Activation of PPAR γ and δ by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease

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 γ (PPAR γ)-dependent mechanism. Methods: The expression of PPAR γ, δ, 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-κ B (NF-κB) p65 activation was quantified in the colon. To determine the involvement of PPAR γ in the mechanism of action of CLA directly, specific deletions of PPAR γ in the colon were performed in mice by using the Cre-lox recombination system. Colonic PPAR γ 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 +CD45RBhi transfer colitis model. Results: CLA induced PPAR γ and δ, transcriptionally modulated PPAR γ and δ-responsive gene clusters involved in lipid metabolism (uncoupling protein [UCP]1, UCP3, PPAR γ coactivator 1α [PGC-1α], and CD36) and epithelial cell maturation (Gob-4 and Keratin 20). Additionally, CLA repressed tumor necrosis factor α (TNF-α) expression and NF-κB activation while inducing the immunoregulatory cytokine transforming growth factor β 1 (TGF-β1). Clinically, CLA ameliorated DSS- and CD4+-induced colitis. Loss of the PPAR γ 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 γ-dependent mechanism.