title: PPARα-dependent exacerbation of experimental colitis by the hypolipidemic drug fenofibrate.
abstract: Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor-α (PPARα) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPARα in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPARα target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPARα activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNFα found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid β-oxidation, which were possibly related to the exacerbated colitis.
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Chad N
authors.initials: CN
authors.lastname: Brocker
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Bryce X
authors.initials: BX
authors.lastname: Bredell
authors.affiliation: Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D002518:Ceramides / Q000097:blood; D003092:Colitis / Q000378:metabolism*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011345:Fenofibrate / Q000009:adverse effects* / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D011345:Fenofibrate
keywords: PPARα; colitis; fenofibrate; lipidomics; sphingomyelin