Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
PLoS One. 2009 Dec 1;4(12):e8089. doi: 10.1371/journal.pone.0008089.
Hepatic fat deposition with hepatocellular damage, a feature of non-alcoholic fatty liver disease, is mediated by several putative factors including prostaglandins. In the present study, we examined whether group IVA phospholipase A(2) (IVA-PLA(2)), which catalyzes the first step in prostanoid biosynthesis, is involved in the development of fatty liver, using IVA-PLA(2)-knockout mice. Male wild-type mice on high-fat diets (20% fat and 1.25% cholesterol) developed hepatocellular vacuolation and liver hypertrophy with an increase in the serum levels of liver damage marker aminotransferases when compared with wild-type mice fed normal diets. These high-fat diet-induced alterations were markedly decreased in IVA-PLA(2)-knockout mice. Hepatic triacylglycerol content was lower in IVA-PLA(2)-knockout mice than in wild-type mice under normal dietary conditions. Although high-fat diets increased hepatic triacylglycerol content in both genotypes, the degree was lower in IVA-PLA(2)-knockout mice than in wild-type mice. Under the high-fat dietary conditions, IVA-PLA(2)-knockout mice had lower epididymal fat pad weight and smaller adipocytes than wild-type mice. The serum level of prostaglandin E(2), which has a fat storage effect, was lower in IVA-PLA(2)-knockout mice than in wild-type mice, irrespective of the kind of diet. In both genotypes, high-fat diets increased serum leptin levels equally between the two groups, but did not affect the serum levels of adiponectin, resistin, free fatty acid, triacylglycerol, glucose, or insulin. Our findings suggest that a deficiency of IVA-PLA(2) alleviates fatty liver damage caused by high-fat diets, probably because of the lower generation of IVA-PLA(2) metabolites, such as prostaglandin E(2). IVA-PLA(2) could be a promising therapeutic target for obesity-related diseases including non-alcoholic fatty liver disease.
肝脂肪沉积伴有肝细胞损伤，这是一种非酒精性脂肪肝疾病的特征，由几种假定因素介导，包括前列腺素。在本研究中，我们研究了是否第四组磷脂酶 A2（IVA-PLA2），它催化前列腺素生物合成的第一步，是否参与了脂肪肝的发展，使用 IVA-PLA2-敲除小鼠。雄性野生型高脂肪饮食（20%脂肪和 1.25%胆固醇）的小鼠与正常饮食喂养的野生型小鼠相比，出现肝细胞空泡化和肝肥大，血清肝损伤标志物转氨酶水平升高。这些高脂肪饮食引起的改变在 IVA-PLA2-敲除小鼠中明显减少。IVA-PLA2-敲除小鼠在正常饮食条件下的肝三酰甘油含量低于野生型小鼠。虽然高脂肪饮食增加了两种基因型的肝三酰甘油含量，但 IVA-PLA2-敲除小鼠的程度低于野生型小鼠。在高脂肪饮食条件下，IVAPLA2-敲除小鼠的附睾脂肪垫重量和脂肪细胞体积小于野生型小鼠。具有脂肪储存作用的前列腺素 E2 的血清水平在 IVA-PLA2-敲除小鼠中低于野生型小鼠，而与饮食类型无关。在两种基因型中，高脂肪饮食同样增加了两组血清瘦素水平，但不影响血清脂联素、抵抗素、游离脂肪酸、三酰甘油、葡萄糖或胰岛素水平。我们的研究结果表明，IVA-PLA2 的缺乏减轻了高脂肪饮食引起的脂肪肝损伤，可能是由于 IVA-PLA2 代谢物，如前列腺素 E2 的生成减少。IVA-PLA2 可能是肥胖相关疾病（包括非酒精性脂肪肝疾病）的一个有前途的治疗靶点。
