鼠HDL组成正常化 和功能，从而减少小鼠中LCAT诱导的动脉粥样硬化。