Hepatokine ITIH3 Protects Against Hepatic Steatosis by Downregulating Mitochondrial Bioenergetics and De Novo Lipogenesis

Abstract

Accumulating evidence suggest that mitochondrial functions are altered and contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). As a result, research is being conducted to discover targets that alter mitochondrial functions to ameliorate NAFLD, and its progression towards non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Recent studies demonstrate that liver secretory proteins regulate normal development, obesity, simple steatosis to NASH progression. Inter-α-trypsin inhibitors (ITI) are one such proteins secreted by liver, altered in NAFLD, but their functional importance in mitochondrial metabolism is poorly understood. Here, we have identified that ITIH3 is a potential candidate gene that protects against NAFLD by targeting mitochondrial metabolism. We used an integrative multiomics approach using transcriptomic data from approximately 100 different mouse strains called hybrid mouse diversity panel (HMDP) and a cohort of bariatric surgery patients and identified Itih3/ITIH3 expression to be inversely associated with NAFLD/NASH progression and hepatic TG accumulation. Our network enrichment analyses revealed NAFLD-related pathways such as mitochondria, TCA cycle, fatty acid metabolism, cholesterol metabolism, coagulation and fibrinolysis. Next, disease enrichments by ToppGene revealed metabolic syndrome-related disease traits including dyslipidemia, steatosis, NASH and fibrosis. Our in vitro and in vivo studies using loss and gain of function mouse and cell culture models demonstrated that hepatic ITIH3 reduced liver triglyceride accumulation and de novo lipogenesis (DNL). Remarkably, hepatic ITIH3 also lowered mitochondrial respiration and lipid droplet accumulation. This was accompanied by increased STAT1 signaling and Stat3 expression, both of which are known to protect against NAFLD/NASH. Together, we conclude that ITIH3 plays a unique role in regulating the hepatic lipid profile, DNL, and mitochondrial metabolism, all of which have implications for NAFLD treatment. Our findings indicate hepatokine ITIH3 as a potential biomarker and/or treatment for NAFLD. R00DK120875. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.