Nonalcoholic steatohepatitis is a major public health concern and is characterized by the accumulation of triglyceride in hepatocytes and inflammation in the liver. Steatosis is caused by dysregulation of the influx and efflux of lipids, lipogenesis, and mitochondrial β-oxidation. Extracellular lysophosphatidic acid (LPA) regulates a broad range of cellular processes in development, tissue injury, and cancer. In the present study, we examined the roles of LPA in steatohepatitis induced by a methionine-choline-deficient (MCD) diet in mice. Hepatocytes express LPA receptor (Lpar) 1-3 mRNAs. Steatosis developed in mice fed the MCD diet was reduced by treatment with inhibitors for pan-LPAR or LPAR1. Hepatocyte-specific deletion of the Lpar1 gene also reduced the steatosis in the MCD model. Deletion of the Lpar1 gene in hepatocytes reduced expression of Cd36, a gene encoding a fatty acid transporter. Although LPA/LPAR1 signaling induces expression of Srebp1 mRNA in hepatocytes, LPA does not fully induce expression of SREBP1-target genes involved in lipogenesis. Human hepatocytes repopulated in chimeric mice are known to develop steatosis and treatment with an LPAR1 inhibitor reduces expression of CD36 mRNA and steatosis. Our data indicate that antagonism of LPAR1 reduces steatosis in mouse and human hepatocytes by down-regulation of Cd36.

非酒精性脂肪性肝炎是一个主要的公共卫生问题，其特征是肝细胞中甘油三酯的积累和肝脏炎症。脂肪变性是由脂质流入和流出、脂肪生成和线粒体β-氧化失调引起的。细胞外溶血磷脂酸 (LPA) 调节发育、组织损伤和癌症中的广泛细胞过程。在本研究中，我们研究了 LPA 在蛋氨酸胆碱缺乏 (MCD) 饮食诱导的小鼠脂肪性肝炎中的作用。肝细胞表达 LPA 受体 ( Lpar ) 1-3 mRNA。通过使用泛 LPAR 或 LPAR1 抑制剂进行治疗，可以减少喂食 MCD 饮食的小鼠中发生的脂肪变性。肝细胞特异性删除Lpar1基因也减少了 MCD 模型中的脂肪变性。肝细胞中Lpar1基因的缺失会降低Cd36 （一种编码脂肪酸转运蛋白的基因）的表达。尽管 LPA/LPAR1 信号传导诱导肝细胞中Srebp1 mRNA 的表达，但 LPA 并不能完全诱导参与脂肪生成的 SREBP1 靶基因的表达。已知在嵌合小鼠中重新填充的人类肝细胞会发生脂肪变性，并且用 LPAR1 抑制剂治疗可减少CD36 mRNA 的表达和脂肪变性。我们的数据表明，LPAR1 的拮抗作用通过下调Cd36来减少小鼠和人类肝细胞的脂肪变性。