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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Polymicrobial 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 (PPAR\u03b1) 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 PPAR\u03b1 and GR dysfunction is not known.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods &amp;amp; results<\/jats:title><jats:p>We investigated the hypothesis that hypoxia and\/or activation of hypoxia inducible factors (HIFs) might play a role in these issues with PPAR\u03b1 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 HIF1\u03b1 and HIF2\u03b1, and an enrichment of HIF-dependent gene signatures. Therefore, we generated hepatocyte-specific knock-out mice for HIF1\u03b1, HIF2\u03b1 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 HIF1\u03b1 and\/or HIF2\u03b1 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 HIF1\u03b1 in hepatocytes causes less inactivation of PPAR\u03b1 transcriptional function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We conclude that HIF1\u03b1 and HIF2\u03b1 are activated in hepatocytes in sepsis, but their contribution to the mechanisms leading to lethality are minimal.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1124011","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T05:43:49Z","timestamp":1678945429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The impact of hepatocyte-specific deletion of hypoxia-inducible factors on the development of polymicrobial sepsis with focus on GR and PPAR\u03b1 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