The Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, CA, 90033, United States.
Department of Research and Development, PhoenixBio Co., Ltd., Higashi-Hiroshima, Hiroshima, 739-0046, Japan.
Prostaglandins Other Lipid Mediat. 2021 Oct;156:106577. doi: 10.1016/j.prostaglandins.2021.106577. Epub 2021 Jun 17.
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关注点，其特征是肝细胞中甘油三酯的积累和肝脏的炎症。脂肪变性是由脂质的流入和流出、脂肪生成和线粒体 β-氧化的失调引起的。细胞外溶血磷脂酸（LPA）在发育、组织损伤和癌症中调节广泛的细胞过程。在本研究中，我们研究了 LPA 在 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 mRNAs。用 pan-LPAR 或 LPAR1 的抑制剂治疗可减少 MCD 饮食喂养的小鼠中的脂肪变性。Lpar1 基因在肝细胞中的特异性缺失也减少了 MCD 模型中的脂肪变性。肝细胞中 Lpar1 基因的缺失降低了编码脂肪酸转运蛋白的 Cd36 基因的表达。尽管 LPA/LPAR1 信号诱导了肝细胞中 Srebp1 mRNA 的表达，但 LPA 不能完全诱导参与脂肪生成的 SREBP1 靶基因的表达。已知在嵌合体小鼠中重新填充的人肝细胞会发生脂肪变性，并且 LPAR1 抑制剂的治疗可降低 CD36 mRNA 的表达和脂肪变性。我们的数据表明，LPAR1 拮抗剂通过下调 Cd36 减少了小鼠和人肝细胞中的脂肪变性。
