Pituitary adenylate cyclase-activating polypeptide induces expression of corticosteroid-binding globulin in cultured fetal hepatocytes: synergy with tri-iodothyronine

Abstract

The purpose of the present study was to determine whether functional receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are expressed in cultured rat fetal hepatocytes and eventually play a role in regulating gene expression of corticosteroid-binding globulin (CBG). We found PACAP38 and PACAP27 to elevate cAMP levels in hepatocytes in a dose-dependent manner, with a plateau being achieved at 10 nM and EC50 values of about 0.5–1 nM. PACAP failed to alter the turnover of inositol phosphates, whereas PACAP and VIP stimulated cAMP accumulation in an equipotent manner, suggesting the presence in these cells of type II receptor isoforms. As revealed by measurements of both CBG mRNA levels and concentrations of binding sites, long-term treatment of fetal cells with 10 nM PACAP, although resulting in partial desensitization of peptide-induced cAMP accumulation, caused a significant 3-fold elevation in CBG synthesis. This stimulatory influence of PACAP was mimicked by the cell permeant N6,2´-O-dibutyryladenosine 3´,5´-phosphate (dbcAMP). Treatment of hepatocytes with tri-iodothyronine (T3) enhanced CBG expression and, most interestingly, appeared to synergize with PACAP to elicit a 2–3-fold amplification of CBG synthesis. This study thus provides first evidence for the up-regulation by PACAP and cAMP of CBG expression in fetal hepatocytes and for T3's playing a synergistic role in enhancing PACAP-induced synthesis of the binder.

Effects of PACAP on Oxidative Stress-Induced Cell Death in Rat Kidney and Human Hepatocyte Cells

“…Differential expression of PACAP receptors has been identified in hepatocellular carcinoma cells (Reubi et al 1999(Reubi et al , 2000. In line with the presence of receptors, the cyclic adenosine monophosphate (cAMP)-stimulating effect of PACAP has also been confirmed in the liver (El Fahime et al 1996;Gagnon et al 1994;Yokota et al 1995). Although PACAP had greater potency than VIP to stimulate cAMP, the two peptides did not have additive effects when applied simultaneously, suggesting that they act on the same receptors (Guijarro et al 1995).…”

“…PACAP infusion elicited a significant increase in hepatic bicarbonate output in the pig, though only at pharmacological doses, suggesting that PACAP does not play a physiological role in this process (Glad et al 2003). It has also been demonstrated that PACAP induces expression of corticosteroid-binding globulin in cultured fetal hepatocytes (El Fahime et al 1996).…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Likewise, in cultured hepatocytes, PACAP causes a dose-dependent accumulation of cAMP but does not affect inositol phosphate turnover (el Fahime et al, 1996). The fact that VIP exerts a mitogenic action on rat hepatocytes (Kar et al, 1996) strongly suggests that PACAP could also be involved in the control of liver cell proliferation.…”

PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential

“…By contrast, glucagon and catecholamines stimulate glycogenolysis via activating adenylate cyclase. Although mRNAs for three types of PACAP receptors are expressed in the liver, VPAC1-R is most highly expressed [16,52] and both PACAP and VIP stimulate adenylate cyclase activity in hepatocytes [53,54]. However, PACAP is more potent than VIP in stimulating glucose output from the liver [55].…”