Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for XXXX health and disease.

@entity1 @entity5 @entity517 @entity694 @entity4910 @entity5601 @entity1412 @entity1718 @entity65 @entity6864 @entity11589
Peroxisome proliferator activated receptors (PPARs) are a family of related receptors implicated in a diverse array of biological processes. There are 3 main isotypes of PPARs known as @entity5601 , @entity11589 and @entity6864 and each is organized into domains associated with a function such as ligand binding, activation and DNA binding. PPARs are activated by ligands, which can be both endogenous such as @entity1718 or their derivatives, or synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene transcription. The different isotypes differ in their expression patterns, lending clues on their function. @entity5601 is expressed mainly in liver whereas @entity6864 is expressed in fat and in some macrophages. Activation of @entity5601 in rodent liver is associated with peroxisome proliferation and with suppression of apoptosis and induction of cell proliferation. The mechanism by which activation of @entity5601 regulates apoptosis and proliferation is unclear but is likely to involve target gene transcription. Similarly, @entity6864 is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. However, it has been implicated in the regulation of cell cycle and cell proliferation in @entity694 models. Less in known concerning @entity11589 but it was identified as a downstream target gene for @entity1412 /beta-catenin/T cell factor-4 @entity5 suppressor pathway, which is involved in the regulation of growth promoting genes such as @entity517 and @entity4910 . Marked species and tissue differences in the expression of PPARs complicate the extrapolation of pre-clinical data to @entity1 . For example, @entity5601 ligands such as the hypolipidaemic fibrates have been used extensively in the clinic over the past 20 years to treat @entity65 and side effects of clinical fibrate use are rare, despite the observation that these compounds are rodent carcinogens. Similarly, adverse clinical responses have been seen with @entity6864 ligands that were not predicted by pre-clinical models. Here, we consider the response to @entity5601 ligands seen in pre-clinical models of efficacy and safety in the context of @entity1 health and disease.
