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New study finds solution to drug-induced cardiac toxicity

Researchers belonging to the Lewis Katz School of Medicine at Temple University (LKSOM) show have successfully demonstrated, for the first time, how dual PPARα/γ diabetes drugs have a highly toxic effect on the generation and function of mitochondria, the powerhouse of the cell. Konstantinos Drosatos, Ph.D., Assistant Professor, Pharmacology, and Assistant Professor, Center for Translational Medicine and the Center for Metabolic Disease Research, LKSOM, was the senior investigator on the study. Dr. Drosatos explains they found that the combined activation of PPARα and PPARγ receptors by one agonist drug named tesaglitazar was able to block the activity of proteins associated with mitochondrial biogenesis and energy generation, along with the protein SIRT1. The team’s work has been published in the journal JCI Insight.

Dr. Drosatos adds that when the team reactivated SIRT1 using resveratrol, an antioxidant found in grape skins, they observed that it reduced the heart toxicity and the benefits of dual lowering of lipid and glucose levels were conserved in mice treated with tesaglitazar. The effect of activation of the two receptors was somewhat close to the results the team was hoping to achieve. The PPARα receptor can bind molecules like fibrates that help lower blood triglyceride levels and increase the levels of high-density lipoproteins (HDLs), commonly referred to as “heart-healthy” fats. On the other hand, the PPARγ receptors can attach molecules that help lower blood glucose levels. The popular diabetes drugs called thiazolidinediones (TZDs) that includes pioglitazone and rosiglitazone, bind to PPARγ receptors. These drugs, when administered alone, have been known to increase heart toxicity, which gave way to the idea of dual PPARα/γ activation through a single drug, which was seen as the only way to bring about the combined glucose- and lipid-lowering effects of PPARα/γ co-activation.

Dr. Drosatos says that this study has given them a clearer idea of how toxicity in the heart arises from treatment with dual PPARα/γ agonists, which enables them to pilot the development of PPAR-targeting drugs in the future. In the next stage, the team aims to gain a deeper understanding of the signaling pathway that controls the effects of PPAR drugs to identify a single target.

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