2. Academic Validation
  3. MicroRNA-411-5p alleviates lipid deposition in metabolic dysfunction-associated steatotic liver disease by targeting the EIF4G2/FOXO3 axis

MicroRNA-411-5p alleviates lipid deposition in metabolic dysfunction-associated steatotic liver disease by targeting the EIF4G2/FOXO3 axis

  • Cell Mol Life Sci. 2024 Sep 11;81(1):398. doi: 10.1007/s00018-024-05434-6.
Zhiping Wan # 1 2,  Xiaoquan Liu # 1 2,  Xiaoan Yang # 1 2,  Zexuan Huang 2,  Xiaoman Chen 1 2,  Qingqing Feng 1 2,  Hong Cao 3 4,  Hong Deng 5 6
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
  • 2 Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
  • 3 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. caohong@mail.sysu.edu.cn.
  • 4 Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. caohong@mail.sysu.edu.cn.
  • 5 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. dhong@mail.sysu.edu.cn.
  • 6 Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. dhong@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39261317 DOI: 10.1007/s00018-024-05434-6
Abstract

Background: Abnormal lipid deposition is an important driver of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). MicroRNA-411-5p (miR-411-5p) and eukaryotic translation initiation factor 4γ2 (EIF4G2) are related to abnormal lipid deposition, but the specific mechanism is unknown.

Methods: A high-fat, high-cholesterol diet (HFHCD) and a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and a high-fructose diet (HFrD) were used to establish MASLD rat and mouse models, respectively. MiR-411-5p agomir and mimic were used to upregulate the miR-411-5p in vivo and in vitro, respectively. Adeno-associated virus type 8 (AAV8) carrying EIF4G2 short hairpin RNA (shRNA) and small interfering RNA (siRNA) were used to downregulate the EIF4G2 expression in vivo and in vitro, respectively. Liver histopathological analysis, Biochemical analysis and other experiments were used to explore the functions of miR-411-5p and EIF4G2.

Results: MiR-411-5p was decreased in both MASLD rats and mice, and was negatively correlated with liver triglycerides and serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. Upregulation of miR-411-5p alleviated liver lipid deposition and hepatocellular steatosis. Moreover, miR-411-5p targeted and downregulated EIF4G2. Downregulation of EIF4G2 not only reduced liver triglycerides and serum ALT and AST levels in MASLD model, but also alleviated lipid deposition. Notably, upregulation of miR-411-5p and downregulation of EIF4G2 led to the reduction of forkhead box class O3 (FOXO3) and inhibited the expression of sterol regulatory-element binding protein 1 (SREBP1), Acetyl-CoA Carboxylase 1 (ACC1) and fatty acid synthase (FASN), thereby reducing fatty acid synthesis.

Conclusions: Upregulation of miR-411-5p inhibits EIF4G2 to reduce the FOXO3 expression, thereby reducing fatty acid synthesis and alleviating abnormal lipid deposition in MASLD.

Keywords

Fat metabolism; Fatty liver disease; MicroRNA.

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