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

Abstract

<h3>Background:</h3><p>Recent research has shown that the adhesion G protein-coupled receptor F1 (<em>Adgrf1;</em> also known as <em>GPR110; PGR19; KPG_012; hGPCR36</em>) is an oncogene. The evidence is mainly based on high expression of <em>Adgrf1</em> in numerous cancer types, and knockdown <em>Adgrf1</em> can reduce the cell migration, invasion, and proliferation. <em>Adgrf1</em> is, however, mostly expressed in the liver of healthy individuals. The function of <em>Adgrf1</em> in liver has not been revealed. Interestingly, expression level of hepatic <em>Adgrf1</em> is dramatically decreased in obese subjects. Here, the research examined whether <em>Adgrf1</em> has a role in liver metabolism.</p><h3>Methods:</h3><p>We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic <em>Adgrf1</em> expression level in diet-induced obese mice to investigate the role of <em>Adgrf1</em> 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.</p><h3>Results:</h3><p>The expression of <em>Adgrf1</em> in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (<em>Scd1</em>), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of <em>Adgrf1</em> by RNA-sequencing analysis. Treatment with the liver-specific <em>Scd1</em> inhibitor MK8245 and specific shRNAs against <em>Scd1</em> in primary hepatocytes improved the hepatic steatosis of <em>Adgrf1</em>-overexpressing mice and lipid profile of hepatocytes, respectively.</p><h3>Conclusions:</h3><p>These results indicate <em>Adgrf1</em> regulates hepatic lipid metabolism through controlling the expression of <em>Scd1</em>. Downregulation of <em>Adgrf1</em> 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 <em>Adgrf1</em>.<br></p>