Mechanisms for the development of atherosclerosis with low HDL levels and of fatty liver

低 HDL 水平动脉粥样硬化和脂肪肝的发生机制

基本信息

批准号：
20590072
负责人：
AKIBA Satoshi
金额：
$ 3万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Metabolic syndrome with local inflammation progresses to atherosclerosis and non-alcoholic fatty liver disease (NAFLD). The present study examined the possible involvement of group IVA phospholipase A_2 (IVA-PLA_2), which catalyzes the first step of the biosynthesis of inflammatory lipid mediators, in the development of (1) atherosclerosis and (2) NAFLD using IVA-PLA_2-knockout (KO) mice.(1) Wild-type mice on high-fat diets developed the formation of atherosclerotic lesions in the aortic root with low serum levels of HDL-cholesterol (HDL-C), compared with wild-type mice fed normal diets. IVA-PLA_2-KO mice on high-fat diets exhibited resistance to the formation of lesions even with low serum levels of HDL-C. These findings indicate that a deficiency of IVA-PLA_2 alleviates the high-fat diet-induced formation of atherosclerotic lesions without improving dyslipidemia.(2) Wild-type mice on high-fat diets developed fatty liver, compared with wild-type mice fed normal diets. However, these high-fat diet-induced alterations were markedly decreased in IVA-PLA_2-KO mice. Furthermore, high-fat diets induced liver fibrosis with the expression of collagen type I A_2 and transforming growth factor-β mRNA in the liver of wild-type mice but not IVA-PLA_2-KO mice. These findings indicate that a deficiency of IVA-PLA_2 protected mice against the high-fat diet-induced development of NAFLD with fibrosis.The present results suggest the possible involvement of IVA-PLA_2 in development of atherosclerosis and NAFLD.

局部炎症的代谢综合征发展为动脉粥样硬化和非酒精性脂肪肝病（NAFLD）。本研究检查了IVA磷脂酶A_2（IVA-PLA_2）的可能参与，该研究催化了炎症性脂质介质的生物合成的第一步，在（1）动脉粥样硬化和（2）NAFLD NAFLA-PLA_2-pla_2-knockockouckockout（KO）wirtsemiate（KO）wirtsemiate（KO）中（1）NAFLACE（1）NAFLACE（KO）。与喂养正常饮食的野生型小鼠相比，血清血清胆固醇（HDL-C）水平较低的主动脉根部的动脉粥样硬化病变形成。高脂饮食上的IVA-PLA_2-KO小鼠即使血清血清水平低的HDL-C，也暴露了对病变形成的抗性。这些发现表明，IVA-PLA_2的缺乏减轻了高脂饮食诱导的动脉粥样硬化病变的形成而不会改善血脂异常。（2）与喂养正常饮食的野生饮食相比，高脂饮食上野生饮食中野生型小鼠发育的脂肪肝脏。但是，这些高脂饮食引起的改变在IVA-PLA_2-KO小鼠中明显降低。此外，高脂饮食以I型A_2的表达诱导肝纤维化，并在野生型小鼠的肝脏中转化生长因子-βMRNA，但不转化IVA-PLA_2-KO小鼠。这些发现表明，IVA-PLA_2的缺乏保护小鼠免受高脂饮食诱导的NAFLD发育而使用纤维化的发育。目前的结果表明，IVA-PLA_2可能参与动脉粥样硬化和NAFLD的发展。