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


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.

SUBMITTER: Weiss JM 

PROVIDER: S-EPMC10290955 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Weiss Jonathan M JM   Palmieri Erika M EM   Gonzalez-Cotto Marieli M   Bettencourt Ian A IA   Megill Emily L EL   Snyder Nathaniel W NW   McVicar Daniel W DW  

Nature metabolism 20230612 6


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 res  ...[more]

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