Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity

Archives of Toxicology

Volumn 88, Issue 4, 2014, Pages 983-996

  Liu, Aiming ^a,b   Krausz, Kristopher W ^b   Fang, Zhong Ze ^b   Brocker, Chad ^b   Qu, Aijuan ^b   Gonzalez, Frank J ^b  

^a NINGBO UNIVERSITY   (China)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Bile acid; Gemfibrozil; Hepatotoxicity; Metabolomics; Phospholipid; PPAR

Indexed keywords

BILE ACID; GEMFIBROZIL; LYSOPHOSPHATIDYLCHOLINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; TAURO ALPHA MURICHOLIC ACID; TAURO BETA MURICHOLIC ACID; TAUROCHOLIC ACID; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BILE ACID METABOLISM; CONTROLLED STUDY; GENE ACTIVATION; GENE CONTROL; GENE EXPRESSION; GENETIC TRANSCRIPTION; HOMEOSTASIS; LIPID TRANSPORT; LIVER TOXICITY; MALE; METABOLOMICS; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; TIME OF FLIGHT MASS SPECTROMETRY; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY; 129 MOUSE; AGONISTS; ANIMAL; DEFICIENCY; DRUG EFFECTS; DRUG-INDUCED LIVER INJURY; ELECTROSPRAY MASS SPECTROMETRY; GENETICS; GENOTYPE; KNOCKOUT MOUSE; LIQUID CHROMATOGRAPHY; LIVER; MASS SPECTROMETRY; METABOLISM; MULTIVARIATE ANALYSIS; PROCEDURES; TIME FACTOR;

MUS;

ANIMALS; BILE ACIDS AND SALTS; CHROMATOGRAPHY, LIQUID; DRUG-INDUCED LIVER INJURY; GEMFIBROZIL; GENOTYPE; HOMEOSTASIS; LIVER; LYSOPHOSPHATIDYLCHOLINES; METABOLOMICS; MICE, 129 STRAIN; MICE, KNOCKOUT; MULTIVARIATE ANALYSIS; PHENOTYPE; PPAR ALPHA; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION; SPECTROMETRY, MASS, MATRIX-ASSISTED LASER DESORPTION-IONIZATION; TIME FACTORS;

EID: 84897116245     PISSN: 03405761     EISSN: 14320738     Source Type: Journal    
DOI: 10.1007/s00204-013-1188-0     Document Type: Article

References (36)

1. Cheema SK, Agellon LB (2000) The murine and human cholesterol 7alpha-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor alpha. J Biol Chem 275:12530-12536 (Pubitemid 30241398)
2. Chen C, Shah YM, Morimura K, Krausz KW, Miyazaki M, Richardson TA, Morgan ET, Ntambi JM, Idle JR, Gonzalez FJ (2008) Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab 7:135-147 (Pubitemid 351168558)
3. 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(Pt 3):781-786 (Pubitemid 26097736)
4. Cunningham ML, Collins BJ, Hejtmancik MR, Herbert RA, Travlos GS, Vallant MK, Stout MD (2010) Effects of the PPARalpha agonist and widely used antihyperlipidemic drug gemfibrozil on hepatic toxicity and lipid metabolism. PPAR Res 2010:14. doi:10.1155/2010/681963
5. Fang ZZ, Krausz KW, Tanaka N, Li F, Qu A, Idle JR, Gonzalez FJ (2013) Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum. Arch Toxicol 87:1975-1987
6. Fievet C, Staels B (2009) Combination therapy of statins and fibrates in the management of cardiovascular risk. Curr Opin Lipidol 20:505-511
7. Garcia-Canaveras JC, Donato MT, Castell JV, Lahoz A (2012) Targeted profiling of circulating and hepatic bile acids in human, mouse, and rat using a UPLC-MRM-MS-validated method. J Lipid Res 53:2231-2241
8. Hajdu D, Aiglova K, Vinklerova I, Urbanek K (2009) Acute cholestatic hepatitis induced by fenofibrate. J Clin Pharm Ther 34:599-602
9. Hays T, Rusyn I, Burns AM, Kennett MJ, Ward JM, Gonzalez FJ, Peters JM (2005) Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis. Carcinogenesis 26:219-227 (Pubitemid 40207717)
10. Hirschfield GM, Heathcote EJ, Gershwin ME (2010) Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 139:1481-1496
11. Holoshitz N, Alsheikh-Ali AA, Karas RH (2008) Relative safety of gemfibrozil and fenofibrate in the absence of concomitant cerivastatin use. Am J Cardiol 101:95-97
12. Hunt MC, Yang YZ, Eggertsen G, Carneheim CM, Gafvels M, Einarsson C, Alexson SE (2000) The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis. J Biol Chem 275:28947-28953
13. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ (2003) Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 73:538-544 (Pubitemid 37249124)
14. Lee S, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15:3012-3022
15. Lehmann R, Franken H, Dammeier S, Rosenbaum L, Kantartzis K, Peter A, Zell A, Adam P, Li J, Xu G, Konigsrainer A, Machann J, Schick F, Hrabe de Angelis M, Schwab M, Staiger H, Schleicher E, Gastaldelli A, Fritsche A, Haring HU, Stefan N (2013) Circulating lysophosphatidylcholines are markers of a metabolically benign nonalcoholic Fatty liver. Diabetes Care 36:2331-2338
16. Li F, Patterson AD, Krausz KW, Tanaka N, Gonzalez FJ (2012) Metabolomics reveals an essential role for peroxisome proliferator-activated receptor alpha in bile acid homeostasis. J Lipid Res 53:1625-1635
17. Liu A, Xie S, Sun H, Gonzalez FJ, Wei X, Dai R (2009) Myotoxicity of gemfibrozil in cynomolgus monkey model and its relationship to pharmacokinetic properties. Toxicol Appl Pharmacol 235:287-295
18. Liu A, Yang J, Gonzalez FJ, Cheng GQ, Dai R (2011a) Biphasic regulation of intracellular calcium by gemfibrozil contributes to inhibiting L6 myoblast differentiation: implications for clinical myotoxicity. Chem Res Toxicol 24:229-237
19. Liu A, Yang J, Zhao X, Jiao X, Zhao W, Ma Q, Tang Z, Dai R (2011b) Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats. Pharmacol Rep 63:157-164
20. Liu A, Yang J, Huang X, Xiong J, Wong AH, Chang L, Dai R (2012) Relaxation of rat thoracic aorta by fibrate drugs correlates with their potency to disturb intracellular calcium of VSMCs. Vascul Pharmacol 56:168-175
21. Marcoff L, Thompson PD (2007) The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 49:2231-2237 (Pubitemid 46856819)
22. Matsubara T, Tanaka N, Patterson AD, Cho JY, Krausz KW, Gonzalez FJ (2011) Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice. Hepatology 53:1282-1293
23. Mukherjee R, Jow L, Noonan D, McDonnell DP (1994) Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol 51:157-166 (Pubitemid 24372859)
24. Palmer CN, Hsu MH, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53:14-22 (Pubitemid 28068368)
25. Peters JM, Cheung C, Gonzalez FJ (2005) Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand? J Mol Med 83:774-785 (Pubitemid 41407861)
26. Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM (2001) Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol 21:1840-1845 (Pubitemid 34219790)
27. Prindiville JS, Mennigen JA, Zamora JM, Moon TW, Weber JM (2011) The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout. Toxicol Appl Pharmacol 251:201-208
28. Roglans N, Vazquez-Carrera M, Alegret M, Novell F, Zambon D, Ros E, Laguna JC, Sanchez RM (2004) 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 (Pubitemid 38333675)
29. Sabordo L, Sallustio BC (1997) Effects of gemfibrozil and clofibric acid on the uptake of taurocholate by isolated rat hepatocytes. Biochem Pharmacol 54:215-218 (Pubitemid 27353241)
30. Sausen PJ, Teets VJ, Voss KS, Miller RT, Cattley RC (1995) Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats. Cancer Lett 97:263-268
31. Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CD, Windass AS, Raza A (2004) The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75:455-463 (Pubitemid 38534566)
32. Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ (2012) Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology 56:118-129
33. Wagner M, Zollner G, Trauner M (2011) Nuclear receptors in liver disease. Hepatology 53:1023-1034
34. Yang J, Zhao X, Liu X, Wang C, Gao P, Wang J, Li L, Gu J, Yang S, Xu G (2006) High performance liquid chromatography-mass spectrometry for metabonomics: potential biomarkers for acute deterioration of liver function in chronic hepatitis B. J Proteome Res 5:554-561 (Pubitemid 43364095)
35. Yang Q, Nagano T, Shah Y, Cheung C, Ito S, Gonzalez FJ (2008) The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha. Toxicol Sci 101:132-139 (Pubitemid 350239017)
36. Yin P, Wan D, Zhao C, Chen J, Zhao X, Wang W, Lu X, Yang S, Gu J, Xu G (2009) A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry. Mol BioSyst 5:868-876