MOLECULAR REGULATION OF STEROL METABOLISM BY BILE ACIDS IN CULTURED HUMAN HEPATOCYTES

Disruption of hepatic cholesterol homeostasis may predispose to important clinical conditions such as cholelithiasis and atherosclerosis. The regulatory role of nuclear receptors has recently been underlined but the integration of the different metabolic pathways is largely unknown. AIM of the present study is to analyze the expression of a number of genes involved in cholesterol and bile acid metabolism in cultured human hepatocytes. METHODS. HepG2 cells were incubated with 100 micromol concentrations of different bile acids (DCA, CDCA, UDCA) for 24 hr. mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1), LDL-receptor, HMG-CoA reductase and a number of nuclear receptors and coactivators involved in sterol metabolism were assayed by real-time RT-PCR. RESULTS. A significant effect of bile acid treatment, detected by ANOVA, was shown on the expression of CYP7A1 and SHP, which were respectively reduced and increased by treatment with the hydrophobic bile acids DCA and CDCA, but not with UDCA; expression of SREBP-2 and LDL-receptor were also significantly increased by hydrophobic bile acids. CONCLUSIONS. Hydrophobic, but not hydrophilic bile acids suppress CYP7A1 expression, possibly via increased expression of SHP. Surprisingly, the same bile acids seem to enhance the expression of SREBP-2 and of genes involved in LDL uptake, mimicking a condition of cholesterol depletion. Knowledge of the subtle relationships linking bile acid and cholesterol metabolism might provide useful information for the management of cholesterol accumulation conditions.