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Modulation of biliary lipid secretion by forskolin and cyclic AMP analogues.

ABSTRACT: Exposure of isolated perfused rat livers to either 100 microM-forskolin, a potent activator of adenylate cyclase, or to 0.5 mM-concentrations of the cAMP analogues chlorophenylthio cAMP (CPTcAMP), dibutyryl cAMP (dbcAMP) and 8-bromo cAMP (8BrcAMP), to provoke increases in intracellular concentrations of cAMP, resulted in marked changes in bile volume and composition. Bile flow reached a peak after 10 min, before declining towards control levels, and an increase in several secretory parameters was also observed at this time. At 20 min, a substantial decrease in the output of both phospholipid and cholesterol was evident, and this suppression of secretion was maintained throughout the remainder of the experiment. The order of effectiveness of the cAMP-elevating agents at decreasing biliary lipid output was CPTcAMP greater than forskolin greater than dbcAMP greater than 8BrcAMP. Biliary output of bile acids was essentially unaltered compared with controls; similarly, no decrease in the secretion of protein and triacylglycerols into the perfusion medium was observed. This suggests that the elevation of intracellular levels of cAMP may cause a selective inhibition of biliary lipid output rather than a more general inhibition of hepatic secretion.

SUBMITTER: Hamlin S

PROVIDER: S-EPMC1133713 | biostudies-other | 1990 Feb

REPOSITORIES: biostudies-other

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Project description:Autocrine/paracrine factors generated in response to 17β-estradiol (E2) within the fallopian tube (FT) facilitate fertilization and early embryo development for implantation. Since cyclic AMP (cAMP) plays a key role in reproduction, regulation of its synthesis by E2 may be of biological/pathophysiological relevance. Herein, we investigated whether cAMP production in FT cells (FTCs) is regulated by E2 and environmental estrogens (EE's; xenoestrogens and phytoestrogens). Under basal conditions, low levels of extracellular cAMP were detectable in bovine FTCs (epithelial cells and fibroblasts; 1:1 ratio). Treatment of FTCs with forskolin (AC; adenylyl cyclase activator), isoproterenol (β-adrenoceptor agonist) and IBMX (phosphodiesterase (PDE) inhibitor) dramatically (>10 fold) increased cAMP; whereas LRE1 (sAC; soluble AC inhibitor) and 2',5'-dideoxyadenosine (DDA; transmembrane AC (tmAC)) inhibitor decreased cAMP. Comparable changes in basal and stimulated intracellular cAMP were also observed. Ro-20-1724 (PDE-IV inhibitor), but not milrinone (PDE-III inhibitor) nor mmIBMX (PDE-I inhibitor), augmented forskolin-stimulated cAMP levels, suggesting that PDE-IV dominates in FTCs. E2 increased cAMP levels and CREB phosphorylation in FTCs, and these effects were mimicked by EE's (genistein, 4-hydroxy-2',4',6'-trichlorobiphenyl, 4-hydroxy-2',4',6'-dichlorobiphenyl). Moreover, the effects of E2 and EE were blocked by the tmAC inhibitor DDA, but not by the ERα/β antagonist ICI182780. Moreover, BAPTA-AM (intracellular-Ca2+ chelator) abrogated the effects of E2, but not genistein, on cAMP suggesting differential involvement of Ca2+. Treatment with non-permeable E2-BSA induced cAMP levels and CREB-phosphorylation; moreover, the stimulatory effects of E2 and EEs on cAMP were blocked by G15, a G protein-coupled estrogen receptor (GPER) antagonist. E2 and IBMX induced cAMP formation was inhibited by LRE1 and DDA suggesting involvement of both tmAC and sAC. Our results provide the first evidence that in FTCs, E2 and EE's stimulate cAMP synthesis via GPER. Exposure of the FT to EE's and PDE inhibitors may result in abnormal non-cyclic induction of cAMP levels which may induce deleterious effects on reproduction.

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Modulation of biliary lipid secretion by forskolin and cyclic AMP analogues.

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