Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice

Author:

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

Abstract

AbstractItaconate, the product of the decarboxylation of cis-aconitate, regulates numerous biological processes. We and others have revealed itaconate as a regulator of fatty acid β-oxidation, generation of mitochondrial reactive oxygen species and the metabolic interplay between resident macrophages and tumors. In the present study, we show that itaconic acid is upregulated in human non-alcoholic steatohepatitis and a mouse model of non-alcoholic fatty liver disease. Male mice deficient in the gene responsible for itaconate production (immunoresponsive gene (Irg)-1) have exacerbated lipid accumulation in the liver, glucose and insulin intolerance and mesenteric fat deposition. Treatment of mice with the itaconate derivative, 4-octyl itaconate, reverses dyslipidemia associated with high-fat diet feeding. Mechanistically, itaconate treatment of primary hepatocytes reduces lipid accumulation and increases their oxidative phosphorylation in a manner dependent upon fatty acid oxidation. We propose a model whereby macrophage-derived itaconate acts in trans upon hepatocytes to modulate the liver’s ability to metabolize fatty acids.

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Physiology (medical),Endocrinology, Diabetes and Metabolism,Internal Medicine

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