Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/3/2003
Publication Date: 9/9/2003
Citation: Badger, T.M., Ronis, M.J., Frank, S.J., He, L. 2003. Effects of chronic ethanol on hepatic and renal cyp2c11 in the male rat: interactions with the janus-kinase 2-signal transducer and activators of transcription proteins 5b pathway. Endocrinology. 144(9):3969-3976.
Interpretive Summary: Growth and health maintenance are in good part affected by both nutrition and the actions of growth hormone (GH). GH has important actions on health even after humans or animals reach adult size. We have been studying the effects of nutrition and ethanol on GH and on GH actions and found that ethanol alters the pattern of GH release from the pituitary gland. The pattern of GH release is related to the mechanisms by which GH signals cells. We further found that GH signals cells differently in liver than in the kidney of rats fed ethanol containing diets. Specifically, ethanol-fed rats had increases in a factor known as JAK2 in the liver, but it decreased this factor in the kidney. These effects were responsible of changes in the production of a key enzyme in the liver and kidney, known as CYP2C11. Thus, ethanol and nutrition affect GH-mediated actions in kidney and liver by altering the mechanisms by which GH signals the cell to act.
Technical Abstract: Chronic alcohol intake in male rats results in: 1) demasculinization of the GH pulse pattern; 2) reduced serum testosterone concentrations; and 3) decreased expression hepatic CYP2C11. Hepatic CYP2C11 expression is regulated by the male pattern of GH through the Janus-kinase/signal transducer and activators of transcription proteins (JAK/STAT) signal transduction pathway in the male rat. Renal CYP2C11 is regulated by testosterone, not GH. The involvement of the JAK/STAT5b signal transduction pathway in renal CYP2C11 signaling has not been studied. We tested the hypothesis that ethanol reduces CYP2C11 levels by interfering with the JAK/STAT5b pathway. Using a total enteral nutrition (TEN) model to feed rats a well-balanced diet, we have studied the effects of chronic ethanol intake (21 d) on hepatic and renal JAK/STAT pathway of adult male rats (8-10/group). We found decreased hepatic and renal expressions of CYP2C11 in ethanol-fed rats with concomitant decreases in STAT5b and phospho-STAT5b, decreased in vitro hepatic STAT5b binding to a CYP2C11 promoter element and no effects on hepatic GHR levels. Ethanol caused tissue specific effects in phospho-JAK2 and JAK2, with increased levels in the liver, but decreased JAK2 expression in the kidney. We conclude that ethanol suppression of CYP2C11 expression is clearly associated with reductions in STAT5b levels, but not necessarily in reductions of JAK2 levels. The mechanisms underlying ethanol-induced suppression of STAT5b is yet to be determined, as is the question of whether this is secondary to hormonal effects or a direct ethanol effect.