Peroxisome proliferator–activated receptor gamma (PPARγ) is a nuclear receptor, originally described in
adipose tissue, that controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization.
Well known by endocrinologists, thiazolidinediones (TZDs) are classical PPARγ synthetic agonists which were
currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. While the clinical benefits of TZDs in treating
metabolic disorders have been clearly demonstrated, new studies performed in animal models of colitis and in patients
with ulcerative colitis have also revealed the key roles of PPARγ activation in the regulation of inflammation and immune
response, notably in the colon through epithelial cells. During inflammation, PPAR acts directly to negatively regulate
gene expression of proinflammatory genes in a ligand-dependent manner by antagonizing the activities of other transcription
factors such as members of the NF-κB and AP-1 families. A major mechanism that underlies the ability of PPARs to
interfere with the activities of these transcription factors has been termed transrepression. PPARγ acts by inhibiting signaldependent
transcription factors that mediate inflammatory programs of gene activation. However, due to safety issues
concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment
of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARγ agonists with major
transrepressive effects and without toxicity. By the demonstration that the anti-inflammatory effects of 5-
aminosalicylic acid (5-ASA) in patients with ulcerative colitis were mediated by PPARγ activation, several molecules
having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxypropionic
acids named GED-0507-34-Levo (GED). This compound activating PPARγ has 100-to 150-fold higher
anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo,
without toxicity and is currently evaluated in a phase 2 clinical trial. The aim of this review is to present and discuss the
evidence suggesting that PPARγ targeting is of therapeutic interest in the treatment of UC.
Keywords: 5-aminosalicylic acid, clinical trials, drug design, experimental colitis, peroxisome proliferator activated receptor γ, thiazolidinediones, ulcerative colitis.
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