title: Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.
abstract: Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China, liuaiming@nbu.edu.cn.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Chad
authors.initials: C
authors.lastname: Brocker
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002853:Chromatography, Liquid; D015248:Gemfibrozil / Q000633:toxicity*; D005838:Genotype; D006706:Homeostasis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D015999:Multivariate Analysis; D047493:PPAR alpha / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D008244:Lysophosphatidylcholines; D047493:PPAR alpha; D015248:Gemfibrozil