biostudies-literatureTalari NKChina Scholarship CouncilNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of Health109709https://www.ebi.ac.uk/biostudies/studies/S-EPMC11059128biostudies-literatureUnknown27(5)Recent studies demonstrate that liver secretory proteins, also known as hepatokines, regulate normal development, obesity, and simple steatosis to non-alcoholic steatohepatitis (NASH) progression. Using a panel of ∼100 diverse inbred strains of mice and a cohort of bariatric surgery patients, we found that one such hepatokine, inter-trypsin inhibitor heavy chain 3 (ITIH3), was progressively lower in severe non-alcoholic fatty liver disease (NAFLD) disease states highlighting an inverse relationship between <i>Itih3</i>/<i>ITIH3</i> expression and NAFLD severity. Follow-up animal and cell culture models demonstrated that hepatic ITIH3 overexpression lowered liver triglyceride and lipid droplet accumulation, respectively. Conversely, ITIH3 knockdown in mice increased the liver triglyceride iiScienceHepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and <i>de novo</i> lipogenesis.PMC11059128R00DK120875R00 DK120875Talari NKPeterfy MRahman APChella Krishnan KPihlajamaki JPajukanta PMattam UKaminska DSotomayor-Rodriguez IfalseHepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and <i>de novo</i> lipogenesis.Recent studies demonstrate that liver secretory proteins, also known as hepatokines, regulate normal development, obesity, and simple steatosis to non-alcoholic steatohepatitis (NASH) progression. Using a panel of ∼100 diverse inbred strains of mice and a cohort of bariatric surgery patients, we found that one such hepatokine, inter-trypsin inhibitor heavy chain 3 (ITIH3), was progressively lower in severe non-alcoholic fatty liver disease (NAFLD) disease states highlighting an inverse relationship between <i>Itih3</i>/<i>ITIH3</i> expression and NAFLD severity. Follow-up animal and cell culture models demonstrated that hepatic ITIH3 overexpression lowered liver triglyceride and lipid droplet accumulation, respectively. Conversely, ITIH3 knockdown in mice increased the liver triglyceride i2024-01-01T00:00:00Z2024 May2026-06-01T23:50:02.933Z2026-05-23T03:08:11.432ZS-EPMC110591283868963610.1016/j.isci.2024.109709