Tripartite motif 16 ameliorates nonalcoholic steatohepatitis by promoting the degradation of phospho-TAK1

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and liver disorders have become the leading causes for the need of liver transplantation in developed countries. Lipotoxicity plays a central role in NASH progression by causing endoplasmic reticulum stress and disrupting protein homeostasis. To identify key molecules that mitigate the detrimental consequences of lipotoxicity, we performed integrative multiomics analysis and identified the E3 ligase tripartite motif 16 (TRIM16) as a candidate molecule. In particular, we found that lipid accumulation and inflammation in a mouse NASH model is mitigated by TRIM16 overexpression but aggravated by its depletion. Multiomics analysis showed that TRIM16 suppressed NASH progression by attenuating the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; specifically, by preferentially interacting with phospho-TAK1 to promote its degradation. Together, these results identify TRIM16 as a promising therapeutic target for the treatment of NASH. [Display omitted] •TRIM16 is transcriptionally activated by EGR2 in response to lipotoxicity•TRIM16 ameliorates lipid accumulation and inflammation during NASH progression•TRIM16 inhibits the JNK/p38 pathway by catalyzing ubiquitin-mediated degradation of pTAK1•AAV8-mediated TRIM16 overexpression attenuates NASH progression in HFHC-fed mice Wang et al. report that TRIM16 ameliorates lipid accumulation and inflammation during NASH progression by facilitating the ubiquitination-dependent degradation of phospho-TAK1. Further, they show that overexpressing TRIM16 in a mouse model of NASH ameliorates pathology.