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

代谢综合征伴局部炎症发展为动脉粥样硬化和非酒精性脂肪性肝病（NAFLD）。本研究以IVA- pla_2敲除（KO）小鼠为研究对象，探讨IVA磷脂酶A_2 （IVA- pla_2）可能参与了(1)动脉粥样硬化和(2)NAFLD的发生。IVA- pla_2是炎症性脂质介质生物合成的第一步催化剂。(1)与正常饮食的野生型小鼠相比，高脂肪饮食的野生型小鼠在主动脉根部形成动脉粥样硬化病变，血清高密度脂蛋白胆固醇（HDL-C）水平较低。高脂肪饮食的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。这些结果表明，缺乏IVA-PLA_2可以减轻高脂肪饮食诱导的动脉粥样硬化病变的形成，但不会改善血脂异常。(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出现了脂肪肝。然而，这些高脂肪饮食引起的改变在IVA-PLA_2-KO小鼠中明显减少。此外，高脂肪饮食可诱导野生型小鼠肝脏I型胶原A_2和转化生长因子-β mRNA的表达，而IVA-PLA_2-KO小鼠无此作用。这些发现表明，缺乏IVA-PLA_2可以保护小鼠免受高脂肪饮食诱导的NAFLD伴纤维化的发展。提示IVA-PLA_2可能参与动脉粥样硬化和NAFLD的发生。

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.