PPARs: History and Advances
Peroxisome proliferator-activated receptors (PPARs) are members of the steroid hormone receptor superfamily, discovered in 1990.
To date, three PPAR subtypes have been identified; PPARα, PPAR β/δ, and PPARγ
These receptors share a high degree of homology but differ in tissue distribution and ligand specificity.
Three types of PPARs have been identified: alpha, gamma, and delta (beta)
- α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
- β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
γ (gamma) - although transcribed by the same gene, this PPAR through alternative splicing is expressed in three forms:
γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
γ2 - expressed mainly in adipose tissue (30 amino acids longer than γ1)
γ3 - expressed in macrophages, large intestine, white adipose tissue.
PPARs have been implicated in the etiology as well as treatment of several important diseases and pathological conditions such as diabetes, inflammation, senescence-related diseases, regulation of fertility, and various types of cancer.
Consequently, significant efforts to discover novel PPAR roles and delineate molecular mechanisms involved in their activation and repression as well as develop safer and more effective PPAR modulators, as therapeutic agents to treat a myriad of diseases and conditions, are underway.
This volume of Methods in Molecular Biology contains details of experimental protocols used in researching these receptors.
Discovery of the PPARs. Landmark events in the advancement of PPARs research
It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation.
Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on.
With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes.
In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments.
Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs.
Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer.
Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice.
In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.
Roles of PPARs in the energy metabolism of various organs.
The three types of PPARs are widely expressed in various organs, including the liver, WAT, BAT, pancreas, heart, intestine, and SKM. Regulation differences of these PPARs in different tissues are shown and the first item in each list represents the main PPAR subtype and function for the organ.
The filled circle represents PPARα; the empty circle represents PPARγ; the triangle represents PPARβ/δ; the green arrow represents beneficial effect; and the red arrow represents adverse effect.
For example, among the three types of PPARs, PPARα is the master regulator in the liver and the activation of it increases FAO, induces ketogenesis, and decreases lipid storage in the liver.