Like catching two fish with one worm, treating two problems with a single drug is efficient, but exceedingly difficult. In particular, for new diabetes medications, in which one drug aims to tackle two major complications of diabetes – the excess of both lipids and glucose in the blood – the therapeutic benefits, while great, frequently are accompanied by dangerous toxic effects to the heart. Why and how these drugs, known as dual PPARα/γ agonists cause heart dysfunction in diabetes patients has been unclear. But now, in new research published in the journal JCI Insight, scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) show for the first time that dual PPARα/γ diabetes drugs have a profound toxic effect on the generation and function of mitochondria, the energy factories that power cells. Konstantinos Drosatos, PhD, Assistant Professor of Pharmacology in the Center for Translational Medicine and the Center for Metabolic Disease Research at LKSOM is the senior investigator of the research.
The popular diabetes drugs known as thiazolidinediones (TZDs), which include pioglitazone and rosiglitazone (the latter marketed as Avandia), bind to PPARγ receptors. Because these drugs given alone have been questioned for cardiac toxicity, the idea emerged for dual PPARα/γ activation by a single drug – the one piece of bait that in theory successfully lures the two fish – the combined lipid- and glucose-lowering effects of PPARα/γ coactivation. The effects of PPARα and PPARγ receptor activation are like the fish that researchers are trying to bait. The PPARα receptor binds molecules such as fibrates, which help reduce blood triglyceride levels and increase levels of high-density lipoproteins (HDLs) – popularly known as “heart-healthy” fats. Meanwhile, PPARγ receptors attach molecules that help lower blood glucose levels. Scientists found that the combined activation of PPARα and PPARγ receptors by a single agonist drug, tesaglitazar, blocked the activity of proteins involved in mitochondrial biogenesis and energy production, including a protein known as SIRT1.
SIRT1 encodes for sirtuin-1, an enzyme which uses vitaminic cofactor NAD+ to drive metabolism, genome stability and cellular aging. When the team reactivated SIRT1 with resveratrol, an antioxidant widely known for its presence in grape skins, heart toxicity was reduced and the benefits of dual lowering of lipid and glucose levels were maintained in tesaglitazar-treated mice. To understand why these new drugs are accompanied by just as much cardiac toxicity, if not more, than TZDs, Dr. Drosatos and colleagues carried out a series of studies in diabetic mice treated with the dual PPARα/γ agonist tesaglitazar. Despite reduced triglyceride and glucose levels in the blood, the mice developed cardiac dysfunction. Molecular analyses of heart tissue from affected animals revealed a significant reduction in the expression and activation of a protein known as cardiac PPARγ coactivator 1-α (PGC1α), which plays a critical role in mitochondrial biogenesis. This reduction was accompanied by decreases in SIRT1 expression and in mitochondrial abundance.
The researchers then repeated their experiment, this time treating diabetic mice with tesaglitazar in combination with resveratrol, which serves as an activator of SIRT1. Mice treated with the combination of the two drugs had reduced heart toxicity, relative to tesaglitazar-only therapy, and their heart cells exhibited normal mitochondrial function. Heart is highly dependent on mitochondria since it uses fatty acids to be burned inside them to produce energy. In this process, mitochondria need carnitine as a shuttle and coenzyme Q as redox cofactor. Both metabolites often are low in chronic heart failure and diabetes; their supplementation may confer some benefits in both conditions, since in either cases drug therapy with statins is advised. Statins, indeed, may lower coenzyme Q production as chronic side effect. One of the team’s next aims is to further elucidate the signaling pathway that moderates the effects of PPAR drugs in order to identify a single target – the example of one worm to catch a tuna instead of a mackarel. Beside, by targeting fewer proteins, there should be fewer toxic effects to worry about.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Kalliora C et al., Drosatos K. JCI Insight. 2019 Aug 8;5.
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