Loss of lysophosphatidic acid receptor 1 in hepatocytes reduces steatosis via down-regulation of CD36.

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.