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

Nat Metab. 2023 Jun;5(6):981-995. doi: 10.1038/s42255-023-00801-2. Epub 2023 Jun 12.

Abstract

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Fatty Acids / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism
  • Lipids
  • Male
  • Mice
  • Non-alcoholic Fatty Liver Disease* / metabolism

Substances

  • itaconic acid
  • Fatty Acids
  • Lipids

Associated data

  • figshare/10.6084/m9.figshare.21183331