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

In this study, Weiss, Palmieri et al. show that macrophage-derived itaconate impinges on hepatocyte lipid metabolism. This mechanism participates in the crosstalk of the immune system with hepatocytes during the development of non-alcoholic fatty liver disease. Itaconate, the product of the decarboxylation of cis-aconitate, regulates numerous biological processes. We and others have revealed itaconate as a regulator of fatty acid beta-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.

Automated summary

In this study, the authors demonstrate that itaconate derived from macrophages impacts hepatocyte lipid metabolism, which is involved in the crosstalk between the immune system and hepatocytes during non-alcoholic fatty liver disease development. Itaconate regulates various biological processes, including fatty acid beta-oxidation and metabolic interaction between macrophages and tumors. The study shows upregulation of itaconic acid in human non-alcoholic steatohepatitis and a mouse model of non-alcoholic fatty liver disease. Deficiency in the gene responsible for itaconate production exacerbates lipid accumulation, glucose and insulin intolerance, and fat deposition in the liver. Treatment with a derivative of itaconate reverses dyslipidemia associated with high-fat diet feeding. Mechanistically, itaconate treatment reduces lipid accumulation and increases oxidative phosphorylation in hepatocytes through fatty acid oxidation.