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

Cell Metab. 2021 Jul 6;33(7):1372-1388.e7. doi: 10.1016/j.cmet.2021.05.019. Epub 2021 Jun 18.

Abstract

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.

Keywords: TAK1; TRIM16; nonalcoholic steatohepatitis; phosphorylation; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • HEK293 Cells
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver / metabolism*
  • Liver / pathology
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Proteolysis
  • Signal Transduction / genetics
  • Tripartite Motif Proteins / physiology*
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • Phosphoproteins
  • Tripartite Motif Proteins
  • Trim16 protein, mouse
  • Ubiquitin-Protein Ligases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7