共轭亚油酸对PPARγ和δ的激活介导了对实验性炎症性肠病的保护作用。

Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease.

作者信息

Bassaganya-Riera Josep, Reynolds Kathryn, Martino-Catt Susan, Cui Yongzhi, Hennighausen Lothar, Gonzalez Frank, Rohrer Jurg, Benninghoff Alejandro Uribe, Hontecillas Raquel

机构信息

Laboratory of Nutritional Immunology & Molecular Nutrition, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.

出版信息

Gastroenterology. 2004 Sep;127(3):777-91. doi: 10.1053/j.gastro.2004.06.049.

DOI:10.1053/j.gastro.2004.06.049

PMID:15362034

Abstract

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 beta 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.

摘要

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尚不清楚。我们采用功能缺失方法研究CLA是否通过过氧化物酶体增殖物激活受体γ（PPARγ）依赖性机制改善结肠炎。

方法

通过定量实时聚合酶链反应（PCR）在7天葡聚糖硫酸钠（DSS）攻击后，检测喂食对照或补充CLA饮食小鼠结肠中PPARγ、δ及其靶基因的表达。此外，对结肠中核因子κB（NF-κB）p65激活进行定量。为直接确定PPARγ是否参与CLA的作用机制，利用Cre-lox重组系统在小鼠结肠中对PPARγ进行特异性缺失。给结肠PPARγ基因敲除小鼠和野生型同窝小鼠喂食补充CLA或对照饮食42天，并用2.5% DSS攻击。还通过CD4 + CD45RBhi转移结肠炎模型检测CLA的治疗效果。

结果

CLA诱导PPARγ和δ，转录调节参与脂质代谢（解偶联蛋白[UCP]1、UCP3、PPARγ共激活因子1α[PGC-1α]和CD36）和上皮细胞成熟（Gob-4和角蛋白20）的PPARγ和δ反应性基因簇。此外，CLA抑制肿瘤坏死因子α（TNF-α）表达和NF-κB激活，同时诱导免疫调节细胞因子转化生长因子β1（TGF-β1）。临床上，CLA改善DSS和CD4 +诱导的结肠炎。结肠中PPARγ基因缺失消除了CLA对DSS结肠炎的有益作用。