Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy. Finally, more studies are also needed to confirm the involvement of PPARs α and γ in gastric ulcer.

Keywords: Evidences; Gastric ulcer; Peroxisome proliferator-activated receptors.

Figure 1

Peroxisome proliferator-activated receptors - mediated mechanisms of transcriptional regulation. In the absence of ligands, peroxisome proliferator-activated receptors (PPARs) bind the promoters of their target genes and repress transcription by recruiting the corepressor complex. In the presence of ligands, PPARs can induce either ligand-dependent transactivation or transrepression. Transactivation involves PPARs heterodimerization with the retinoid X receptors (RXRs) followed by recognition of specific PPAR response elements (PPREs) and interaction with coactivators. Transrepression involves interference with other signal transduction pathways, including NF-κB, STAT, and AP1. NCoR: Nuclear receptor corepressor; NF-κB-RE: NF-κB response element; IFN-RE: Interferon-stimulated gene factor responsive element; TRE-RE: O-tetradecanoylphorbol 13-acetate-responsive element; HDAC: Histone deacetylase; CBP: CREB binding protein; PGC1:Peroxisome proliferator activated receptor gamma coactivator 1; STATs: Signal transducers and activators of transcription.