Peroxisome proliferator-activated receptors (PPAR) Background
The peroxisome proliferator-activated receptor-α (PPARα) was cloned from rodent liver in 1990. Two additional members of the PPAR subfamily were first identified in Xenopus and later in mammals, and termed PPARβ (also referred to as PPARδ, PPARβ/δ) and PPARγ. The three PPARs are expressed in many species including rodents and humans. PPARs belong to the type 2 class of ligand-activated nuclear receptor superfamily, historically referred to as “orphan receptors”. The PPARs are involved in a number of biological responses, including adipogenesis, lipid homeostasis, immune function, cell proliferation/apoptosis and carcinogenesis. There are a number of mechanisms by which PPARs modulate transcription (See figure below).
Functional roles of PPARs
The biological roles of PPARα and PPARγ are considerably better defined as compared to PPARβ/δ. This is due in part to the findings that they are targets for drugs used in the treatment of dyslipidemias and type 2 diabetes, respectively. It is well accepted that PPARα, a target of the fibrate class of hypolipidemic drugs, has a critical role in regulating lipid homeostasis by increasing transcription of target genes encoding products that mobilize lipids from adipose, proteins that transport fatty acids in the cell and bloodstream and enzymes that facilitate fatty acid catabolism in tissues such as liver, kidney and heart. In contrast, PPARγ, a target of the thiazolidinedione class of type 2 diabetes drugs, is required for adipocyte differentiation and fatty acid storage. Ligands for PPARα, PPARβ/δ, and PPARγ have also been found to suppress inflammation and potentially decrease atherosclerotic lesions. In addition to these well-accepted functional roles for PPARα and PPARγ, there is also good evidence that these receptors are involved in processes that regulate cell proliferation, apoptosis and differentiation. However, it is of interest to point out that the roles of PPARα and PPARγ in the aforementioned pathways are, in some cases, still controversial due to conflicting reports in the literature. This is also true for PPARβ/δ, since convincing functional roles of this PPAR isoform remain somewhat unclear, despite recent advances made with loss-of-function and gain-of-function models coupled with highly specific ligands.
The focus of our laboratory is to determine the biological/functional roles of PPARs in toxicology, carcinogenesis and homeostasis, with a keen interest in identification and characterization of the molecular events mediated by these receptors. While the main focus of our laboratory is on the role of PPARβ/δ, we also have active research examining interactions of PPARβ/δ with other nuclear receptors and transcription factors. Our laboratory is uniquely positioned to pursue these goals because we have many tools ranging from specific ligands for PPARβ/δ, gain-of-function and loss-of-function cell based and animal models, and state-of-the-art research technologies available here at The Huck Institute of Life Sciences at The Pennsylvania State University, and the shared resource facilities at The Penn State Cancer Institute. There are a number of areas currently under investigation in our laboratory including:
- Determining the functional role of PPARβ/δ in skin and epithelium and how modulation of this regulatory pathway can be used for chemoprevention and/or chemotherapeutic targets in epithelial cancers.
- Determining the functional role of PPARβ/δ in liver homeostasis and how modulation of this regulation can influence hepatotoxicity and cancer.
- Delineating functional roles of primary, direct PPARβ/δ target genes in specific tissues and how they modulate cancer.
- Examining how PPARβ/δ interacts with other receptors and transcription factors and determining the functional significance of these interactions.
- Identifying and characterizing endogenous ligands for PPARβ/δ and how these can be used for cancer chemoprevention and chemotherapy.