Codependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on signal transducer and activator of transcription 5b and hepatic nuclear factor 4alpha

Abstract

Targeted disruption of the signal transducer and activator of transcription 5b gene (STAT5b) leads to decreased expression in male mouse liver of a male-predominant cytochrome (Cyp) 2d protein, whereas female-predominant Cyp2b proteins are increased. Presently, we characterize the effects of STAT5b deficiency on 15 specific, individual Cyp RNAs and other sexually dimorphic liver gene products. All seven male-specific RNAs investigated were decreased to normal female levels in STAT5b-deficient male liver, whereas five of eight female-specific RNAs, designated class I female genes, were increased in expression up to 200-fold or more. STAT5b deficiency had a much more modest effect on the expression of these genes in females. Hypophysectomy and GH replacement studies demonstrated positive GH pulse regulation of all seven male RNAs and negative GH pulse regulation of class I, but not class II, female RNAs in wild-type, but not in STAT5b-deficient, male mice. A majority of the sex-specific genes responded in parallel to the loss of STAT5b and the loss of hepatocyte nuclear factor 4alpha, indicating that both transcription factors are essential and suggesting they may coregulate sexually dimorphic liver gene expression. Continuous GH treatment of intact male mice, which overrides the endogenous male, pulsatile plasma GH pattern, down-regulated all seven male RNAs and induced expression of the five class I female RNAs within 4-7 d; however, induction of class II female RNAs was delayed until d 7-14. Given the slow responses of all 15 genes to changes in plasma GH status, GH regulation of sex-specific Cyp expression is proposed to be indirect and mediated by STAT5b- and hepatocyte nuclear factor 4alpha-dependent factors that may include repressors of female-specific Cyps and other targets of GH action.