The Impact of Lrat on Cardiomyocyte Energetics and Survival

在工业化国家，心力衰竭是主要的死亡原因，超过了大多数类型癌症的死亡率，大约一半的患者在首次诊断后5年内死亡。此外，2型糖尿病的发病率正在以惊人的速度增加。2型糖尿病的特征是胰岛素抵抗和最初的高胰岛素血症，这会加速心力衰竭的发生。以前的研究报告了2型糖尿病患者维生素A代谢紊乱。此外，我们的初步数据表明，卵磷脂：视黄醇酰基转移酶(LRAT)具有心脏保护作用，它介导维生素A代谢物(维甲酸)的储存。与Lrat类似，视黄酸6(Stra6)在维甲酸的稳态中起核心作用，并介导细胞内对视黄醇的摄取。然而，Lrat和Stra6对心脏能量学的影响和心力衰竭的发展缺乏详细的分析，并将在本提案中进行评估。总之，这些研究将为心脏维甲酸代谢提供新的见解，并将确定新的维甲酸介导的心脏保护机制。

Heart failure is a major cause of death in industrialized nations and exceeds the mortality of most types of cancers with about half of patients dying within 5 years of the initial diagnosis. Furthermore, the incidence of type 2 diabetes is increasing at an alarming rate. Type 2 diabetes is characterized by insulin resistance and initial hyperinsulinemia, which accelerate the onset of heart failure. Previous studies reported perturbed vitamin A metabolism in type 2 diabetic patients. Furthermore, our preliminary data indicate a cardioprotective role for lecithin:retinol acyltransferase (Lrat), which mediates the storage of vitamin A metabolites (retinoids). Similar to Lrat, stimulated by retinoic acid 6 (Stra6) plays a central role in retinoid homeostasis and mediates intracellular uptake of retinol. However, detailed analysis of the impact of Lrat and Stra6 on cardiac energetics and the development of heart failure is lacking and will be evaluated in this proposal. Together, these studies will provide new insight into cardiac retinoid metabolism and will identify novel, retinoid-mediated cardioprotective mechanisms.