Abstract 12532: The Tandem Zinc Finger mRNA Binding Protein, Tristetraprolin, is a Novel Regulator of Cardiac Fatty Acid Metabolism Through its Effect on PPARa

Abstract

Introduction: Altered substrate utilization has been described in type II diabetes and heart failure (HF), but current therapies do not target the metabolic derangements in these disorders. Identification of novel pathways regulating cellular metabolism could facilitate the development of new therapies. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich regions in the 3’ untranslated region (UTR) of mRNA molecules and causes their degradation. Its expression is reduced in patients with diabetes, and its cellular level is regulated by mTOR, a key protein involved in cellular metabolism. Furthermore, the yeast homolog of TTP has been suggested to play a role in metabolism. Thus, we hypothesized that TTP regulates cardiac metabolism and plays a role in the development of HF through its effects on substrate utilization in the heart. Results: We first assessed the effects of TTP modulation on cellular substrate utilization, and found that TTP downregulation in cultured cardiomyocytes resulted in higher palmitate uptake and oxidation while its overexpression had the opposite effect. Since TTP regulates its targets at the mRNA level, we studied the mRNA levels of all genes involved in lipid metabolism, and found that only PPARα mRNA to be significantly increased with TTP downregulation. Furthermore, we demonstrated that TTP physically interacts with PPARα mRNA, and the activity of a luciferase reporter harboring full-length PPARα 3’UTR is increased with TTP downregulation. Additionally, PPARα mRNA is stabilized with TTP knockdown. We then studied the role of TTP in cardiac metabolism using mice with cardiac-specific TTP knockout. Although cardiac-specific TTP knockout mice had normal cardiac function at baseline, they displayed higher fatty acid utilization compared to wild type littermate control in an ex vivo heart perfusion setup. We also demonstrated a significantly higher TTP levels in failing human and mouse cardiac samples, suggesting that TTP levels are altered in HF. Conclusion: Our results demonstrate that TTP is a novel regulator of cardiac fatty acid metabolism through its effect on PPARα, and that its levels are increased in HF. Thus, modulation of TTP may be a viable therapeutic approach for HF.