Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.
Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, South Carolina.
Am J Physiol Endocrinol Metab. 2021 Jan 1;320(1):E30-E42. doi: 10.1152/ajpendo.00257.2020. Epub 2020 Oct 26.
G-protein-coupled receptor 40 (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 a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, 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 body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a 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 a 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.
G 蛋白偶联受体 40（GPR40）在胰腺胰岛中高度表达，其激活可增加胰腺的葡萄糖刺激胰岛素分泌。因此，GPR40 被认为是 2 型糖尿病（T2DM）的靶点。由于非酒精性脂肪性肝病（NAFLD）与 T2DM 相关，并且 GPR40 也由肝细胞和巨噬细胞表达，因此了解 GPR40 在 NAFLD 中的作用很重要。然而，GPR40 在动物模型中的 NAFLD 中的作用尚未得到很好的定义。在这项研究中，我们用高脂肪饮食（HFD）喂养野生型或 GPR40 敲除 C57BL/6 小鼠 20 周，然后评估 GPR40 缺失对 HFD 诱导的 NAFLD 的影响。代谢参数检测显示，HFD 增加了体重、葡萄糖、胰岛素、胰岛素抵抗、胆固醇和丙氨酸转氨酶（ALT），而 GPR40 缺失并没有减轻 HFD 引起的代谢异常。相反，我们发现 GPR40 缺失与对照组低脂饮食（LFD）喂养小鼠的体重、胰岛素、胰岛素抵抗、胆固醇和 ALT 增加有关。令人惊讶的是，组织学和油红 O 染色显示，LFD 喂养的 GPR40 缺失小鼠的脂肪变性增加。免疫组织化学分析显示，GPR40 缺失也增加了 LFD 喂养小鼠的巨噬细胞标志物 F4/80。此外，结果表明，GPR40 缺失导致肝脂肪酸转运蛋白（FAT）/CD36 的表达显著上调。最后，我们的体外研究表明，siRNA 敲低或 GPR40 拮抗剂可增加棕榈酸诱导的肝细胞 FAT/CD36 mRNA。综上所述，这项研究表明，GPR40 在肝脏代谢和炎症的稳态中起重要作用，并通过可能调节 FAT/CD36 的表达来抑制非酒精性脂肪性肝炎。
