TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation

Cell Metab. 2020 Apr 7;31(4):726-740.e8. doi: 10.1016/j.cmet.2020.03.007.

Abstract

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.

Keywords: NASH; TAK1; TGF-β-activated kinase 1; TNFAIP3 interacting protein 3; TNIP3; TRIM8; nonalcoholic steatohepatitis; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver* / metabolism
  • Liver* / pathology
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • TNIP3 protein, human
  • TRIM8 protein, human
  • Trim8 protein, mouse
  • Ubiquitin-Protein Ligases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tnfaip3 protein, mouse