MiR‐484 promotes nonalcoholic fatty liver disease progression in mice via downregulation of Sorbs2

• Published in: Obesity (Silver Spring, Md.) Vol. 31; no. 12; pp. 2972 - 2985
• Main Authors: Jia, Yinzhao, Pan, Hao, Liu, Jing, Huang, Tiezeng, Han, Ke, Mei, Qiaojuan, Zeng, Ling, Zhou, Jinzhao, Zhang, Yong
• Format: Journal Article
• Language: English
• Published: United States 01.12.2023
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Diet, High-Fat; Down-Regulation; Hepatocytes - metabolism; Humans; Lipid Metabolism - genetics; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; RNA-Binding Proteins - genetics
• ISSN: 1930-7381; 1930-739X
• DOI: 10.1002/oby.23884

Objective MicroRNA 484 (miR‐484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether miR‐484 is involved in lipid metabolism or exerts a role in nonalcoholic fatty liver disease remains unclear. Methods miR‐484 levels were examined in the livers of male mice fed a high‐fat diet and in hepatocytes treated with free fatty acids. Sorbin and SH3 structural domain‐containing protein 2 (Sorbs2) were identified as a novel target of miR‐484 by sequencing mRNA in the livers of miR‐484 knockout mice. Sorbs2 liver‐specific knockdown mice were constructed by tail vein injection of adeno‐associated virus vector to miR‐484 knockout mice. In addition, genetic manipulation of SORBS2 was performed in human hepatocyte lines, mouse primary hepatocytes, and the liver. Results Serum and hepatic miR‐484 levels are upregulated in nonalcoholic fatty liver disease mice. miR‐484 knockdown ameliorated hepatocyte steatosis, whereas miR‐484 overexpression increased hepatocyte lipid load. miR‐484 knockdown‐mediated alleviation of hepatic steatosis, liver injury, inflammation, and apoptosis was compromised after high‐fat diet‐induced knockdown of Sorbs2 in mouse liver and free fatty acid‐induced primary mouse hepatocytes. Conclusions These results identify Sorbs2‐mediated mitochondrial β‐oxidation and apoptosis that promote miR‐484 knockdown‐mediated remission of hepatic steatosis. miR‐484 targets Sorbs2 to mediate NAFLD onset