Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice

Joy X. Jiang, Alexey Tomilov, Claire Montgomery, Chun Kui Hui, Natalie J. Török, Gino Cortopassi

Research output: Contribution to journalArticlepeer-review

Abstract

Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH—thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.

Original languageEnglish (US)
Article numbere22876
JournalJournal of Biochemical and Molecular Toxicology
Volume35
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • fibrosis
  • idebenone
  • inflammation
  • NASH
  • Shc

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Toxicology
  • Health, Toxicology and Mutagenesis

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