Skip to main content
SpringerLink
Log in

Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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 7α-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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B (2002) Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22:717–726

    Article  CAS  PubMed  Google Scholar 

  2. Kesäniemi A, Grundy SM (1984) Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA 251:2241–2246

    PubMed  Google Scholar 

  3. Einarsson K, Angelin B (1986) Hyperlipoproteinemia, hypolipidemic treatment and gallstone disease. Atheroscler Rev 15:67–97

    Google Scholar 

  4. Stahlberg D, Reihnér E, Rudling M, Berglund M, Einarsson K, Angelin B (1995) Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: reduced activity of cholesterol 7alpha-hydroxylase. Hepatology 21:1025–1030

    CAS  PubMed  Google Scholar 

  5. Post SM, Duez H, Gervois PP, Kuipers F, Princen HMG (2001) Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol 21:1840–1845

    CAS  PubMed  Google Scholar 

  6. Bertolotti M, Concari M, Loria P, Abate N, Pinetti A, Guicciardi ME, Carulli N (1995) Effects of different phenotypes of hypercholesterolemia and of treatment with fibric acid derivatives on the rates of cholesterol 7alpha hydroxylation in humans. Arterioscler Thromb Vasc Biol 15:1064–1069

    CAS  PubMed  Google Scholar 

  7. Princen HMG, Post SM, Twisk J (1997) Regulation of bile acid biosynthesis. Curr Pharm Des 3:59–84

    CAS  Google Scholar 

  8. Chiang JYL (1998) Regulation of bile acid synthesis. Front Biosci 3:D176–D193

    CAS  PubMed  Google Scholar 

  9. Davis RA, Miyake JH, Hui TY, Spann NJ (2002) Regulation of cholesterol-7alpha-hydroxylase: barely missing a SHP. J Lipid Res 43:533–543

    CAS  PubMed  Google Scholar 

  10. Russell DW, Setchell KD (1992) Bile acid byosinthesis. Biochemistry 31:4737–4749

    CAS  PubMed  Google Scholar 

  11. Wang DPD, Stroup M, Marrapodi M, Crestani M, Galli G, Chiang JYL (1996) Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene (CYP7A9) in HepG2 cells. J Lipid Res 37:1831–1841

    CAS  PubMed  Google Scholar 

  12. Tobin KA, Steineger HH, Alberti S, Spydevol O, Auwerx J, Gustafsson JK, Nebb HI (2000) Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor alpha. Mol Endocrinol 14:741–752

    CAS  PubMed  Google Scholar 

  13. Chiang JY, Kimmel R, Stroup D (2001) Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 262:257–265

    Article  CAS  PubMed  Google Scholar 

  14. Bocos C, Castro M, Quack G, Herrera E (1993) Studies with etofibrate in the rat. II: a comparison of the effects of prolonged and acute administration on plasma lipids, liver enzymes and adipose tissue lipolysys. Biochim Biophys Acta 1168:340–347

    Article  CAS  PubMed  Google Scholar 

  15. Combettes-Souverain M, Milliat F, Sérougne C, Férézou J, Lutton C (1999) SR-BI et metabolisme du cholesterol. Medicine/Sciences 15:1252–1258

  16. Sehayek E, Ono JG, Shefer S, Nguyen LB, Wang N, Batta AK, Salen G, Smith JD, Tall AR, Breslow JL (1998) Biliary cholesterol excretion: a novel mechanism that regulates cholesterol absorption. Proc Natl Acad Sci U S A 95:10194–10199

    Article  CAS  PubMed  Google Scholar 

  17. Fucks M, Ivandic B, Müller O, Schalla C, Scheibner J, Bartsch P, Stange EF (2001) Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI. Hepatology 33:1451–1459

    Article  PubMed  Google Scholar 

  18. Mardones P, Quiñone V, Amigo L, Moreno M, Miquel JF, Schwarz M, Miettinen HE, Trigatti B, Krieger M, VanPatten S, Cohen DE, Rigotti A (2001) Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. J Lipid Res 42:170–180

    CAS  PubMed  Google Scholar 

  19. Schmitz G, Langmann T, Heimerl S (2001) Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res 42:1513–1520

    CAS  PubMed  Google Scholar 

  20. Borst P, Zelcer N, van Helvoort A (2000) ABC transporters in lipid transport. Biochim Biophys Acta 1486:128–144

    CAS  PubMed  Google Scholar 

  21. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapmam J, Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B (2000) CLA-1/SR-BI expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 101:2411–2417

    CAS  PubMed  Google Scholar 

  22. Chianale J, Vollrath V, Wielandt AM, Amigo L, Rigotti A, Nervi F, Gonzalez S, Andrade L, Pizarro M, Accatino L (1996) Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse. Biochem J 314:781–786

    CAS  PubMed  Google Scholar 

  23. Miranda S, Vollrath V, Wielandt AM, Loyola G, Bronfman M, Chianale J (1997) Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver. J Hepatol 26:1331–1339

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC (1998) Linkage between cholesterol 7 alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest 101:1283–1291

    CAS  PubMed  Google Scholar 

  25. Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP (2002) Human cholesterol 7 α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109–117

    Article  CAS  PubMed  Google Scholar 

  26. Roglans N, Peris C, Verd JC, Alegret M, Vázquez M, Sánchez RM, Laguna JC (2001) Increase in hepatic expression of SREBP-2 by gemfibrozil administration to rats. Biochem Pharmacol 62:803–809

    Article  CAS  PubMed  Google Scholar 

  27. Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolisis of a membrane-bound transcription factor. Cell 89:331–340

    CAS  PubMed  Google Scholar 

  28. Horton JD, Shimoura I (1999) Sterol regulatory element-binding proteins activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol 10:143–150

    CAS  PubMed  Google Scholar 

  29. Roglans N, Bellido A, Rodríguez C, Cabrero A, Novell F, Ros E, Zambón D, Laguna JC (2002) Fibrate treatment does not modify the expression of acyl-CoA oxidase in human liver. Clin Pharmacol Ther 72:692–701

    Article  CAS  PubMed  Google Scholar 

  30. Roglans N, Sanguino E, Peris C, Alegret M, Vázquez M, Adzet T, Díaz C, Hernández G, Laguna JC, Sánchez RM (2002) Atorvastatin treatment induced PPAR alpha expression and decreased plasma non-esterified fatty acids and liver triglyceride in fructose fed rats. J Pharmacol Exp Ther 302:232–239

    Article  CAS  PubMed  Google Scholar 

  31. Gause WC, Adamovicz J (1995) Use of PCR to quantitate relative differences in gene expression. In: Dieffenbach CW and Dveksler GS (eds) PCR primer. A laboratory manual. Cold Spring Harbor Laboratory Press, New York

  32. Cheema SK, Agellon LB (2000) The murine and human cholesterol 7 alpha hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor alpha. J Biol Chem 275:12530–12536

    Article  CAS  PubMed  Google Scholar 

  33. Marrapodi M, Chiang JYL (2000) Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7 alpha hydroxylase gene (CYP7A1) transcription. J Lipid Res 41:514–520

    CAS  PubMed  Google Scholar 

  34. Patel DD, Knight BL, Soutar AK, Gibbons GF, Wade DP (2000) The effect of peroxisome-proliferator-activated receptor alpha on the activity of the cholesterol 7 alpha hydroxylase gene. Biochem J 351:747–753

    Article  CAS  PubMed  Google Scholar 

  35. Stahlberg D, Reihnér E, Ewerth S, Einarsson K, Angelin B (1991) Effects of bezafibrate on hepatic cholesterol metabolism. Eur J Clin Pharmacol 40:S33–S36

    PubMed  Google Scholar 

  36. Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH (2002) Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A 99:16237–16242

    Article  CAS  PubMed  Google Scholar 

  37. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH (2002) Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 110:671–680

    Article  CAS  PubMed  Google Scholar 

  38. Einarsson K, Angelin B (1986) Hyperlipoproteinemia, hypolipidemic treatment, and gallstone disease. Atheroscler Rev 15:67–97

    Google Scholar 

  39. Sato R, Inoue J, Kawabe Y, Kodama T, Takano T, Maeda M (1996) Sterol-dependent transcriptional regulation of sterol regulatory element-binding protein-2. J Biol Chem 271:26461–26464

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was financially supported by grants from the Fundació Privada Catalana de Nutrició i Lípids, Comisión Interministerial de Ciencia y Tecnologia (SAF98–0105; SAF00–0201), MCYT (BFI 2002–05167) and Generalitat de Catalunya (2001SGR00141).

Author information

Authors and Affiliations

  1. Pharmacology Unit, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

    Núria Roglans, Manuel Vázquez-Carrera, Marta Alegret, Juan C. Laguna & Rosa M. Sánchez

  2. The Surgical Department, Hospital Clínic i Provincial, University of Barcelona, Barcelona, Spain

    Ferran Novell

  3. Lipid Clinic, Nutrition and Dietetics Service, Hospital Clínic i Provincial, University of Barcelona, Barcelona, Spain

    Daniel Zambón & Emilio Ros

  4. Unidad de Farmacología, Facultad de Farmacia, Núcleo Universitario de Pedralbes, 08028, Barcelona , Spain

    Rosa M. Sánchez

Authors
  1. Núria Roglans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel Vázquez-Carrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marta Alegret
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ferran Novell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Zambón
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emilio Ros
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan C. Laguna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rosa M. Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa M. Sánchez.

Additional information

E.R., D.Z., and J.C.L. are members of Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roglans, N., Vázquez-Carrera, M., Alegret, M. et al. Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol 59, 855–861 (2004). https://doi.org/10.1007/s00228-003-0704-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-003-0704-1

Keywords

Search

Navigation