A schema of bile acid signaling in pancreatic acinar cells. Extracellular bile acid enters pancreatic acinar cells through Na+-dependent transporter Ntcp at the luminal membrane and Na+-independent transporter Oatp at the basolateral membrane. Cytosolic bile acid induces intracellular Ca2+ overload to activate iP3R, RyRs, and Orai channel and to inhibit SERCA pump. Intracellular Ca2+ overload induces MPTP opening and subsequent acinar cell necrosis by ATP depletion. On the other hand, ROS and intracellular Ca2+ overload can induce acinar cell apoptosis by cytochrome c/caspase pathway, as well. The intercellular signaling of bile acid receptor Gpbar1 in pancreatic acinar cells is still largely unknown. Gpbar1 G protein-coupled bile acid receptor, Ntcp Na+-taurocholate cotransporting polypeptide, Oatp organic anion-transporting polypeptide, IP 3 R inositol trisphosphate receptor, RyRs ryanodine receptors, SERCA sarco/endoplasmic reticulum Ca2+ ATPase, STIM stromal interaction molecule, ROS Reactive oxygen species, MPTP mitochondrial permeability transition pore, ATP adenosine triphosphate
Thus, some of the molecular mechanisms by which bile acids induce acute pancreatitis have been elucidated so far. Importantly, there have been several experimental therapeutic attempts to identify molecular targets for preventing the processes of bile acid-induced acute pancreatitis.
Raraty M, Ward J, Erdemli G, Vaillant C, Neoptolemos JP, Sutton R, Petersen OH. Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proc Natl Acad Sci U S A. 2000;97(24):13126–31.CrossRefPubMedPubMedCentral