Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol
7α‐hydroxylase activity

Abstract

Abstract. Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Bjo Èrkhem I, Rudling M, Einarsson C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute, Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7a-hydroxylase activity. J Intern Med 1999; 246: 399±407.Objectives. Based on animal studies, hydrophobic bile acids have been postulated to be particularly strong inhibitors of bile acid synthesis. The present study was undertaken to characterize in humans the effects of one of the most hydrophobic of the common bile acids, deoxycholic acid (DCA), on the transcriptional regulation and activity of the cholesterol 7a-hydroxylase, on hepatic cholesterol metabolism and on biliary lipid metabolism and plasma lipids. Design, subjects and settings. Thirteen patients with cholesterol gallstone disease were treated with DCA (750 mg day 21 ) for 3 weeks prior to cholecystectomy. Blood samples were collected before and during treatment. At operation, a liver biopsy and gallbladder bile were obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy served as controls. The study was carried out at a university hospital. Results. Deoxycholic acid comprised 72 6 6% (mean 6 SEM) of total biliary bile acids in DCAtreated patients (n = 8), and 21 6 2% in the controls (n = 16; P , 0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated (n = 7) and untreated (n = 16) patients. Cholesterol 7a-hydroxylase and HMG CoA reductase activities and mRNA levels were not different between DCA-treated and untreated gallstone patients. The LDL receptor mRNA levels were similar in both groups of patients. Plasma levels of total cholesterol were lowered by 10% upon DCA treatment (P , 0.05). Conclusions. Treatment with DCA did not significantly affect mRNA levels and activity of hepatic cholesterol 7a-hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There was no effect on the saturation of gallbladder bile, Thus, the present study could not verify that the hydrophobicity of the bile acid pool is a major factor regulating human hepatic cholesterol 7a-hydroxylase activity.

Suppression of Bile Acid Synthesis, But Not of Hepatic Cholesterol 7α–Hydroxylase Expression, by Obstructive Cholestasis in Humans

“…This would also support evidence in humans showing a discrepancy between indices of bile acid synthesis in vivo and 7␣-hydroxylase expression and activity in vitro, as in obesity 53,54 or during deoxycholic acid treatment. 11,12,55 The finding of more pronounced suppression, or lack of increase, of bile acid synthesis in vivo compared with the determination of tissue expression of the enzyme is consistent with regulation beyond enzyme transcription and translation.…”

Reduced ileal expression of OSTα-OSTβ in non-obese gallstone disease

“…In experimental animals, deoxycholate is a strong inhibitor of bile acid synthesis (22), compatible with a low rate of bile acid formation in some gallstone patients (23). On the other hand, the effect of deoxycholate in humans is controversial (24,25) and most studies in gallstone patients report an increase in both bile acid turnover (19,26) and synthesis (27,28). Increased biliary deoxycholate levels, bile acid turnover, and synthesis may all occur as a response to an increased ileal loss of bile acids.…”

Apical sodium bile acid transporter and ileal lipid binding protein in gallstone carriers

“…Based on animal studies, it was postulated that hydrophobic bile acids are particularly strong inhibitors of bile acid synthesis (34)(35)(36). Bile acid feedback regulation in humans has also been established (37), although Hillebrant et al (38) found no effect of deoxycholic acid treatment on hepatic cholesterol 7-a-hydroxylase in patients with cholesterol gallstones. Furthermore, the fractional catabolic rates of cholic and chenodeoxycholic acid were found to be increased in gallstone carriers compared with controls (32).…”