Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 (<i>Adgrf1</i>).

Abstract

Recent research has shown that the adhesion G protein-coupled receptor F1 (<i>Adgrf1;</i> also known as <i>GPR110; PGR19; KPG_012; hGPCR36</i>) is an oncogene. The evidence is mainly based on high expression of <i>Adgrf1</i> in numerous cancer types, and knockdown <i>Adgrf1</i> can reduce the cell migration, invasion, and proliferation. <i>Adgrf1</i> is, however, mostly expressed in the liver of healthy individuals. The function of <i>Adgrf1</i> in liver has not been revealed. Interestingly, expression level of hepatic <i>Adgrf1</i> is dramatically decreased in obese subjects. Here, the research examined whether <i>Adgrf1</i> has a role in liver metabolism. We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic <i>Adgrf1</i> expression level in diet-induced obese mice to investigate the role of <i>Adgrf1</i> in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. The expression of <i>Adgrf1</i> in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (<i>Scd1</i>), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of <i>Adgrf1</i> by RNA-sequencing analysis. Treatment with the liver-specific <i>Scd1</i> inhibitor MK8245 and specific shRNAs against <i>Scd1</i> in primary hepatocytes improved the hepatic steatosis of <i>Adgrf1</i>-overexpressing mice and lipid profile of hepatocytes, respectively. These results indicate <i>Adgrf1</i> regulates hepatic lipid metabolism through controlling the expression of <i>Scd1</i>. Downregulation of <i>Adgrf1</i> expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting <i>Adgrf1</i>. This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.