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

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

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 7

FASN inhibition blocks the effect of Trim56 ablation on lipid accumulation.

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FASN inhibition blocks the effect of Trim56 ablation on lipid accumulati...
(A) Silencing efficiency of adenovirus vector encoding an shRNA against Fasn (Ad-shFasn) in primary mouse hepatocytes. Hepatocytes were infected with control adenovirus (Ad-GFP) or Ad-shFasn (MOI = 2) for 24 hours before whole-cell lysate was collected for Western blotting (n = 3). (B) Primary mouse hepatocytes were isolated from WT and Trim56-KO mice. Then, hepatocytes were infected with Ad-GFP or Ad-shFasn in the presence of PO for 18 hours before intracellular TG levels were determined (n = 6). One-way ANOVA followed by Bonferroni’s post hoc test. (C) Nile Red staining of WT and Trim56-KO hepatocytes treated as described in B (n = 3.). Scale bar: 50 μm. (D) mRNA expression of Scd1, Elovl5, and Elovl6 in hepatocytes from the indicated groups (n = 5). One-way ANOVA followed by Bonferroni’s post hoc test for Elovl5; Kruskal-Wallis test for Scd1 and Elovl6. (E) Effect of the FASN inhibitor C75 on FASN protein expression. Primary mouse hepatocytes were treated with vehicle (0.1%DMSO) or C75 (a pharmacological inhibitor of FASN, 20 μM) for 24 hours (n = 3). (F) Primary mouse hepatocytes were isolated from WT and Trim56-KO mice. Then, hepatocytes were treated with vehicle or C75 (20 μM) in the presence of PO before intracellular TG analysis (n = 6). One-way ANOVA followed by Bonferroni’s post hoc test. (G) Nile Red staining was performed on hepatocytes treated as described in F (n = 3). Scale bar: 50 μm. (H) Enriched pathway analysis in WT and Trim56-KO hepatocytes treated with vehicle control or C75 (20 μM) in the presence of PO (n = 5). (I) Dot analysis of the enriched pathways identified in H (n = 5). (J) Heatmap analysis revealed the expression profile of genes involved in lipid metabolism, fatty acid biosynthesis, and steroid metabolism in WT and Trim56-KO hepatocytes treated with vehicle or C75 (20 μM) (n = 5). *P < 0.05 and ***P < 0.001 (B, D, and F).