The Impact of Lrat on Cardiomyocyte Energetics and Survival

心力衰竭是工业化国家死亡的主要原因，超过了大多数癌症的死亡率，大约一半的患者在最初诊断后的5年内死亡。此外，2型糖尿病的发病率正以惊人的速度增长。2型糖尿病的特点是胰岛素抵抗和初始高胰岛素血症，这加速了心力衰竭的发生。先前的研究报道了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（类维生素a）的储存。与Lrat类似，受视黄酸6 （Stra6）的刺激，在类视黄酸稳态中起核心作用，并介导细胞内视黄醇的摄取。然而，缺乏Lrat和Stra6对心脏能量学和心力衰竭发展的影响的详细分析，将在本提案中进行评估。总之，这些研究将为心脏类维甲酸代谢提供新的见解，并将确定新的、类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.