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Clinical Science (2008) 115, (107–127) (Printed in Great Britain)

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Review article

Role of peroxisome-proliferator-activated receptor β/δ (PPARβ/δ) in gastrointestinal tract function and disease

Jeffrey M. PETERS*†, Holly E. HOLLINGSHEAD*† and Frank J. GONZALEZ‡

*Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, PA 16802, U.S.A., †Graduate Program in Biochemistry, Microbiology and Molecular Biology, Pennsylvania State University, University Park, PA 16802, U.S.A., and ‡Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892 U.S.A.

Key words: colon cancer, differentiation, gastrointestinal tract, inflammatory bowel disease, nuclear receptor, peroxisome-proliferator-activated receptor β/δ (PPARβ/δ).

Abbreviations: ADRP, adipose differentiation-related protein; ANGPTL4, angiopoietin-like protein 4; AP1, activator protein 1; APC, adenomatous polyposis coli; CLA, conjugated linoleic acid; COX, cyclo-oxygenase; FABP, fatty-acid-binding protein; 13-S-HODE, 13(S)-hydroxyoctadecadienoic acid; IL, interleukin; ILK, integrin-linked kinase; L-FABP, liver FABP; LOX1, lipoxygenase 1; NF-κB, nuclear factor κB; NSAID, non-steroidal anti-inflammatory drug; PDK1, phosphoinositide-dependent kinase 1; PPAR, peroxisome-proliferator-activated receptor; PTEN, phosphatase and tensin homologue deleted on chromosome 10; STAT3, signal transducer and activator of transcription 3; Tcf4, T-cell transcription factor 4; TNFα, tumour necrosis factor α; VDR, vitamin D receptor; VEGF, vascular endothelial growth factor.

Correspondence: Dr Jeffrey M. Peters (jmp21@psu.edu).

PPARβ/δ (peroxisome-proliferator-activated receptor β/δ) is one of three PPARs in the nuclear hormone receptor superfamily that are collectively involved in the control of lipid homoeostasis among other functions. PPARβ/δ not only acts as a ligand-activated transcription factor, but also affects signal transduction by interacting with other transcription factors such as NF-κB (nuclear factor κB). Constitutive expression of PPARβ/δ in the gastrointestinal tract is very high compared with other tissues and its potential physiological roles in this tissue include homoeostatic regulation of intestinal cell proliferation/differentiation and modulation of inflammation associated with inflammatory bowel disease and colon cancer. Analysis of mouse epithelial cells in the intestine and colon has clearly demonstrated that ligand activation of PPARβ/δ induces terminal differentiation. The PPARβ/δ target genes mediating this effect are currently unknown. Emerging evidence suggests that PPARβ/δ can suppress inflammatory bowel disease through PPARβ/δ-dependent and ligand-independent down-regulation of inflammatory signalling. However, the role of PPARβ/δ in colon carcinogenesis remains controversial, as conflicting evidence suggests that ligand activation of PPARβ/δ can either potentiate or attenuate this disease. In the present review, we summarize the role of PPARβ/δ in gastrointestinal physiology and disease with an emphasis on findings in experimental models using both high-affinity ligands and null-mouse models.

Received 21 January 2008/27 February 2008; accepted 29 February 2008

Published on the Internet 15 July 2008, doi:10.1042/CS20080022

© The Authors Journal compilation © 2008 Biochemical Society