The regulation of acid-labile subunit gene expression and secretion by cyclic adenosine 3',5'-monophosphate

Circulating acid-labile subunit (ALS) is mainly hepatocyte derived and is GH dependent. ALS buffers the metabolic effects of the insulin-like growth factors by sequestering them in a ternary complex with insulin-like growth factor-binding protein-3. Nutritional regulation of ALS may be mediated by cAMP and changes in circulating GH levels or tissue GH sensitivity. Therefore, we examined the regulation by cAMP of ALS steady state messenger RNA (mRNA) levels and secretion in isolated hepatocytes under basal and GH-induced conditions. Increasing intracellular cAMP in primary hepatocytes produced a dose-dependent suppression of ALS mRNA levels and secretion. This effect was not related to a reduction in mRNA stability. In the presence of GH there was a parallel suppression of mRNA levels and secretion. However, under basal conditions cAMP had less effect on ALS mRNA levels than on secretion. Thus, in the absence of GH, expression of ALS may be predominantly posttranscriptionally regulated by cAMP. Our study suggests that cAMP affects ALS gene transcription, perhaps by interrupting the GH signaling pathway, and also inhibits posttranscriptional events in ALS expression.