This excellent animation from the Hybrid team shows in detail the process of activation of the PPAR receptor, its interaction with the RXR and the ligand.

This animation is an excellent oportunity to review the drugs that act as ligands of the PPAR receptor and its subtypes (Alpha and Gamma). Novel agents that target PPAR delta are being developed.

Drugs acting on peroxisome proliferator–activated receptor-alpha (PPAR-α): fibrates

Drug members: Bezafibrate (Bezalip), Ciprofibrate (Modalim), Gemfibrozil (Lopid), Fenofibrate (TriCor)

Mechanism of action of fibrates. From Lippincott Illustrated Reviews: Pharmacology

The peroxisome proliferator–activated receptors (PPARs) are members of the nuclear receptor supergene family that regulates lipid metabolism. PPARs functions as a ligand-activated transcription factor. Upon binding to its natural ligand (fatty acids or eicosanoids) or hypolipidemic drugs, PPARs are activated. They then bind to peroxisome proliferator response elements, which are localized in numerous gene promoters. In particular, PPARs regulates the expression of genes encoding for proteins involved in lipoprotein structure and function. Fibrate-mediated gene expression ultimately leads to decreased triacylglycerol concentrations by increasing the expression of lipoprotein lipase and decreasing apo CII concentration. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII. Fenofibrate is a prodrug, producing an active metabolite, fenofibric acid, which is responsible for the primary effects of the drug.

Peroxisome proliferator–activated receptor-gamma (PPARγ) agonists: Glitazones or thiazolidinediones (TZDs)

Members: Rosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin)

Mechanism of action of Thiazolidinediones (TZDs) or glitazones. From Lippincott Illustrated Reviews: Pharmacology.

Although the exact mechanism by which the TZDs lower insulin resistance remains to be elucidated, they are known to target the peroxisome proliferator–activated receptor-γ (PPARγ)—a nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated HbA1c levels are improved. Interestingly, LDL levels are not affected by pioglitazone monotherapy or when the drug is used in combination with other agents, whereas LDL levels have increased with rosiglitazone. HDL levels increase with both drugs. The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues. [Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.

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