Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases

Abstract

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARa, PPARg, and PPARb/d, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARa activation represses NF-kB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARg ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a), interleukin (IL)-6, and Il-1b. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.

Gut microbiota-derived inosine from dietary barley leaf supplementation attenuates colitis through PPARγ signaling activation

“…Patients with ulcerative colitis display decreased expression of peroxisome proliferator-activated receptor (PPAR)γ in the colonic epithelium, which may be an important factor for the cause of intestinal dysfunction and chronic inflammation [ 6 ]. Clinically, PPARγ is also a crucial pharmacological target for anti-inflammatory drugs such as 5-aminosalicylic acid and corticosteroids [ 7 ]. However, most of the current drug-based interventions lack specificity and may have adverse effects [ 8 ].…”

Thymoquinone, a Dietary Bioactive Compound, Exerts Anti-Inflammatory Effects in Colitis by Stimulating Expression of the Colonic Epithelial PPAR-γ Transcription Factor

“…Decreased expression of PPAR-γ has been reported in colons of UC patients compared to healthy colons. Increased transcriptional activity of PPAR-γ is associated with decreased production of proinflammatory cytokines, such as IL-6 and IL-8, and chemokines, including CXCL1 (GRO-α), CXCL2 (MIP2-α), and CXCL3 (MIP-2β), in colonic tissues [ 6 ]. Our result indicates that TQ treatment increased PPAR-γ expression at protein and mRNA levels.…”

“…Recent reports show low expression of PPAR-γ in the colon of UC patients, suggesting an inverse correlation between PPAR-γ and UC progression [ 6 , 7 ]. PPAR-γ is a known modulator of cytokine/chemokine production [ 6 , 7 ], making it a useful therapeutic target for IBD [ 8 ]. Some phytochemical ligands that modulate the PPAR-γ pathway have been shown experimentally to limit colonic inflammation.…”

15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis

“…In contrast, PPAR γ was also found to mediate M2 polarization by inducing Arg-1 and CD36 expression ( 63 , 64 ). Though the role for PPARγ in IBD is controversial ( 65 ), a plethora of studies suggest that PPARγ activation might impede pathophysiological imbalances associated with IBD ( 66 ).15d-PGJ 2 , as an endogenous PPARγ ligand, has been reported to inhibit pro-inflammatory signaling ( 16 , 67 ). Pretreatment with PPARγ agonists 15d-PGJ 2 and rosiglitazone prevented acute stress-induced colonic inflammation and barrier dysfunction in rats, and these effects were reverted by a PPARγ specific antagonist ( 68 ).…”