Gallbladder prostaglandins and lysophospholipids as mediators of mucin secretion during cholelithiasis.
Mucin hypersecretion from the gallbladder epithelium contributes to cholesterol gallstone formation by accelerating the nucleation of cholesterol-supersaturated bile. Prostaglandins (PGs) and lysophosphatidylcholine (LPC) have both been implicated as potential mediators of mucin hypersecretion, but their roles are unclear. We fed prairie dogs a lithogenic diet (0.34% cholesterol), and after 1, 2, 4, or 6 wk of cholesterol feeding, we measured glycoprotein and LPC concentrations in bile and PG synthesis in gallbladder and liver slices. Hypercholesterolemia and cholesterol supersaturation of bile occurred after 1 wk of cholesterol feeding, but marked crystal formation was delayed until 4 wk, when glycoprotein concentrations became markedly elevated. Glycoprotein hypersecretion was preceded by increased synthesis of PGF2 alpha (P less than 0.002), PGE2 (P less than 0.001), prostacyclin (P less than 0.05), and thromboxane (P = 0.07) in the gallbladder after only 2 wk of cholesterol feeding, but PG synthesis in the liver remained unchanged (P greater than 0.14). LPC concentrations in gallbladder bile also increased at 2 wk (P less than 0.02), but LPC in hepatic bile was unchanged (P = 0.35). In organ culture studies, LPC caused a dose-dependent stimulation of [3H]glycoprotein release from guinea pig gallbladder mucosa that could not be explained solely by LPC's detergent properties. We conclude that gallbladder PG synthesis and LPC production are increased at an early stage of cholesterol gallstone formation in the prairie dog model. These changes probably play a significant role in gallstone pathogenesis, since they mediate hypersecretion of gallbladder mucin and thus favor the nucleation of cholesterol-supersaturated bile.
D000818:Animals; D001646:Bile / Q000378:metabolism; D002769:Cholelithiasis / Q000209:etiology / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009077:Mucins / Q000378:metabolism*; D009924:Organ Culture Techniques; D011453:Prostaglandins / Q000378:metabolism*; D012589:Sciuridae
D002791:Cholesterol, Dietary; D006023:Glycoproteins; D008244:Lysophosphatidylcholines; D009077:Mucins; D011453:Prostaglandins