Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease.
OBJECTIVE
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.
Bassaganya-Riera
Josep
J
Laboratory of Nutritional Immunology & Molecular Nutrition, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. jbassaga@vt.edu
Reynolds
Kathryn
K
Martino-Catt
Susan
S
Cui
Yongzhi
Y
Hennighausen
Lothar
L
Gonzalez
Frank
F
Rohrer
Jurg
J
Benninghoff
Alejandro Uribe
AU
Hontecillas
Raquel
R
D000818:Animals; D002352:Carrier Proteins / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000178:diet therapy / Q000276:immunology*; D044243:Linoleic Acids, Conjugated / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D002352:Carrier Proteins; D044243:Linoleic Acids, Conjugated; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors