Inhibition of cholesterol synthesis in rat liver by physiological doses of taurocholate.

Abstract

This report deals with the controversial problem whether bile acids exert a direct inhibitory effect on the rate of hepatic cholesterol synthesis. For this purpose rats have been provided with an 'extracorporeal bile duct', an experimental model which makes it possible to initiate a bile fistula two weeks after last surgery. In the animals that recovered completely from operative trauma, a 6-h infusion of 33.4 mumol sodium taurocholate x (100 g body weight)-1 x h-1, prevented the threefold rise of hepatic cholesterol synthesis following bile diversion. The rate of cholesterol synthesis was monitored by incorporation of [14C] acetate in vitro. There was no difference whether the animals were infused from 4--10 h (dark/light transition) or from 16--22 h (light/dark transition) besides the fact that taurocholate caused a more extensive inhibition during the light-dark transition. A parallel kind of response was observed for the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34), the regulatory enzyme of cholesterol synthesis. A twofold rise of hepatic fatty acid synthesis was observed following bile diversion which was not seen in case of simultaneous bile salt infusion. It is concluded that bile salts exert direct feedback inhibition of hepatic cholesterol synthesis and that opposite results reported by other investigators are probably due to the infusion of too low doses of taurocholate.