Growth Hormone Regulation of Sex-Dependent Liver Gene Expression

The liver is a primary target for the action of GH, a pituitary protein hormone that regulates a broad range of physiological processes, including long bone growth, fatty acid oxidation, glucose uptake, and hepatic steroid and foreign compound metabolism. GH exerts sex-dependent effects on the liver in many species, with many hepatic genes, most notably genes coding for cytochrome P450 (CYP) enzymes, being transcribed in a sex-dependent manner. Sex differences in CYP expression are most striking in rats and mice (up to 500-fold male-female differences), but are also seen, albeit to a much smaller degree, in humans, where they are an important determinant of the sex dependence of hepatic drug and steroid metabolism. This article examines the mechanisms whereby GH, via its sex-dependent temporal patterns of pituitary release, activates intracellular signaling leading to the sexually dimorphic transcription of CYPs and other liver-expressed genes. Recent findings implicating the GH-regulated transcription factor STAT5b (signal transducer and activator of transcription 5b), hepatocyte nuclear factors 3beta, 4alpha and 6, and sex differences in DNA methylation and chromatin structure in the sex-dependent actions of GH are reviewed, and current mechanistic models are evaluated.