Pleiotropic Effects of Glitazones: A Double Edge Sword?

Abstract

Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

Assessing Hepatoxicants based on High-throughput Quantitative SILAC Proteomics and Causal Biological Networks

“…Ros and other TZDs affect glucose and lipid metabolism through activation of the PPARγ receptor. The TZDs have recently been reported to have many effects that go beyond glucose and lipid metabolism, such as reducing inflammation by decreasing some cytokines [43] and inducing autophagy through HIF1 alpha activation [44], and some of these effects are thought to occur via PPAR γ-independent pathways [43]. The upregulation of HIF1 alpha expression by rosiglitazone is consistent with the hypothesis, HIF1A + .…”

The CD36-PPARγ Pathway in Metabolic Disorders

“…Part of the noxious effects of troglitazone in liver was associated with the production of toxic reactive metabolites and signs of mitochondrial DNA damage, mitochondrial defects and cell death [ 124 , 125 ], which emphasizes anti-oxidant strategies [ 126 ]. However, some evidence indicates that the toxic effect of troglitazone might be independent of PPARγ activity [ 127 ]. Recent studies have reported beneficial hepatic effects of PPARγ agonists in reversing nonalcoholic steatohepatitis (NASH) in patients, reducing liver inflammation, fibrosis and triglyceride content [ 128 , 129 ].…”

Advances in BAT physiology for understanding and translating into Pharmacotherapies for obesity and comorbidities

“…Once PPAR γ is activated by thiazolidenediones, they affect both lipid along with carbohydrate metabolism by various mechanisms when used for treatment of T2DM. 89 Since brown adipocytes increase energy expenditure, increase of brown fat adipogenesis could explain the good effects of these drugs in insulin sensitivity in humans. Rosiglitazone helps in proadipocyte cell line differentiation and helps in increasing IBAT mass.…”