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

伴有局部炎症的代谢综合征进展为动脉粥样硬化和非酒精性脂肪性肝病（NAFLD）。本研究采用IVA-PLA_2基因敲除（KO）小鼠，探讨了Ⅳ A族磷脂酶A_2（IVA-PLA_2）在（1）动脉粥样硬化（AS）和（2）非酒精性脂肪肝（NAFLD）中的作用。(1)与正常饮食的野生型小鼠相比，高脂饮食的野生型小鼠在主动脉根部形成动脉粥样硬化病变，血清HDL-胆固醇（HDL-C）水平较低。高脂饮食的IVA-PLA_2-KO小鼠即使在低血清HDL-C水平下也表现出对病变形成的抵抗力。提示IVA-PLA_2缺乏可加重高脂饮食引起的动脉粥样硬化病变，但不能改善血脂异常。(2)与正常饮食的野生型小鼠相比，高脂肪饮食的野生型小鼠患上了脂肪肝。而IVA-PLA_2-KO小鼠则明显降低了高脂饮食引起的这些变化。此外，高脂饮食可诱导野生型小鼠肝纤维化，但IVA-PLA_2-KO小鼠肝组织中Ⅰ A_2型胶原和转化生长因子-β mRNA表达无明显变化。这些结果提示IVA-PLA_2缺乏可保护小鼠免受高脂饮食诱导的NAFLD并纤维化的发展，提示IVA-PLA_2可能参与了动脉粥样硬化和NAFLD的发展。

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.