1. Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.
- Author
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Jiang, Joy X, Tomilov, Alexey, Montgomery, Claire, Hui, Chun Kui, Török, Natalie J, and Cortopassi, Gino
- Subjects
Liver ,Leukocytes ,Mononuclear ,Animals ,Mice ,Inbred C57BL ,Mice ,Liver Cirrhosis ,Choline Deficiency ,Disease Models ,Animal ,Ubiquinone ,Alanine Transaminase ,Aspartate Aminotransferases ,Methionine ,Protective Agents ,Therapeutics ,Diet ,Signal Transduction ,Phosphorylation ,Male ,Shc Signaling Adaptor Proteins ,Fast Foods ,Non-alcoholic Fatty Liver Disease ,NASH ,Shc ,fibrosis ,idebenone ,inflammation ,Chronic Liver Disease and Cirrhosis ,Biotechnology ,Digestive Diseases ,Hepatitis ,Liver Disease ,Nutrition ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Oral and gastrointestinal ,Pharmacology and Pharmaceutical Sciences ,Toxicology - 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.
- Published
- 2021