Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

Hepatic bile acid synthesis is regulated by recirculating bile acids, possi bly by modulating the availability of newly synthesized and preformed chole sterol. Because data in the hamster on this mechanism are lacking, we fitte d these animals with an extracorporeal bile duct and administered tritiated water intraperitoneally to label newly formed cholesterol. After interrupt ion of the enterohepatic circulation, physiological and double-physiologica l doses of conjugated cholate (25 or 50 mu mol/100 g h) or of unconjugated deoxycholate (6 or 12 mu mol) were infused intraduodenally for 54 hours and compared with controls. De novo and preformed cholesterol directly secrete d into bile or used for cholate and chenodeoxycholate synthesis were quanti tated by high-pressure liquid chromatography (HPLC)-liquid scintillation, D irectly after depletion of the bile acid pool (6-9 hours) at nearly physiol ogical conditions, chenodeoxycholate synthesis was significantly reduced by cholate and deoxycholate by up to 45% to 51%, whereas cholate formation de creased by approximate to 22% during deoxycholate, This short-term effect w as mainly mediated by reduced synthesis from preformed cholesterol. After l ong-term bile depletion (30-54 hours), bile acid synthesis returned to cont rol levels during 25 mu mol of cholate and of both deoxycholate doses. In c ontrast, only 50 mu mol of cholate prevented derepression of bile acid synt hesis. This long-term effect was mainly attributed to a diminished formatio n from de novo cholesterol exceeding the reduced synthesis from preformed c holesterol, In summary, short- and long-term regulation of bile acid synthe sis in hamsters differs with respect to availabilities of preformed and de novo cholesterol.