Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease

Abstract

PPARbeta/delta (peroxisome-proliferator-activated receptor beta/delta) is one of three PPARs in the nuclear hormone receptor superfamily that are collectively involved in the control of lipid homoeostasis among other functions. PPARbeta/delta not only acts as a ligand-activated transcription factor, but also affects signal transduction by interacting with other transcription factors such as NF-kappaB (nuclear factor kappaB). Constitutive expression of PPARbeta/delta 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 PPARbeta/delta induces terminal differentiation. The PPARbeta/delta target genes mediating this effect are currently unknown. Emerging evidence suggests that PPARbeta/delta can suppress inflammatory bowel disease through PPARbeta/delta-dependent and ligand-independent down-regulation of inflammatory signalling. However, the role of PPARbeta/delta in colon carcinogenesis remains controversial, as conflicting evidence suggests that ligand activation of PPARbeta/delta can either potentiate or attenuate this disease. In the present review, we summarize the role of PPARbeta/delta in gastrointestinal physiology and disease with an emphasis on findings in experimental models using both high-affinity ligands and null-mouse models.

Figure 1. PPARβ/δ-mediated regulation of transcription

PPARβ/δ can directly up-regulate target genes in response to ligand activation (A), interact with other transcription factors such as NF-κB and possibly others such as AP1 (B), or repress gene expression (C). CBP, CREB (cAMP-response-element-binding protein)-binding protein; HAT, histone acetylase; HDAC, histone deacetylase; NCoR, nuclear receptor co-repressor; RNA Pol II, RNA polymerase II; RXRα, retinoid X receptor α; SMRT, silencing mediator for retinoic acid receptor and thyroid-hormone receptor.

Figure 2. Functional role of PPARβ/δ in the intestine and a working hypothesis of how PPAR β/δ functions when expression is increased

Constitutive expression of PPARβ/δ is high in the epithelial cells of the small and large intestine. Activation of PPARβ/δ by endogenous ligands probably serves to maintain a population of terminally differentiated cells allowing for normal absorption function and/or modulation of inflammation. Expression of PPARβ/δ can be increased by inflammation (e.g. in response to TNFα and AP1 signalling). It is a working hypothesis that this increase in PPARβ/δ-mediated signalling will lead to increased differentiation, inhibition of cell proliferation and anti-inflammatory activity that will culminate by resolution in the affected cell(s).

Figure 3. Hypothetical roles of PPARβ/δ in colon carcinogenesis

(A) Ligand activation of PPARβ/δ potentiates colon cancer. In this model, PPARβ/δ is a downstream target of the APC/β-catenin/Tcf4 pathway and, through unknown target genes, leads to enhanced cell proliferation. COX-2-derived prostacyclin (PGI₂) may be an endogenous ligand for PPARβ/δ in this model, and inhibition of COX2 by NSAIDs may prevent activation of PPARβ/δ and unknown target genes. Alternatively, there is also evidence that NSAIDs may inhibit PPARβ/δ expression leading to reduced anti-apoptotic activity mediated through ill-defined mechanisms. ?, pathways of uncertainty. PGIS, prostaglandin I₂ synthase. (B) Ligand activation of PPARβ/δ attenuates colon cancer. In this model, ligand activation of PPARβ/δ leads to the induction of well-characterized target genes, including FABP and ADRP, that are associated with terminal differentiation and probably other unidentified target genes that participate. PPARβ/δ can also interfere with NF-κB and AP1 signalling, causing anti-inflammatory activities. The induction of terminal differentiation and anti-inflammatory activities are associated with inhibition of cell proliferation. RXRα, retinoid X receptor α.