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TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase
Suowen Xu, … , Yan-Xiao Ji, Jianping Weng
Suowen Xu, … , Yan-Xiao Ji, Jianping Weng
Published January 11, 2024
Citation Information: J Clin Invest. 2024;134(5):e166149. https://doi.org/10.1172/JCI166149.
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Research Article Hepatology Article has an altmetric score of 12

TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase

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Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination–dependent degradation. Finally, using artificial intelligence–based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.

Authors

Suowen Xu, Xiumei Wu, Sichen Wang, Mengyun Xu, Tingyu Fang, Xiaoxuan Ma, Meijie Chen, Jiajun Fu, Juan Guo, Song Tian, Tian Tian, Xu Cheng, Hailong Yang, Junjie Zhou, Zhenya Wang, Yanjun Yin, Wen Xu, Fen Xu, Jinhua Yan, Zhihua Wang, Sihui Luo, Xiao-Jing Zhang, Yan-Xiao Ji, Jianping Weng

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Figure 3

Hepatocyte TRIM56 protects against HFD-induced hepatic steatosis.

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Hepatocyte TRIM56 protects against HFD-induced hepatic steatosis.
(A) Sc...
(A) Scheme for the generation of hepatocyte-specific Trim56-KO mice (Trim56-HepKO) and western blot validation (n = 3). (B) Body weight and liver weight of WT and Trim56-HepKO after 16 weeks of HFD feeding (n = 6 for NCD; n = 8 for HFD). One-way ANOVA followed by Bonferroni’s post hoc test for body weight and Tamhane’s T2 analysis for liver weight. (C) Liver TG content in WT and Trim56-HepKO. after 16 weeks of HFD feeding (n = 6 for NCD; n = 8 for HFD) for B and C. (D) Representative H&E and Oil Red O staining of liver sections from mice indicated groups of the indicated groups (n = 4). Scale bars: 50 μm. (E) Serum TC content of WT and Trim56-HepKO mice after 16 weeks of HFD feeding (n = 8). Two-tailed Student’s t test. (F) Serum ALT and AST levels of the mice after 16 weeks of HFD feeding (n = 8). Two-tailed Student’s t test. (G) Cluster profile of WT and Trim56-HepKO mice fed a HFD for 16 weeks. (H) Enriched pathway analysis of liver tissues from Trim56-HepKO mice versus control mice (n = 3). (I) Heatmap illustrating overrepresented pathways of fatty acid biosynthesis, lipid metabolism, and steroid metabolism genes in liver tissues from Trim56-HepKO mice (n = 3). (J) GSEA showing overrepresentedthat pathways of fatty acid biosynthesis, lipid metabolism, and steroid metabolism genes were overrepresented in liver tissues from Trim56-HepKO mice (n = 3). (K) Scheme for the generation of hepatocyte-specific Trim56-overexpressing mice (Trim56-HepOE) and using Trim56–sleeping beauty plasmid injection. Control mice receive an injection of empty vector. Successful deletion of TRIM56 protein in the liver was verified by Western blotting validation (n = 3). (L) Body weight and liver weight of WT (GFP) and Trim56-HepOE mice after 16 weeks of NCD or HFD feeding (n = 8). One-way ANOVA followed by Bonferroni’s post hoc test for body weight and Tamhane’s T2 analysis for liver weight. (M) Liver TG content in WT and Trim56-HepOE mice after 16 weeks of HFD feeding (n = 8). Mann-Whitney U test. (N) Representative H&E and Oil Red O staining of liver sections from mice in the indicated groups (n = 3). Scale bars: 50 μm. (O) Serum TC content of WT and Trim56-HepOE mice after 16 weeks of HFD feeding (n = 8). Two-tailed Student’s t test. (P) Serum ALT and AST content levels in WT and Trim56-HepOE mice after 16 weeks of HFD feeding (n = 8). Two-tailed Student’s t test. *P < 0.05 and **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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