Physiology
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, a large collection of nuclear hormone receptors that includes thyroid hormone receptors, steroid hormone receptors, the vitamin D3 receptor (VDR), retinoid acid receptors (RAR) and PPARs themselves. Among the PPARs, three known isoforms exist (α, δ, and γ), each interacting with different DNA response elements on the nuclear retinoic acid receptor.
PPAR-α transcription factors, for example, are expressed in various tissues such as the kidneys, cardiomyocytes, intestinal mucosa, and brown adipose tissue. Upon activation, PPAR-α modulates fatty acid metabolism, thus contributing to a reduction in lipid levels. PPAR-δ, ubiquitously distributed throughout the body, can promote fatty acid oxidation and lipid uptake when activated. The third isoform, PPAR-γ, is primarily localized in adipose tissue (both white and brown), intestinal tract, and immune cells. Activation of PPAR-γ stimulates adipocyte differentiation and promotes triglyceride storage.
Table 1. Physiologic effects of PPAR activation
| PPAR subtype | Physiologic effects |
| PPARα | Stimulates beta-oxidation of fatty acids (lipid catabolism). Controls vascular integrity. |
| PPARδ | Increases glucose uptake and glycogenesis in skeletal muscle. |
| PPARγ | Increases fatty acid oxidation in skeletal muscle, liver, and adipose tissue. Increase insulin-stimulated glucose uptake by adipocytes, skeletal muscles, and hepatocytes. Increase HDL cholesterol and reduced triglycerides. |
Transcriptional regulation mediated by Peroxisome Proliferator-Activated Receptors (PPARs) entails the formation of PPAR-retinoid X Receptor (RXR) heterodimers. This process is initiated by the binding of specific ligands, such as fatty acids, to PPARs. This ligand interaction induces a conformational alteration in the PPAR protein, enabling its heterodimerization with RXR.
Following its recruitment to the promoter region, the PPAR-RXR heterodimer binds to unique DNA sequences known as peroxisome proliferator response elements (PPREs) located upstream of the gene of interest. Subsequently, the PPAR-RXR heterodimer collaborates with additional transcription factors and coactivators to instigate the transcription of the target gene. Notably, PPAR-RXR heterodimers can also antagonize the action of other transcription factors by competing for binding to identical DNA sequences, thereby inhibiting the expression of certain genes.
The role of PPAR-RXR heterodimer-mediated gene transcription regulation is crucial for controlling metabolic pathways, among other biological processes. The transcription process culminates in pre-mRNA formation, followed by mRNA processing, leading to the synthesis of functional proteins that participate in metabolism.
Mechanism of action of pioglitazone (TZDs)
Pioglitazone forms associations with peroxisome proliferator-activated receptors (PPARs), which are present in adipose tissue, liver, and skeletal muscle. These PPARs play an essential role in the management of glucose and lipid metabolism through the regulation of gene transcription, influencing glucose utilization, lipid storage, and insulin sensitivity.
The therapeutic action of pioglitazone involves the enhancement of insulin sensitivity, which is achieved by promoting glucose uptake and utilization in adipose tissue, skeletal muscle, and liver tissue. This activity contributes to better glycemic control, as more glucose is transported into cells for energy consumption. Furthermore, pioglitazone acts to reduce the rate of hepatic gluconeogenesis, thereby mitigating the incidence of fasting hyperglycemia.
In addition, pioglitazone can increase insulin sensitivity by stimulating the differentiation and proliferation of preadipocytes, which consequently increases the mass of adipose tissue. This expansion of the storage capacity of adipose tissue is crucial for glucose and lipid sequestration and the subsequent enhancement of insulin sensitivity.
Practice Guide
Pioglitazone plays a multifaceted role in the management of metabolic disorders, including the amelioration of insulin resistance, preservation of pancreatic beta cell function in type 2 diabetes mellitus, enhancement of the lipid profile, and reversal of steatosis in individuals suffering from nonalcoholic fatty liver disease.
Table 2. Mechanism of key side effects related to pioglitazone
| Side effect | Mechanism |
| Weight gain | Stimulates PPAR gamma receptors in adipocytes, which induces adipogenesis |
| Fluid retention | Promotes peripheral vasodilation and enhances renal sodium conservation |
| Fragility fractures | Not yet elucidated |
| Bladder cancer | Not yet elucidated |
References
- Jay MA, Ren J (2007) Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Curr Diabetes Rev 3:33–39
- Ferré P (2004) The Biology of Peroxisome Proliferator-Activated Receptors: Relationship With Lipid Metabolism and Insulin Sensitivity. Diabetes 53:S43–S50
- Grygiel-Górniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review. Nutr J 13:17
- Viswakarma N, Jia Y, Bai L, Vluggens A, Borensztajn J, Xu J, Reddy JK (2010) Coactivators in PPAR-Regulated Gene Expression. PPAR Res 2010:e250126
- Leonardini A, Laviola L, Perrini S, Natalicchio A, Giorgino F (2010) Cross-Talk between PPAR and Insulin Signaling and Modulation of Insulin Sensitivity. PPAR Res 2009:818945
- Smith U (2001) Pioglitazone: mechanism of action. Int J Clin Pract Suppl 13–18
- Kobayashi M, Iwanishi M, Egawa K, Shigeta Y (1992) Pioglitazone increases insulin sensitivity by activating insulin receptor kinase. Diabetes 41:476–483
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