Decoding genome-wide DNA binding sites for AR and ERRα in mouse primary hepatocytes

ABSTRACT: The hormone glucagon, which is primarily recognized for its ability to raise blood glucose levels, may also have a significant role in regulating liver fat content by increasing lipid breakdown. This topic has been extensively investigated in both clinical and basic research studies, generating considerable interest and discussion.Using both chemical and genetic means, we uncovered the unexpected role of hepatic androgen receptor in mediating glucagon response. AR regulated transcriptome in hepatocyes was for the first time defined through RNAseq analysis. Sex difference in response to glucagon was shown at different level in both primary hepatocytes and mice. AR direct regulation on PGC1α/ERRα axis was proved through co-immunoprecipitation assay.Androgn receptor has been found to regulate glucagon function in both gluconeogenesis and lipid catabolism through moludation of basal mitochondrial respiration. Notably, female mouse hepatocytes express up to three times more AR than their male littermates. Consequently, they respond to glucagon to a much greater extent in terms of glucose production and lipid catabolism outcomes. Moreover, liver-specific AR knockout impairs the effect of glucagon in inducing blood glucose production, especially in female mice. Mechanistically, we demonstrate that hepatic AR drives a PGC1α/ERRα-mitochondria axis to promote lipid catabolism for liver glucose production in response to glucagon treatment. Together, our study sheds light on the role of hepatic AR in mediating glucagon activity in orchestrating glucose and lipid metabolism, and sex-differentiated AR expression contributes to sexual dimorphism in hepatic glucagon sensitivity.

ORGANISM(S): Mus musculus

PROVIDER: GSE261197 | GEO | 2025/01/01

REPOSITORIES: GEO