The impact of hepatocyte-specific deletion of hypoxia-inducible factors on the development of polymicrobial sepsis with focus on GR and PPARα function

Frontiers in Immunology

Immunology

Ben Wielockx¹  Deepika Watts¹  Niek Sanders²  Joyca De Temmerman²  Sylviane Dewaele³  Rudi Beyaert³  Jolien Vandewalle³  Tineke Vanderhaeghen³  Tino Hochepied³  Charlotte Wallaeys³  Claude Libert³  Joke Vanden Berghe³  Steven Timmermans³  Louise Nuyttens³  Melanie Eggermont³ 

[1] Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany;Deutsche Forschungsgemeinschaft (DFG) Research Centre and Cluster of Excellence for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany;Department of Nutrition, Genetics, and Ethology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium;Department of Pathology, Bacteriology, and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium;Flanders Institute for Biotechnology (VIB) Center for Inflammation Research, Ghent, Belgium;Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium;

关键词: sepsis;    hypoxia;    detection;    metabolism;    glucocorticoids (GCs);    PPARalpha;   

DOI  :  10.3389/fimmu.2023.1124011

 received in 2022-12-14, accepted in 2023-02-27,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPolymicrobial sepsis causes acute anorexia (loss of appetite), leading to lipolysis in white adipose tissue and proteolysis in muscle, and thus release of free fatty acids (FFAs), glycerol and gluconeogenic amino acids. Since hepatic peroxisome proliferator-activated receptor alpha (PPARα) and glucocorticoid receptor (GR) quickly lose function in sepsis, these metabolites accumulate (causing toxicity) and fail to yield energy-rich molecules such as ketone bodies (KBs) and glucose. The mechanism of PPARα and GR dysfunction is not known.Methods & resultsWe investigated the hypothesis that hypoxia and/or activation of hypoxia inducible factors (HIFs) might play a role in these issues with PPARα and GR. After cecal ligation and puncture (CLP) in mice, leading to lethal polymicrobial sepsis, bulk liver RNA sequencing illustrated the induction of the genes encoding HIF1α and HIF2α, and an enrichment of HIF-dependent gene signatures. Therefore, we generated hepatocyte-specific knock-out mice for HIF1α, HIF2α or both, and a new HRE-luciferase reporter mouse line. After CLP, these HRE-luciferase reporter mice show signals in several tissues, including the liver. Hydrodynamic injection of an HRE-luciferase reporter plasmid also led to (liver-specific) signals in hypoxia and CLP. Despite these encouraging data, however, hepatocyte-specific HIF1α and/or HIF2α knock-out mice suggest that survival after CLP was not dependent on the hepatocyte-specific presence of HIF proteins, which was supported by measuring blood levels of glucose, FFAs, and KBs. The HIF proteins were also irrelevant in the CLP-induced glucocorticoid resistance, but we found indications that the absence of HIF1α in hepatocytes causes less inactivation of PPARα transcriptional function.ConclusionWe conclude that HIF1α and HIF2α are activated in hepatocytes in sepsis, but their contribution to the mechanisms leading to lethality are minimal.

【 授权许可】

Unknown   
Copyright © 2023 Vanderhaeghen, Timmermans, Eggermont, Watts, Vandewalle, Wallaeys, Nuyttens, De Temmerman, Hochepied, Dewaele, Berghe, Sanders, Wielockx, Beyaert and Libert