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

Abstract

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.

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

“…44,45 Inhibition of biliary de novo cholesterol secretion was observed only for supraphysiological doses of cholate, most likely by inhibiting cholesterol synthesis late during the experiment. This is in line with data obtained in rabbits, 59 but not in rats, 42 indicating a species difference. However, increased availability of preformed cholesterol during high-dose cholate infusion either from intestinal 60,61 and/or hepatic 58 sources may have contributed to the lower proportion of de novo cholesterol.…”

“…Biliary cholesterol secretion in hamsters, as shown previously for rats, 10,42 increased during bile acid infusions as a function of the bile acid hydrophobicity and the transhepatic bile acid flux, but independent of the cholesterol source. Under physiological conditions (6-9 hours), biliary secretion of de novo cholesterol amounted to no more than 18% in rats 45,47,55,56 and 5% in hamsters and humans.…”

“…In addition, bile acids appear to influence cholesterol availability for bile acid synthesis from both sources in a differential fashion, as has been previously shown for rats. 42 Because little information is available for hamsters, the aim of the present study was to characterize in detail the mechanisms of the feedback regulation of bile acid synthesis in this species.…”

“…This short-term feedback control is in accordance with Spady' s findings in hamsters, 2 but could not be shown in rats. 42 Most likely, this short-term inhibition is the result of a parallel down-regulation 38 of both cholesterol 7␣-2 and of 27-hydroxylase, because the latter enzyme activity dominates in hamsters, 62 and chenodeoxycholate is assumed to be a main end-product of this acidic pathway. 63 Because the amount of deoxycholate infused represented only 24% of the cholate dose, a superior suppressive capacity of this more hydrophobic bile acid is likely, at least under physiological conditions.…”

“…Using the tritiated-water technique, 41 the importance of newly synthesized cholesterol for the regulation of bile acid synthesis was estimated. In contrast to rats, 42 synthesis of individual bile acids is both short-termand long-term-regulated in the hamster. The latter effect was mainly, but not exclusively, mediated by a reduced formation from cholesterol newly synthesized during the experiment.…”