The role of LPCAT3 in pathogenesis of diabetic cardiomyopathy

心血管疾病是全球头号死因。大多数心血管疾病是由风险引起的 吸烟、高血压、肥胖或糖尿病等因素。糖尿病心肌病(DC)是 以在没有其他心脏危险因素的情况下心脏结构和功能异常为特征 在糖尿病患者中通常没有诊断出来。如果不治疗，这种情况会增加患上 与没有糖尿病的人相比，男性心力衰竭至少是男性的2.4倍，女性是5.1倍。 尽管在过去几十年中病例数量有所增加，但潜在的分子 DC的发病机制仍然知之甚少，从而阻碍了 有效的诊断工具和药物疗法以及预防战略。新兴市场之一 假说是细胞膜多不饱和脂肪酸组成改变可以激活内质网应激 细胞中的信号、氧化应激和炎症。据推测，增加的膜 磷脂饱和可能是许多代谢紊乱的潜在原因。 溶血磷脂酰胆碱酰基转移酶3(LPCAT3)是一种主要的心肌酶，它催化 溶血磷脂酰胆碱形成磷脂酰胆碱(PC)。LPCAT3优先合成 在sn-2位含有不饱和脂肪酸的PC。最近的一项研究表明，LPCAT3 肥胖糖尿病db/db小鼠肝脏过表达通过调节PC有效降低内质网应激 饱和度。然而，LPCAT3在心脏代谢中的作用还知之甚少。因此， 拟议的项目旨在确定LPCAT3在心功能中的作用并调查其影响 LPCAT3缺陷可能在DC的发生发展中起作用。此外，该项目还将调查 添加PC的饮食改善肥胖小鼠心脏功能的潜力。最后，建议的研究 将通过其转录因子-肝X受体来研究LPCAT3过表达的可能性 (LXR)激活在急性脂毒性时改善心肌细胞结构和功能。

Cardiovascular diseases are the number one cause of death globally. Most CVDs are caused by risk factors such as tobacco use, hypertension, obesity or diabetes. Diabetic cardiomyopathy (DC) is characterized by abnormal cardiac structure and function in the absence of other cardiac risk factors and is often undiagnosed in patients with diabetes mellitus. Untreated, this condition increases the chance of heart failure at least 2.4-fold in men and 5.1-fold in women compared to individuals without diabetes. Despite the increase in the number of cases in the past several decades, the underlying molecular mechanisms of DC pathogenesis remain poorly understood, thereby preventing the development of effective diagnostic tools and pharmacotherapies as well as preventive strategies. One of the emerging hypothesis is that altered membrane polyunsaturated fatty acid composition can activate ER stress signaling, oxidative stress and inflammation in cells. It has been speculated that increased membrane phospholipid saturation may be an underlying cause of many metabolic disorders. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is a major cardiac enzyme that catalyzes the formation of phosphatidylcholine (PC) from lysophosphatidylcholine. LPCAT3 preferentially synthesizes PC containing unsaturated fatty acids at the sn-2 position. A recent study has shown that LPCAT3 overexpression in livers of obese diabetic db/db mice effectively reduced ER stress by modulating PC saturation. However, the role of LPCAT3 in cardiac metabolism is very poorly understood. Therefore, the proposed project aims at establishing the role of LPCAT3 in cardiac function and investigating the effect that LPCAT3 deficiency may play in development of DC. Additionally, the project will investigate the potential of PC supplemented diet to improve cardiac function in obese mice. Finally, the proposed study will investigate the potential of LPCAT3 overexpression through its transcription factor - liver X receptor (LXR) activation on improving cardiomyocyte structure and function in acute lipotoxicity.