Reprogramming of glucocorticoid receptor function by hypoxia

Abstract

Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA-sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GRresponsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic-pituitaryadrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA-binding as measured by ChIP sequencing. The HPA axis is induced by hypothalamic HIF1a and HIF2a activation and leads to GR-dependent lipolysis and ketogenesis. Acute inflammation, induced by lipopolysaccharide, is prevented by DEX in normoxia but not during hypoxia, and this is attributed to HPA axis activation by hypoxia. We unfold new physiological pathways that have consequences for patients suffering from GC resistance.

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

“…In combination with increased lipolytic activity of WAT, this reduced β-oxidation causes lipotoxicity in liver and kidney after sepsis ( 11 ). Since hypoxia is associated with increased lipolysis, increased FFA levels in the blood ( 26 ), and impaired FFA β-oxidation ( 22 , 23 ), and p300 functions as a co-activator for PPARα ( 38 ), hepatic HIF1α and/or HIF2α might be involved in the declined PPARα signaling during sepsis. Therefore HIF1a AlbKO , HIF2a AlbKO , and HIF1aHIF2a AlbKO mice and wild-type littermates were subjected to CLP and livers were isolated 6h later ( Figure 7A ).…”

“…We used liver hypoxia datasets GSE162100 and GSE162155 that were processed as described in Vanderhaeghen et al. (2021) ( 26 ). Gene level read counts were obtained with featureCounts ( 32 ), and differential expressed genes were found by the DESeq2 R package ( 33 ) with the false discovery rate (FDR) set at 5%.…”

“…Once HIF proteins are stabilized, they will regulate the expression of genes involved in glucose metabolism ( 21 ), lipid metabolism ( 22 , 23 ), and erythropoiesis ( 24 ). Furthermore, a clear crosstalk between the GR and HIFs exists ( 25 , 26 ), and hypoxia is associated with increased lipolysis, increased FFA levels in the blood, and affects fatty acid β-oxidation ( 22 , 23 , 26 ).…”

Glucocorticoids and COVID-19

“…However, it is yet unclear whether GR mutations affect GC response in COVID-19 patients. In the context of severe COVID-19 treatment, when patients require oxygen, a potential cause of variability in GC efficacy could be due to hypoxia that leads to a destruction of the anti-inflammatory actions of GCs [164] . Moreover, there is strong evidence that the effects of SARS-Cov-2 are not limited to the respiratory system, and that the disease may involve a wide range of organs.…”

Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: From Physiology to Clinic

“…Indeed, glucocorticoids have been observed via in vitro studies both to enhance and inhibit HIF pathway activation [ 77 , 78 , 79 , 80 , 81 ]. Analogously, hypoxia has been shown to attenuate the glucocorticoid anti-inflammatory response and to elicit corticosteroid insensitive inflammation [ 238 , 239 , 240 ].…”