Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450.

The liver is a sexually dimorphic organ in many species, including humans. In rodent models, dramatic sex differences characterize the expression of numerous plasma proteins, receptors and other signaling molecules, and enzymes of steroid and foreign compound metabolism, including members of the cytochrome P450 (CYP) superfamily. The sexual dimorphism of liver gene expression is dictated by the temporal pattern of plasma growth hormone (GH) stimulation, which is intermittent and highly pulsatile in males and more frequent in females. Many liver-specific genes, including CYP genes, are regulated by the coordinated action of multiple hepatic nuclear factors (HNFs) through a complex transcriptional hierarchy. These HNFs are proposed to collaborate with the GH pulse-activated latent cytoplasmic transcription factor STAT5b to regulate the sex-dependent expression of liver CYPs. This hypothesis is supported by the finding that certain HNFs are regulated by GH and exhibit a differential responsiveness to the sex-specific pattern of GH secretion. In particular, recent studies of an HNF4alpha-deficient mouse model demonstrate an essential role for this nuclear receptor in regulating several liver-enriched transcription factors and sexually dimorphic CYPs in liver in vivo. Further studies on the mechanisms by which HNF4alpha and other liver factors respond to GH may expand our understanding of the mechanisms by which GH, via the coordinated action of HNFs and STAT5b, regulate sexually dimorphic liver gene expression.