Deoxycholate and cholate modulate the source of cholesterol substrate for bile acid synthesis in the rat

In the current study, the role of the supply of preformed and newly synthesized cholesterol for the feedback control of the synthesis of different bile acids and the secretion of biliary cholesterol was investigated. To define these cholesterol fluxes and the possibility of a different modulation by bile acids with different suppressive capacities, a continuous labeling with tritiated water was used in rats with an extracorporeal bile duct receiving intraduodenal infusions of taurocholate or taurocholate plus deoxycholate. After bile acid pool depletion (6 to 9 hours) total muricholate, cholate, and chenodeoxycholate synthesis was variably increased (24% to 93%) during an infusion of 304 mumol taurocholate/kg per hour. The increase in bile acid synthesis and biliary cholesterol output was predominantly due to the utilization of preformed (unlabeled) cholesterol. The addition of 52 mumol/kg per hour of deoxycholate to 258 mumol/kg per hour of taurocholate had a comparable effect. In the late period (30 to 54 hours), the taurocholate infusion had little impact on total muricholate and chenodeoxycholate synthesis but caused by a significant increase of the proportion from performed cholesterol. Both total cholate production and its synthesis from de novo (labeled) cholesterol was inhibited by 30% (P < .05) and 64% (P < .01), respectively. The secretion rate of total and de novo biliary cholesterol was higher (65% and 72%; P < .01) compared with controls. In comparison, the combined bile acid infusion led to a further increase of total muricholate synthesis (P < .05), which was again due to an enhanced synthesis from performed cholesterol (P < .001). Similar changes were observed in chenodeoxycholate. The more pronounced suppression of total cholate synthesis by 81% (P < .05) was due to a diminished cholate synthesis from both de novo cholesterol by 72% (P < .001) and preformed cholesterol by 91% (P > .05). We conclude that the modulation of the synthesis of the various primary bile acids in the rat differs and feedback regulation of cholate synthesis by taurocholate and deoxycholate is mediated by different mechanisms of control, including inhibition of cholesterol 7 alpha-hydroxylase, HMG-CoA reductase, and uptake of lipoprotein cholesterol.