Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids*

Abstract

To study the role of heaptic cholesterol synthesis in patients with gallstones, the activity of the rate-limiting step in cholesterogenesis, hydroxymethyl glutaryl coenzyme A reductase (HMCoAR), was measured in operative wedge liver biopsies from 10 patients with untreated cholesterol gallstones, 6 with pigment stones and 10 controls. Hepatic HMGCoAR was measured in 6 patients with cholesterol-rich gallstones treated for 1-24 mo. with 14.6-18.6 mg chenodeoxycholic acid (CDCA)/kg per day, in 2 patients with radiolucent pigment stones treated with 17.3 and 17.7 mg CDCA/kg per day and in 10 other patients with cholesterol-rich stones given 4.5-7.2 mg ursodeoxycholic acid/kg per day for 1-6 mo. HMGCoAR activity was related to the free and esterified cholesterol content of both hepatic homogenates and the microsomal fractions. Compared with the controls (HMGCoAR activity 14.6 .+-. 1.6 (SEM [standard error of mean]) pmol mg microsomal/protein per min), the mean activity in untreated cholesterol cholelithiasis was 32.2 .+-. 2.0 (P < 0.001), but was near normal in patients with pigment stones (16.2 .+-. 1.5). In cholesterol gallstone patients, chenodeoxycholic acid treatment reduced the mean enzyme activity by 51% compared with the untreated gallstone group (P < 0.001) and in smaller doses, ursodeoxycholic acid therapy lowered it by 40% (P < 0.001) but in the 2 patients with pigment stones, CDCA did not seem to affect HMGCoAR activity. Despite this 4-fold variation in enzyme activity, there were no significant differences in mean free or esterified cholesterol concentrations in whole liver homogenates or in the microsomal fraction from any patient group.