Itaconate is a negative regulator of hepatic lipid metabolism during sepsis

Abstract

Sepsis is a life‐threatening clinical implication with increased uncontrolled host immune response to an infection, mortality, morbidity, and financial burden worldwide. Due to its critical role in metabolic reprogramming in inflammation, the Irg1/itaconate has received much attention as an immunomodulator. However, understanding of itaconate’s anti‐inflammatory and immunometabolic activities in response to infections is mostly limited to immune cells. By employing multi‐omic approaches, here we show that in the context of sepsis, a disruption in TCA cycle flow drives hepatic itaconate accumulation, indicating potential non‐immune functions. However, the functional role of itaconate in this central organ critical to maintaining systemic metabolism is yet to be elucidated. To gain more insight into its physiological role in the liver during sepsis, we subjected wild‐type and whole‐body Irg1 knockout mice to sepsis via cecal slurry injection. In conjunction with our previous findings, we find wild‐type septic mice develop hepatic steatosis. Interestingly, global Irg1 knockout mice develop a more severe form of a hepatic steatotic phenotype and a significant increase in hepatic lipid burden compared to wild‐type counterparts in response to sepsis. This data demonstrates itaconate as a negative regulator of hepatic lipid accumulation in the context of sepsis. However, the exact molecular mechanism by which itaconate interacts with regulators of hepatic lipid metabolism during sepsis is yet to be uncovered. As an anti‐inflammatory metabolite, itaconate limits the glycolytic response in activated immune cells. Similarly, invitro, we find that 4‐OI, an itaconate derivative, antagonizes LPS induced glycolysis in hepatocytes. Given our findings of heightened lipid accumulation in septic Irg1 knockout mice, we further hypothesize glycolysis to be elevated and fueling de novolipogenesis via the production of acetyl‐CoA. Indeed, unbiased metabolomics data show heightened hepatic lactate levels indicative of hyperactivated glycolysis in knockout septic mice. Mechanistically, we find elevated gene and protein expression of lactate dehydrogenase, the enzyme that facilitates the conversion of pyruvate to lactate, driving this accumulation of lactate seen in septic Irg1 knockout mice. In summary, our preliminary findings thus far highlights itaconate as a negative modulator of hepatic glycolysis as well as de novo lipogenesis in restraining sepsis‐induced hepatic steatosis.