Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice

Frieler, Ryan A.; Vigil, Thomas M.; Song, Jianrui; Leung, Christy Y. Y.; Goldstein, Daniel R.; Lumeng, Carey N.; Mortensen, Richard M.

doi:10.1002/oby.23509

Cited by 19 publications

(15 citation statements)

References 45 publications

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“…Taken together, we demonstrate the plausible role for itaconate in the regulation of lipid metabolism in livers of patients with NASH. A role for Irg1 in metabolic disease was reported recently 33 . In that study, Irg1 expression by adipocytes regulated inflammation and glucose homeostasis, although in that report hepatic expression of Irg1 was not investigated.…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 93%

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

et al. 2023

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“…A role for Irg1 in metabolic disease was reported recently 32 . In that study, Irg1 expression by adipocytes regulated in ammation and glucose homeostasis, although in that report, hepatic expression of Irg1 was not investigated.…”

Section: Discussionmentioning

confidence: 93%

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

Weiss¹,

Palmieri²,

Gonzalez-Cotto³

et al. 2022

Preprint

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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. 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-OI, 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.

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“…We have previously reported sepsis induces a state of hepatic steatosis ( Mainali et al, 2021 ). Given itaconate accumulates within hepatocytes during sepsis and previous reports demonstrating the ability of itaconate to modulate lipid metabolism ( Frieler et al, 2022 ; Li et al, 2020 ; Hall et al, 2013 ; Chu et al, 2022 ), we sought to determine its role, if any, in altering the course of steatosis during sepsis. To achieve this, we subjected 8–10 weeks old male C57BL/6NJ (WT) and C57BL/6NJ- Acod1 em1(IMPC)J /J ( Acod1 KO) to sepsis via cecal slurry injection for 24 hr as previously described ( Gong and Wen, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Mainali,

Buechler,

Otero

et al. 2024

eLife

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One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice

Cited by 19 publications

References 45 publications

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

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

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

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

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