Bile acids exert negative feedback control on bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7α-hydroxylase activity

✍ Scribed by Jaap Kwekkeboom; Dr. Hans M. G. Princen; Eline M. van Voorthuizen; Dr. Herman Jan M. Kempen

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: English
• Weight: 847 KB
• Volume: 12
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840120522

✦ Synopsis

Feedback regulation of bile acid synthesis by its end products was studied in cultured hepatocytes of young weaned pigs. We previously showed that conversion of exogenous ["Cl cholesterol into bile acids was suppressed by addition of bile acids to the culture medium.

In the present study, the effects of bile acids on bile acid mass production and cholesterol ?a-hydroxylase activity were examined. Mass production of bile acids was strongly inhibited by addition of taurocholic acid (50 and 100 pmolb) to the culture medium. The inhibitory action was exerted specifically on activity of cholesterol 7c~hyhxylase because conversion of ["Cl ?a-hydroxycholesterol to bile acids by pig hepatocytes was not affected. Suppression of cholesterol 7ahydroxylase activity after incubation of the hepatocytes with taurocholic acid was concentration-and time-dependent. Maximum suppression ( -80%) was achieved after a 20 to 30 hr incubation of hepatocytes with 100 pmoUL of this bile acid. Decline of enzyme activity caused by 100 pmoUL taurocholic acid followed first-order kinetics with a half-life of 10 hr. Taurocholic acid had no direct effect on cholesterol 7a-hydroxylase activity in homogenates of hepatocytes as assessed by addition of the bile acid to the assay mixture.

The effects of several other bile acids in a concentration of 100 pmoUL on cholesterol 7a-hydroxylase activity were examined in 48 hr incubations. Glycochenodeoxycholic and glycohyodeoxycholic acids, which are the maor bile acids in pig bile, their uncoqjugated forms and also deoxycholic and cholic acid pronouncedly inhibited activity of the enzyme. In contrast, hyocholic acid almost failed to inhibit, whereas ursodeoxycholic acid was a weak inhibitor.

It is concluded that bile acids, in physiological concentrations (i.e., as observed in portal blood), inhibit bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7a-hydroxylase activity