Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ( Adgrf1 )

Recent research has shown that the adhesion G protein-coupled receptor F1 ( also known as ) is an oncogene. The evidence is mainly based on high expression of in numerous cancer types, and knockdown can reduce the cell migration, invasion, and proliferation. is, however, mostly expressed in the liver of healthy individuals. The function of in liver has not been revealed. Interestingly, expression level of hepatic is dramatically decreased in obese subjects. Here, the research examined whether 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 expression level in diet-induced obese mice to investigate the role of 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 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 ( ), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of by RNA-sequencing analysis. Treatment with the liver-specific inhibitor MK8245 and specific shRNAs against in primary hepatocytes improved the hepatic steatosis of -overexpressing mice and lipid profile of hepatocytes, respectively. These results indicate regulates hepatic lipid metabolism through controlling the expression of . Downregulation of 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 . 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.