Persistent activation of growth hormone contributes to sexual dimorphic expression of hepatic drug metabolizing enzymes in Fgf15 transgenic mice.

Abstract

Hepatic sexual dimorphism is critical for maintaining sex-specific metabolic pathways and xenobiotic clearance. We have demonstrated that in fibroblast growth factor 15 (Fgf15) transgenic (Tg) mice, FGF15 overexpression significantly reduced bile acid (BA) levels and induced hepatic feminization in males, marked by a male-to-female shift in expression of the drug metabolizing enzymes. This feminization is linked to the disruption of pulsatile growth hormone (GH) secretion pattern and signaling. However, it remained unclear whether FGF15 overexpression broadly disrupts hepatic sexual dimorphism or specifically drives a directional feminization program independent of biological sex. In this study, we profiled the hepatic transcriptome of female Fgf15 Tg mice and replenished male Fgf15 Tg mice with exogenous, pulsatile GH to test to what degree changes in the GH axis maintain liver dimorphism under low BA conditions. Beyond suppressing BA synthesis and altering steroid metabolism, female Tg mice altered expression of genes in xenobiotic metabolism and detoxification pathways, suggesting that the FGF15/BA axis regulates xenobiotic processing in females as well. Notably, FGF15 overexpression further amplified the baseline female expression profile of drug-metabolizing enzymes, characterized by the upregulation of female-predominant genes (Cyp2b9, Cyp3a41, Sult1e1, and Ugt1a1) and the suppression of male-predominant genes (Cyp7b1, Cyp2d9, Hsd3b5, and Igf1). Furthermore, pulsatile GH replenishment in male Tg mice partially restored male-predominant gene expression patterns. Taken together, these findings demonstrate that overexpression of intestine-derived FGF15 drives the feminization of sexually dimorphic hepatic gene expression independent of biological sex, a process that is at least partially mediated by impaired GH signaling. SIGNIFICANCE STATEMENT: Fibroblast growth factor 15 (Fgf15) overexpression intensified hepatic feminization of drug-metabolizing enzyme expression in female Fgf15 transgenic mice, similar to male Fgf15 transgenic mice. Restoring growth hormone signaling partially rescued the male-predominant gene expression pattern in male Fgf15 transgenic mice. This indicates that disruptions to growth hormone pulsatility, alongside sustained hepatic signal transducer and activator of transcription 5 activation, contribute to FGF15-induced hepatic gene feminization.