2. Academic Validation
  3. Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ( Adgrf1)

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

  • Elife. 2023 Aug 15;12:e85131. doi: 10.7554/eLife.85131.
Mengyao Wu 1,  Tak-Ho Lo 2,  Liping Li 3,  Jia Sun 3,  Chujun Deng 2,  Ka-Ying Chan 2,  Xiang Li 2,  Steve Ting-Yuan Yeh 4,  Jimmy Tsz Hang Lee 5 6,  Pauline Po Yee Lui 7,  Aimin Xu 5 6,  Chi-Ming Wong 2 6 8
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, China.
  • 2 Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong.
  • 3 Zhujiang Hospital, Southern Medical University, China, China.
  • 4 Ionis Pharmaceuticals, Carlsbad, United States.
  • 5 Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.
  • 7 Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 8 Hong Kong Polytechnic University, Shenzhen Research Institute, Hong Kong, China.
PMID: 37580962 DOI: 10.7554/eLife.85131
Abstract

Background: Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous Cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism.

Methods: We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 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.

Results: The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial Enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively.

Conclusions: These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 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 Adgrf1.

Funding: 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.

Keywords

SCD1; cell biology; fatty liver; gpr110; human; lipid metabolism; medicine; mouse; obesity.

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