Plasma growth hormone pulse activation of hepatic JAK-STAT5 signaling: Developmental regulation and role in male-specific liver gene expression

The intracellular signaling molecule STAT5 is activated in rat liver by the intermittent male plasma GH pattern to a 10-fold higher level than by the more continuous pattern of plasma GH stimulation seen in females. Individua l adult male rats are presently shown to exhibit large differences in liver STAT5 DNA-binding activity, which correlates with the presence of signific ant levels of GH in plasma at the time of liver excision. Examination of ST AT5 activity as a function of postnatal development revealed that these int ermittent pulses of liver STAT5 activity are first observed at 5 weeks of a ge, when plasma GH pulsation first begins and expression of male-specific, GH pulse-activated liver genes, including CYP2C11, first occurs. Prepuberta l rats exhibited low liver STAT5 activity, likely a consequence of the abse nce of high plasma GH pulses in these animals. Proteins required for GH act ivation of STAT5 are expressed in liver before puberty, and correspondingly , STAT5 can be precociously activated by exogenous administration of GH pul ses given to 2-week-old rats, albeit with a lower sensitivity to GH than is seen in hypophysectomized adult rats. However, this precocious activation of STAT5, via twice daily administration of GH for 7 days, did not lead to CYP2C11 expression or masculinization of hepatic enzyme profiles, unlike in GH pulse-stimulated hypophysectomized adult rats. Based on these findings we conclude: 1) liver STAT5 is repeatedly activated in adult male rats in d irect response to the intermittent pattern of plasma GH stimulation; 2) the developmental onset of this STAT5 activation pattern supports the proposed requirement of STAT5 transcriptional activity for male-specific, GH pulse- regulated hepatic gene expression; and 3) the activation of STAT5 is, by it self, not sufficient to impart the adult male pattern of liver gene express ion, suggesting a requirement for additional liver factors that are absent in prepubertal rats.