Author Response: Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Le résumé fourni par la source

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 Acod1 knockout mice that are deficient in synthesizing itaconate, we aimed to understand the metabolic role of itaconate in the liver and systemically during sepsis.We find itaconate aids in lipid metabolism during sepsis.Specifically, Acod1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis.Proteomics analysis reveals enhanced expression of enzymes involved in fatty acid oxidation in following 4-octyl 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 Acod1 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. eLife assessmentThis work describes a connection between inflammation and metabolism, in which itaconate stabilizes the mitochondrial fatty acid uptake enzyme Cpt1a to enhance fatty acid oxidation.The mechanism for itaconate action may be generalizable to other protein targets.This is an important advance, which is supported by solid experimental data.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.