1840-P: GPR40 Deficiency Is Associated with Steatosis, Hepatic Inflammation, and CD36 Upregulation in C57BL/6 Mice

Abstract

GPR40 is a G-protein coupled receptor for medium and long-chain fatty acids. Since GPR40 is highly expressed in pancreatic islets and GPR40 activation increases glucose-stimulated insulin secretion from pancreatic beta cells, GPR40 is considered as a potential target for treatment of type 2 diabetes mellitus (T2DM). However, although nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM and GPR40 is also expressed in hepatocytes and macrophages, the role of GPR40 in high-fat diet (HFD)-induced NAFLD in animal models remains unknown. In this study, we fed wild type or GPR40 knockout (KO) C57BL/6 mice low-fat diet (LFD) or HFD for 20 weeks and then analyzed the effect of GPR40 KO on HFD-induced NAFLD. Metabolic assays showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT) as expected, but GPR40 KO did not further change these parameters in HFD-fed mice. Interestingly, in LFD-fed mice, GPR40 KO increased bodyweight, insulin, insulin resistance, cholesterol and ALT. Histological analysis and Oil Red O staining showed that HFD induced steatosis while GPR40 KO only slightly reduced HFD-induced steatosis. Surprisingly, GPR40 KO in LFD-fed mice induced steatosis. Furthermore, study showed that while HFD increased immunostaining of F4/80, a biomarker for macrophages, GPR40 KO also increased F4/80 immunostaining in LFD-fed mice. Finally, we found that while HFD increased mRNA expression of CD36, a scavenger receptor that also imports long-chain fatty acids into cells, by 5-fold in liver, GPR40 KO increased it by 9-fold in LFD-fed mice. Taken together, this study showed that GPR40 deficiency was associated with insulin resistance, dyslipidemia, steatosis and hepatic inflammation in LFD-fed mice. This study also showed that GPR40-deficiency led to a robust upregulation of CD36 expression in liver, which is likely involved in GPR40 deficiency-associated steatosis and hepatic inflammation. Disclosure Z. Lu: None. Y. Li: None. M.F. Lopes-Virella: None. Y. Huang: None. Funding National Institutes of Health (DE027070); U.S. Department of Veterans Affairs (BX000854)