GPR40 is highly expressed in pancreatic islets and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice high-fat diet (HFD) for 20 weeks and then assessed the effect of GPR40-deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT), and GPR40-deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40-deficiency was associated with increased bodyweight, insulin, insulin resistance, cholesterol and ALT in control mice fed low fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40-deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40-deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40-deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.
GPR40-Deficiency Is Associated with Hepatic FAT/CD36 Upregulation, Steatosis, Inflammation and Cell Injury in C57BL/6 Mice