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Identifier 000412912
Title Effects of combined PPARα and PPARγ activation in Cardiac Lipotoxicity
Alternative Title O ρόλος της συνδυασμένης ενεργοποίησης των PPARa και PPARy στην καρδιακή λιποτοξικότητα
Author Καλλιώρα, Χαρίκλεια
Thesis advisor Δροσάτος, κωνσταντίνος
Reviewer Καρδάσης, Δημήτριος
Τσατσάνης, Χρήστος
Abstract Improvements in hyperglycemia and hyperlipidemia constitute the major focus of various therapies for treatment of type 2 Diabetes. Agonists of peroxisome proliferator-activated receptor (PPAR)α and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARα activation reduces circulating triglyceride levels and PPARγ improves insulin sensitivity. PPARs belong to the nuclear receptors super-family and regulate fatty acid (FA) metabolism. PPARα ligands, such as fibrates, lower plasma triglyceride levels and increase HDL-cholesterol levels . Thiazolidinediones (TZDs) are PPARγ ligands. PPARγ agonists increased salt and water retention and were associated with heart failure. The dual-PPARα/γ agonists (glitazars) have been developed to combine the beneficial effects of PPARα and PPARγ agonism. Although these dual-agonists improve metabolic parameters, they have been paradoxically found to aggravate congestive heart failure in patients with type 2 diabetes via mechanisms that remain unknowν. PPARs are important for cardiac FA metabolism . Different PPAR isoforms can regulate the same FA metabolism-related genes. Dominance of one PPAR isoform over the other in controlling FA metabolism in a tissue depends on the abundance of the respective isoform, as well as on the availability of endogenous ligands. Cardiac PPARα regulates the expression of genes that modulate FA oxidation (FAO). PPARγ can also promote cardiac FA, especially when PPARα expression is reduced or ablated. FAO accounts for the production of 70% of the ATP that is produced in the heart. Thus, it is surprising that combined activation of two positive regulators of cardiac FAO, PPARα and PPARγ, causes cardiac dysfunction. PGC1α, the common transcriptional coactivator of PPARα and PPARγ, is involved in cardiac FAO and regulates mitochondrial biogenesis and respiration. PGC1α activation is controlled through reversible lysine side chain hyperacetylation that is regulated by the enzymatic activity of the deacetylase Sirtuin1 (SIRT1) . Our study focused on the mechanistic basis that underlies the cardiac dysfunction caused by combined activation of PPARα/γ, which constitutes the basis for an antidiabetic treatment. Our data from experiments in mice presented that dual-PPARα/γ agonist, Tesaglitazar, caused cardiac dysfunction associated with reduced PGC1α expression and activation. These effects are driven by competition between PPARα and PPARγ for regulation of Pgc1α gene expression, as well as by decreased cardiac SIRT1 expression. Activation of SIRT1 with Resveratrol, attenuated Tesaglitazar-mediated cardiac dysfunction in WT and diabetic (db/db) mice but not in mice with cardiomyocyte-specific ablation of SIRT1. In conclusion, our study elucidated the mechanism that underlies dual PPARα/γ agonist cardiotoxicity and we present a new pharmacologic approach that blunted the cardiotoxic effect of the anti-diabetic dual-PPARα/γ therapy, while it maintained its beneficial anti-hyperlipidemic and anti-hyperglycemic effects.  
Language English
Subject Καρδιακός μεταβολισμός
Issue date 2017-12-12
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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