On the regulation of hepatic cholesterol and bile acid metabolism in gallstone patients

Abstract

The liver plays an important role in the regulation of cholesterol homeostasis, therefore also in the pathogenesis of arteriosclerosis and gallstone disease. The quantitatively most important way by which cholesterol is removed from the human body is via the bile, either as free cholesterol or after transformation to bile acids. Humans have a relatively low capacity for transforming cholesterol to bile acids, an important factor in the pathogenesis of cholesterol gallstone disease.

The aim of this thesis was to study the key enzymes regulating cholesterol and bile acid synthesis under different treatment conditions; interest was also focused on the influence of plasma lipoproteins on biliary lipid composition as well as the impact of hydrophobic bile acids on the feedback regulation of bile acid synthesis. Treatment of gallstone patients with the hydrophobic bile acid deoxycholic acid did not affect the activity of the cholesterol 70a-hydroxylase, regulating bile acid synthesis, in spite of the high proportion of deoxycholic acid achieved in bile (72%), nor was the cholesterol synthesis or cholesterol saturation of bile affected by the treatment.

For the first time, portal venous concentrations of the most hydrophobic bile acid in man, lithocholic acid, was determined in gallstone patients. The hepatic uptake of lithocholic acid was also calculated and found to amount to 78%. There was no correlation between the concentration of lithocholic acid and the activity of the cholesterol 7a-hydroxylase.

In patients with interrupted enterohepatic circulation, a selective low density lipoprotein apheresis was performed during simultaneous collection of bile from the common bile duct. The results show that plasma LDL, and possibly VLDL, are of greater importance for the biliary secretion of bile acids than for the biliary secretion of cholesterol.

Short term treatment with HMG CoA reductase inhibitor in gallstone patients inhibits cholesterol synthesis by about 50% already twelve hours after one single dose of treatment, as measured by the serum lathosterol levels. Treatment for 24, 48 or 72 hours did not further reduce the cholesterol synthesis. Bile acid synthesis was unaffected in all treatment groups. Plasma levels of total cholesterol and LDL cholesterol were also significantly reduced after one single dose. Interruption of treatment with HMG CoA reductase inhibitor in patients with complete bile fistula revealed an increase in the biliary output of bile acids whereas the output of cholesterol remained unchanged. This finding is most likely explained by a lack of substrate for bile acid synthesis during treatment.

Contrary to previous reports, there was no temporary increase in cholesterol saturation of bile due to the cessation of treatment; in fact, cholesterol saturation of bile was lowered, although not significantly. Three weeks of oral treatment with ursodeoxycholic acid and the HMG CoA reductase inhibitor pravastatin was given to gallstone patients. During treatment, ursodeoxycholic acid amounted to about 60% of biliary bile acids, compared to 1.5% in untreated controls. Plasma levels of total and LDL cholesterol were reduced by 17 and 24%, respectively. The cholesterol saturation of bile was 59%, a level reached in previous studies with an equivalent dose of ursodeoxycholic acid as single treatment. Cholesterol synthesis was markedly reduced, whereas bile acid synthesis remained unaffected compared to the controls.