PPAR α - dependent exacerbation of experimental colitis by the hypolipidemic 1 drug fenofibrate

34 Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor α (PPARα) agonists, 35 and have been used for several decades as hypolipidemic agents in the clinic. However, 36 contradictory observations exist on the role of fibrates in host response to acute inflammation, 37 with unclear mechanisms. The role of PPARα in colitis was assessed using fenofibrate and 38 Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three 39 distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid and Salmonella Typhi. 40 Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra41 performance liquid chromatography-coupled with electrospray ionization quadrupole time-of42 flight mass spectrometry. Messenger RNAs of PPARα target genes and genes involved in 43 inflammation were determined by qPCR analysis. Fenofibrate treatment exacerbated 44 inflammation and tissue injury in acute colitis, and this was dependent on PPARα activation. 45 Lipidomics analysis revealed that bioactive sphingolipids including sphingomyelins (SM) and 46 ceramides, were significantly increased in the colitis group compared to the control group; this 47 was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce 48 the markedly increased expression of mRNA encoding TNFα found in the acute colitis model, 49 while it decreased hydrolysis and increased synthesis of SM, up-regulated RIPK3-dependent 50 necrosis, and elevated mitochondrial fatty acid β-oxidation, which were possibly related to the 51 exacerbated colitis. 52