Liver-specific glucocorticoid action in alcoholic liver disease: Study of glucocorticoid receptor knockout and knockin mice

Abstract

Background and aim: Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis (AH), with limited efficacy and various side effects on extrahepatic tissues. Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH. The aim of this study was to determine the role of hepatocellular glucocorticoid receptor (GR) in alcohol-associated steatosis (AS) and AH.

Materials and methods: AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout (LKO) and heterozygote of GR. AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR. Changes in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot.

Results: GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice. Marked steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes. Hepatic protein levels of GR, hepatocyte nuclear factor 4 alpha, and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased, whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice. Interestingly, hepatic expression of estrogen receptor alpha (ERα) was induced, and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice, which was associated with induction of ERα-target genes. Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.

Conclusions: Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge, and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middle-aged mice. Hepatocellular GR is important for protection against AS and AH.

Keywords

Glucocorticoid receptor (GR) / Alcohol-associated steatosis (AS) / Alcoholic hepatitis (AH) / Heterozygote / Liver-specific knockout / Liver-specific knockin / Hepatic protection

Data availability statement

Data are contained within the article or supplementary mate-rial. The data presented in this study are available on request from the corresponding author. The microarray data of the hepatic transcriptome analysis of livers from patients with severe alcoholic hepatitis and normal livers were obtained from GEO DataSets (GSE28619).

Authors’ contributions

Yazheng Wang: Investigation, Data curation, Formal analysis, Visualization, and Writing-original draft. Conor Fahy: Investigation, Data curation, Formal analysis, and Visualization. Hong Lu: Conceptualization, Data curation, Formal analysis, Funding acqui-sition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, and Writing-review & editing. All authors have read and approved the final manuscript.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

We would like to thank Dr. Pierre Chambon (IGBMC, Illkirch, France) for providing the SA(þ/CreERT2) mice. This work was supported by the National Institutes of Health (grant R21AA027349).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2024.06.001.

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