Dichloroacetate improves systemic energy balance and feeding behavior during sepsis

Oh, Tae Seok; Zabalawi, Manal; Jain, Shalini; Long, David; Stacpoole, Peter W.; McCall, Charles E.; Quinn, Matthew

doi:10.1172/jci.insight.153944

Cited by 17 publications

(17 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 34 Despite the lesser effect of PDHK inhibition on LPS-induced cytokine expression in BMDMs ( Figures S1H and S1I ), DCA lowered plasma non-inflammasome cytokines, including TNF and IL-6, in CLP mice. 56 To assess whether DCA promotes sepsis survival by down-regulating the NLRP3 inflammasome during sepsis, we analyzed plasma IL-1β and IL-18 in CLP mice. DCA (25 mg/kg) was given to septic mice 24 h after CLP for 6 h ( Figure 7A ).…”

Section: Resultsmentioning

confidence: 99%

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Meyers¹,

Wang²,

Han³

et al. 2023

Cell Reports

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Meyers¹,

Wang²,

Han³

et al. 2023

Cell Reports

Self Cite

View full text Add to dashboard Cite

“…33 Despite the less effect of PDHK inhibition on LPS-induced cytokine expression in BMDMs ( Figures S1H-S1I ), DCA lowered plasma non-inflammasome cytokines, including TNF and IL-6 in CLP mice. 55 To assess whether DCA promotes sepsis survival by down-regulating the NLRP3 inflammasome during sepsis, we analyzed plasma IL-1β and IL-18 in CLP mice. DCA (25 mg/kg) was given to septic mice 24 h post CLP for 6 h ( Figure 7A ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies of murine sepsis demonstrate that in vivo targeting of PDHK with DCA, administered as a single dose of 25 mg/kg 24 h post CLP, increases the septic survival rate to 71%, whereas the CLP animals not receiving DCA treatment had a survival rate of only 10% over the 14-day observation period (McCall et al, 2018). Despite the less effect of PDHK inhibition on LPS-induced cytokine expression in BMDMs (Figures S1H-S1I), very recently, our group demonstrated that in vivo PDHK inhibition by DCA lowered plasma noninflammasome cytokines, including TNF and IL-6 in the CLP mice (Oh et al, 2022), suggesting an antiinflammatory effect of PDHK inhibitors in bacteria-infected animals. Given that macrophage NLRP3 13 inflammasome plays a critical role in the pathogenesis of sepsis, we asked whether DCA confers survival partially through down-regulation of the NLRP3 inflammasome during sepsis.…”

Section: Pdhk Inhibition Lowers Plasma Il-1β and Blood Monocyte Caspa...mentioning

confidence: 86%

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Meyers¹,

Zhan

Han

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we showed that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuated macrophage NLRP3 inflammasome activation. Broad rewiring of intracellular metabolism and enhanced autophagic flux occurred in inflammasome-activated macrophages, but neither was necessary for the PDHK-regulated reduction of NLRP3 inflammasome activity. PDHK inhibition protected against inflammation-induced mitochondrial fragmentation and cristae remodeling and improved mitochondrial function by repurposing mitochondria from ROS production to ATP generation. Inhibition of PDHK increased the expression of the mitochondrial fusion protein optic atrophy-1 (OPA1). Suppression of OPA1 partially reversed the effect of PDHK inhibition on NLRP3 inflammasome activation. In conclusion, our study suggests that inhibition of PDHK dampens macrophage NLRP3 inflammasome activation during acute inflammation by ameliorating mitochondrial damage in a mechanism separate from its canonical role as a metabolic regulator.

show abstract

“…Specifically, we observe an alteration in mitochondrial function, TCA cycle remodeling, and hepatic lipid accumulation following sepsis ( Mainali et al, 2021 ). Additionally, we have extended these findings to show that hepatic metabolic dysregulation contributes to altered systemic metabolism during sepsis ( Oh et al, 2022 ). Our previous work is consistent with human studies indicating hepatic steatosis is induced during sepsis and an independent predictor of 30 day mortality ( Hou et al, 2021 ; Koskinas et al, 2008 ; Guirgis et al, 2021 ).…”

Section: Introductionmentioning

confidence: 81%

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Mainali,

Buechler,

Otero

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Dichloroacetate improves systemic energy balance and feeding behavior during sepsis

Cited by 17 publications

References 67 publications

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Contact Info

Product

Resources

About