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.

Short-Term Regulation of Canalicular Transport

“…112 Also in perfused rat liver, cAMP and its analogues increased TC and phospholipid excretion into bile. However, the effect on TC excretion is transient and only observed during the first 10 min, 113,114 whereas thereafter TC excretion was no longer stimulated despite the continuing presence of cAMP. 59 Several mechanisms may contribute to the disappearence of the stimulatory cAMP effect, such as a glucagon-or cAMPinduced hepatocyte shrinkage, 104,115 which is known to decrease TC excretion 52 and MAP kinase inhibition at the level of Ras/Raf 59 and a glucagon-or cAMPmediated induction of MAP-kinase phosphatases.…”

Mechanisms and regulation of bile secretion

“…Conflicting reports have stated that CAMP causes a modest increase and decrease in the early peak of HRP excretion; therefore the effect of this agent on paracellular permeability remains unclear ( 12,131). The effects of CAMP on lipid excretion have also been examined ( 137). Both forskolin and chlorophenylthio CAMP caused a progressive 5096 decrease in the excretion of phospholipid and cholesterol despite concomitant increases in total bile flow.…”