Itaconic acid, a metabolite produced during macrophage activation, is upregulated in human non-alcoholic steatohepatitis (NASH) and a mouse model of non-alcoholic fatty liver disease (NAFLD). Male mice deficient in *Irg1* (the gene responsible for itaconate production) exhibited exacerbated lipid accumulation in the liver, glucose and insulin intolerance, and mesenteric fat deposition. Treatment with 4-octyl itaconate reversed dyslipidemia. Mechanistically, itaconate reduced lipid accumulation and increased oxidative phosphorylation in hepatocytes, suggesting macrophage-derived itaconate modulates hepatic fatty acid metabolism.

Jonathan M. Weiss, Erika M. Palmieri, Marieli Gonzalez-Cotto, Ian A. Bettencourt, Emily L. Megill, Nathaniel W. Snyder, Daniel W. McVicar