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.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and.
Am J Physiol Gastrointest Liver Physiol. 2014 Sep 1;307(5):G564-73. doi: 10.1152/ajpgi.00153.2014. Epub 2014 Jul 17.
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.
贝特类药物，如非诺贝特，是过氧化物酶体增殖物激活受体-α（PPARα）激动剂，几十年来一直被用作临床降脂药物。然而，关于贝特类药物在宿主对急性炎症反应中的作用存在相互矛盾的观察结果，其机制尚不清楚。本研究采用非诺贝特和 Ppara 基因敲除小鼠评估了 PPARα 在结肠炎中的作用。野生型或 Ppara 基因敲除小鼠分别采用葡聚糖硫酸钠、三硝基苯磺酸和伤寒沙门氏菌三种不同方案构建急性结肠炎模型。通过超高效液相色谱-电喷雾电离四极杆飞行时间质谱联用分析血清和结肠脂质组学，以表征代谢谱。通过 qunatitative PCR 分析测定 PPARα 靶基因和炎症相关基因的信使 RNA。非诺贝特治疗加重了急性结肠炎的炎症和组织损伤，这依赖于 PPARα 的激活。脂质组学分析显示，与对照组相比，生物活性鞘脂，包括神经鞘磷脂（SM）和神经酰胺，在结肠炎组中显著增加；而非诺贝特治疗进一步增强了这一作用。在结肠中，非诺贝特并未降低急性结肠炎模型中 TNFα 编码 mRNA 的明显增加，反而降低了 SM 的水解，增加了其合成，上调了 RIPK3 依赖性坏死，并增加了线粒体脂肪酸β氧化，这可能与结肠炎的加重有关。
