Aims: Fibrate treatment induces adverse changes in biliary-lipid and bile-acid composition. Since the molecular mechanisms underlying these changes are still unclear, we have investigated the effect of fibrate treatment on key factors involved in bile-acid synthesis, biliary-lipid secretion and cholesterol metabolism in gallstone patients.
Methods: Patients with uncomplicated gallstones and a serum level of low-density lipoprotein (LDL) cholesterol >130 mg/dl were randomly assigned to open-label treatment with bezafibrate, fenofibrate, gemfibrozil, or placebo for 8 weeks before elective cholecystectomy. A liver specimen was obtained at operation, and the mRNA relative levels for cholesterol 7alpha-hydroxylase (CYP7A1), hepatocyte nuclear factor-4 (HNF-4), ATP-binding cassette transporters MDR3, ABCG5, and ABCG8, human homologue scavenger receptor BI, sterol response element binding protein-2 (SREBP-2), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and LDL receptor were determined by means of reverse-transcriptase polymerase chain reaction.
Results: Bezafibrate, fenofibrate and gemfibrozil significantly reduced CYP7A1 mRNA levels. The three fibrates tested raised the mRNA levels of ABCG5 and SREBP-2, but only bezafibrate induced significant changes. Although MDR-3 mRNA levels were slightly increased by the three fibrates, no significant differences were obtained.
Conclusions: These results show for the first time that fibrate administration to humans downregulates CYP7A1. Although ABCG5 and SREBP-2 mRNA levels were slightly increased by all treatment groups, only bezafibrate induced significant changes.