Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients.
OBJECTIVE
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.
Roglans
Núria
N
Pharmacology Unit, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Vázquez-Carrera
Manuel
M
Alegret
Marta
M
Novell
Ferran
F
Zambón
Daniel
D
Ros
Emilio
E
Laguna
Juan C
JC
Sánchez
Rosa M
RM
D001629:Bezafibrate / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use; D042882:Gallstones / Q000188:drug therapy* / Q000378:metabolism; D015248:Gemfibrozil / Q000627:therapeutic use; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D002790:Cholesterol 7-alpha-Hydroxylase; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate