Peroxisome Proliferator-Activated Receptors (PPARs)

What are the Peroxisome Proliferator-Activated Receptors (PPARs)?

The peroxisome proliferator-activated receptors, PPARs, are a family of nuclear receptors that play important roles in regulating metabolic processes such as lipid and glucose homeostasis.There are three subtypes of PPARs: PPAR alpha, PPAR beta/delta and PPAR gamma. PPAR alpha is primarily expressed in the liver and plays a role in fatty acid oxidation and ketone body production. When PPARα is activated, it reduces triglyceride levellevels and aids in regulating energy homeostasis.

PPAR beta/delta is expressed in multiple tissues, including skeletal muscle and adipose tissue, and is involved in fatty acid metabolism and energy expenditure. PPAR gamma is primarily expressed in adipose tissue and plays a key role in adipocyte differentiation and glucose uptake. PPARs are activated by endogenous ligands such as fatty acids and eicosanoids, as well as exogenous ligands such as thiazolidinediones (TZDs), a class of drugs used to treat type 2 diabetes. Activation of PPARs leads to the upregulation of genes involved in fatty acid metabolism, glucose uptake, and inflammation.

Peroxisome proliferator-activated receptor alpha (PPAR alpha)

PPAR alpha is a nuclear receptor that plays a crucial role in the regulation of lipid and glucose metabolism, inflammation, and oxidative stress. It is primarily expressed in the liver but also in other metabolic tissues such as the skeletal muscle and heart. PPAR alpha is activated by endogenous fatty acids, as well as synthetic ligands such as fibric acid derivatives, which are used in the treatment of dyslipidemia. PPAR alpha activation leads to the upregulation of genes involved in fatty acid oxidation, resulting in a reduction in circulating triglycerides and an increase in high-density lipoprotein (HDL) cholesterol. In addition, PPAR alpha activation also has anti-inflammatory and antioxidant effects. Several drugs that target PPAR alpha, such as fibrates, are currently in clinical use for the treatment of dyslipidemia.

Peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta)

PPAR beta/delta is a nuclear receptor that is involved in the regulation of lipid metabolism, glucose homeostasis, and inflammation. It is expressed in various tissues, including adipose tissue, skeletal muscle, and the liver. PPAR beta/delta is activated by endogenous fatty acids, as well as synthetic ligands such as GW501516, which has been shown to improve endurance performance in animal models. PPAR beta/delta activation leads to an increase in fatty acid oxidation and a decrease in lipogenesis, resulting in an improvement in insulin sensitivity and a reduction in circulating triglycerides. PPAR beta/delta is also involved in the regulation of inflammation and is a potential target for the treatment of inflammatory diseases such as atherosclerosis and inflammatory bowel disease. Several drugs that target PPAR delta, such as GW501516, are currently in various stages of preclinical and clinical development.

Peroxisome proliferator-activated receptor gamma (PPAR gamma)

PPAR gamma is a nuclear receptor that plays a crucial role in the regulation of adipogenesis, glucose metabolism, and inflammation. It is expressed primarily in adipose tissue, where it regulates the differentiation of preadipocytes into mature adipocytes. PPAR gamma activation leads to an increase in glucose uptake and utilization, resulting in an improvement in insulin sensitivity. PPAR gamma also has anti-inflammatory effects and is a potential target for the treatment of inflammatory diseases such as atherosclerosis and rheumatoid arthritis. However, PPAR gamma activation also leads to an increase in adipogenesis and may contribute to the development of obesity. Several drugs that target PPAR gamma, such as thiazolidinediones, are currently in clinical use for the treatment of type 2 diabetes, and others are in various stages of preclinical and clinical development for the treatment of metabolic diseases and inflammatory diseases.

PPARs in Drug Discovery

Due to their role in regulating metabolic processes, PPARs have been studied as potential drug targets for various diseases, including type 2 diabetes, dyslipidemia, and cardiovascular disease. TZDs, such as pioglitazone and rosiglitazone, are PPAR gamma agonists used to treat type 2 diabetes. However, their use has been associated with adverse effects such as weight gain and increased risk of heart failure. PPAR agonists and modulators are also being investigated for the treatment of other diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cancer. In addition, natural compounds such as polyunsaturated fatty acids (PUFAs) and resveratrol, a compound found in red wine, have been shown to activate PPARs and may have therapeutic potential.

PPARs in Environmental Toxicology

Several environmental pollutants have been shown to activate or inhibit PPAR activity. For example, perfluorooctanoic acid (PFOA), a chemical used in the production of non-stick coatings, has been found to activate PPARα and promote the expression of its target genes. Bisphenol A (BPA), a chemical used in the production of plastics, has also been shown to activate PPARγ and alter its activity. Phthalates, another class of chemicals used in the production of plastics, activate PPAR alpha and may inhibit PPARγ activity. Other environmental pollutants that have been shown to interact with PPARs include organotins, flame retardants, and polycyclic aromatic hydrocarbons (PAHs).

INDIGO’s PPAR Reporter Assays

INDIGO Biosciences offers cell-based luciferase reporter assay kits for all of the peroxisome proliferator-activated receptors. Our assays provide an all-inclusive luciferase reporter system that includes, in addition to the PPAR Reporter Cells, optimized media for use during cell culture and in diluting test samples, a reference agonist, Luciferase Detection Reagent, and a cell culture-ready assay plate.

INDIGO’s cell-based reporter assays allow scientists to screen and discover drugs that can be used to treat PPAR-related diseases or evaluate environmental samples for contaminants that may alter PPAR bioactivity. The primary application of our nuclear receptor assays is to quantitatively assess the bioactivity of a test compound/sample as an agonist (activator) or antagonist (inhibition of an agonist response) of a given receptor. Want more information? Contact our team to learn more, explore related testing, or request a research study today!