Thiazolidinedione ant its Mechanism of action

Thiazolidinedione drugs referred to as TZD also known as glitazones, named after the prototype drug ciglitazone is a class of heterocyclic compounds composed of five-membered C3NS rings.The term usually refers to a range of drugs introduced in the late 1990s to treat type 2 diabetes.

Mechanism of action

Thiazolidinediones, or TZDs, act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors that are specific for PPARγ (PPAR-γ, PPARG).They are therefore a subset of PPARG agonists of PPAR agonists.The endogenous ligands for these receptors are free fatty acids (FFA) and eicosanoids.When activated, the receptor binds DNA in complex with another nuclear receptor, the retinoid X receptor (RXR), increasing the transcription of many specific genes and decreasing the transcription of others. The main effect of specific gene expression and repression is to increase the storage of fatty acids in adipocytes, thereby reducing the amount of fatty acids present in circulation.As a result, cells become more reliant on the oxidation of carbohydrates, more specifically glucose, in order to generate energy for other cellular processes.

PPARγ TransactivationThiazolidinedione

Activated PPAR/RXR heterodimers bind to peroxisome proliferating hormone response elements upstream of target genes, forming complexes with many coactivators such as nuclear receptor coactivator 1 and CREB binding protein.This results in upregulation of genes (see PPARγ for complete list):

  • Reduced insulin resistance.

  • Modified adipocyte differentiation.

  • Inhibits VEGF-induced angiogenesis.

  • Decreased leptin levels (resulting in increased appetite).

  • Decreased levels of certain interleukins (such as IL-6).

  • Antiproliferative effects.

  • Elevated adiponectin levels

TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, thereby reducing levels of certain types of lipids and circulating free fatty acids.TZDs generally lower triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).Although the increase in LDL-C may be more concentrated in larger LDL particles, which may be less atherogenic, its clinical significance is currently unclear.Still, rosiglitazone, a type of glitazone, was suspended by medical authorities in Europe because it was linked to an increased risk of heart attack and stroke.

PPARγ Transrepression

Binding of PPARγ to coactivators appears to reduce the levels of coactivators available to bind proinflammatory transcription factors such as NF-κB; this results in reduced transcription of many proinflammatory genes, including various interleukins and tumor necrosis factor.

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