role of peroxisome proliferator-activated receptor [gamma] in colon cancer and inflammatory bowel disease, The

Archives of Pathology & Laboratory Medicine, Sep 2003 by Bull, Arthur W

* Objective.-Review the role and therapeutic potential of peroxisome proliferator-activated receptor (PPAR) [gamma] in colonic disorders.

Data Sources.-Recent peer-reviewed scientific literature focusing on PPAR [gamma] in the colon.

Study Selection.-Research reports using animal models, cultured cell lines, and clinical material were examined for content related to the role of PPAR [gamma] in normal colon cell function, colon cancer, and inflammatory bowel disease. Issues concerned with potential therapeutic use were also considered.

Data Synthesis.-Key points pertaining to PPAR function and involvement in colon pathology were extracted and noted. Potential compromises to therapeutic utility are identified.

Conclusions.-The emerging important role of PPAR [gamma] in normal tissue homeostasis and pathologic outcomes suggests this receptor is a good candidate as a drug target. Several potential problems with this approach will require further investigation prior to widespread recommendations for modulation of PPAR as an efficacious therapy for cancer, chemoprevention of colon cancer, or treatment of inflammatory bowel disease. The widespread use of PPAR [gamma] ligands for management of type 2 diabetes (such as the glitazone class of drugs including rosiglitazone and pioglitazone) may provide a fortuitous assessment of the efficacy of long-term PPAR modulation.

The peroxisome proliferator-activated receptors (PPARs) are a subgroup of ligand-activated nuclear receptors responsible for the regulation of cellular events ranging from glucose and lipid homeostasis to cell differentiation and apoptosis.1 Other members of the nuclear receptor superfamily include steroid and thyroid hormone receptors, retinoid receptors, and vitamin D receptors.2,3 Thus, the PPARs are part of a group of versatile and potent regulators of cellular function.

Currently, the 3 known forms of PPAR include [alpha], [delta]/[beta] also known as Nuc 1, and [gamma]. PPAR [alpha] is mostly present in the liver, kidney, heart, and muscle, where it is the target of the fibrate class of drugs and is believed to function in the catabolism of fatty acids.4,5 PPAR [delta]/[beta] is fairly ubiquitous and is often expressed at higher levels than the others.6 Although relatively little is known about the specific functions of this form of the receptor, it does play a role in placentation and adiposity.7 Arguably, the most widely studied form of PPAR is PPAR [gamma], which is expressed in a wide variety of cell types, including adipocytes, macrophages, and colonocytes, among others.8,9 The role of PPAR [gamma] in intestinal cell differentiation, carcinogenesis, and inflammatory bowel disease (IBD) is the focus of the current review.

The special role of PPAR [gamma] in the colon is reflected in part by the cell- and tissue-specific expression of the receptor. In both rodents and humans, the level of receptor in colon tissue is equal to, or greater than, that in adipose tissue. In addition, Lefebvre et al10 have reported higher levels in the distal colon than in the proximal colon and small intestine. Perhaps as important as this observation is the fact that PPAR [gamma] expression is primarily localized in the more differentiated epithelial cells of the colon.10,11 The localization in differentiated cells is consistent with the numerous reports of PPAR [gamma] induction upon differentiation of cultured colon cells.10,12-15 Thus, the expression and activation of PPAR [gamma] are associated with a differentiated phenotype in intestinal cells.

ACTIVATION OF PPAR

The PPAR [gamma] protein is a transcription factor that is activated by a variety of compounds of both endogenous and xenobiotic origin. In the quiescent state, the protein is in complex with a number of corepressor proteins that prevent transcriptional activation of target genes. Upon ligand binding, the receptor becomes activated, the corepressors dissociate, and an active heterodimer of PPAR and the retinoid X receptor binds to DNA.16 There is also evidence for the involvement of coactivator proteins that enhance the activity of the PPAR-retinoid X receptor complex. Binding of the complex to gene regulatory sites on the DNA, termed "peroxisome proliferator response elements," leads to the increased transcription of numerous genes. Target genes induced include those involved in growth regulatory pathways, lipid transport and storage, and, most importantly for the present discussion, colon cell maturation and immune modulation.9,17

The search for an endogenous ligand for PPAR [gamma] has identified a number of compounds that function as activators. Numerous free fatty acids bind the receptor, although polyunsaturated fatty acids generally have a higher affinity for the receptor than do monounsaturated or saturated fatty acids.18,19 Perhaps more importantly, the oxidation products of polyunsaturated fatty acids are more potent activators of PPAR [gamma] than the unoxidized parent compounds.20 That polyunsaturated fatty acid oxidation can be an enzyme-mediated process places metabolic control over the activation of PPAR [gamma]. On the other hand, nonenzymatic lipid oxidation processes could result in the unintentional generation of PPAR activators with potentially pathologic outcomes.20