Activation of PPAR γ and δ by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease
Activation of PPAR γ and δ by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease
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DOI：
10.1053/j.gastro.2004.06.049
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发表时间：
2004-09-01
期刊：
影响因子：
29.4
通讯作者：
Hontecillas, R
中科院分区：
文献类型：
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作者：
Bassaganya-Riera, J;Reynolds, K;Hontecillas, R
背景与目的：共轭亚油酸(CLA)对实验性炎症性肠病(IBD)保护作用的分子靶点不明。我们使用功能丧失的方法来研究CLA是否通过过氧化物酶体增殖物激活受体γ(PPARγ)依赖的机制来改善结肠炎。方法：采用实时定量聚合酶链式反应(PCR)技术，检测给予葡聚糖硫酸钠(DSS)攻击7d的小鼠结肠组织中PPARγ、Delta及其靶基因的表达。此外，核因子-kappaB(核因子-kappaB)p65在结肠中的激活被定量。为了确定PPAR-γ是否直接参与共轭亚油酸的作用机制，利用Cre-lox重组系统对小鼠结肠中的PPAR-γ进行了特异性缺失。将PPARγ基因缺失的小鼠和野生型仔鼠分别饲喂添加共轭亚油酸或对照的饲料42天，并用2.5%的DSS激发。采用CD_4~(+)CD_(45)RB(HI)转移性结肠炎模型观察CLA的治疗效果。结果：CLA诱导PPARγ和Delta，转录调控PPARγ和Delta反应基因簇，参与脂质代谢(解偶联蛋白[UCP]1、UCP3、PPARγ辅活化子1α[PGC-1α]和CD36)和上皮细胞成熟(Gob-4和角蛋白20)。此外，CLA抑制肿瘤坏死因子α(TNF-α)的表达和核因子-kappaB的激活，同时诱导免疫调节细胞因子转化生长因子α1(TGF-β(1))。临床上，CLA可改善DSS-和CD4(+)诱导的结肠炎。结肠中PPAR伽马基因的丢失消除了CLA在DSS结肠炎中的有利作用。结论：我们的研究提供了体内分子证据，表明CLA通过PPAR伽马依赖机制改善结肠炎。
Background & Aims: The molecular targets for the protective actions of conjugated linoleic acid (CLA) on experimental inflammatory bowel disease (IBD) are unknown. We used a loss-of-function approach to investigate whether CLA ameliorated colitis through a peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent mechanism. Methods: The expression of PPAR gamma, delta, and their target genes in the colon of mice fed control or CLA-supplemented diets was assayed after a 7-day dextran sodium sulfate (DSS) challenge by quantitative real-time polymerase chain reaction (PCR). Additionally, nuclear factor-kappa B (NF-kappaB) p65 activation was quantified in the colon. To determine the involvement of PPAR gamma in the mechanism of action of CLA directly, specific deletions of PPAR gamma in the colon were performed in mice by using the Cre-lox recombination system. Colonic PPAR gamma null mice and wild-type littermates were fed either a CLA-supplemented or a control diet for 42 days and challenged with 2.5% DSS. The therapeutic efficacy of CLA also was examined by using the CD4(+)CD45RB(hi) transfer colitis model. Results: CLA induced PPAR gamma and delta, transcriptionally modulated PPAR gamma and delta-responsive gene clusters involved in lipid metabolism (uncoupling protein [UCP]1, UCP3, PPAR gamma coactivator 1alpha [PGC-1alpha], and CD36) and epithelial cell maturation (Gob-4 and Keratin 20). Additionally, CLA repressed tumor necrosis factor alpha (TNF-alpha) expression and NF-kappaB activation while inducing the immunoregulatory cytokine transforming growth factor a 1 (TGF-beta(1)). Clinically, CLA ameliorated DSS- and CD4(+)-induced colitis. Loss of the PPAR gamma gene in the colon abrogated the beneficial effects of CLA in DSS colitis. Conclusions: Our studies provide molecular evidence in vivo, suggesting that CLA ameliorates colitis through a PPAR gamma-dependent mechanism.