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Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.

ABSTRACT: Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subjected to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial tricarboxylic acid (TCA) energetics, and redox balance are significantly reprogrammed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcriptomic analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate that sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.

SUBMITTER: Mainali R

PROVIDER: S-EPMC7901874 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.

Mainali Rabina R Zabalawi Manal M Long David D Buechler Nancy N Quillen Ellen E Key Chia-Chi CC Zhu Xuewei X Parks John S JS Furdui Cristina C Stacpoole Peter W PW Martinez Jennifer J McCall Charles E CE Quinn Matthew A MA

eLife 20210222

Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subjected to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial tricarboxylic acid (TCA) energetics, and redox balance are significantl ...[more]

PMID: 33616039

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Project description:Key pointsNon-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity.AbstractNon-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD.

Dataset Information

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.

Publications

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.

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