LIPIN 1 AND CARDIAC METABOLISM IN THE CONTEXT OF LIPID OVERLOAD

描述（由申请人提供）：Lipin 1正在成为中间代谢的关键调节剂。Lipin 1通过其双功能分子活性将线粒体代谢稳态与甘油脂质代谢联系起来。我们已经表明，脂蛋白1在细胞核中的行为，以调节编码线粒体酶的基因的表达，通过与DNA结合的转录因子和辅激活因子相互作用。然而，脂蛋白1可以在细胞内快速易位，并且还作为内质网（ER）膜处的脂质磷酸酶，使磷脂酸（PA）脱磷酸化以形成二酰基甘油（DAG）;这是甘油脂质代谢和甘油三酯合成中的关键步骤。有证据表明，脂蛋白1的活性受到雷帕霉素复合物1（mTORC 1）的分子靶点丝氨酸/苏氨酸磷酸化以及细胞中脂肪酸和PA浓度的高度影响，它们共同调节脂蛋白1的亚细胞定位。这使得lipin 1能够根据细胞的营养可用性来调节合成代谢和分解代谢途径。我们推测，慢性热量和脂质过剩将导致增加磷酸化和脂蛋白1的细胞质定位。我们还假设，在调节心脏脂质活性的异常促进甘油脂质的合成和抑制其促分解代谢的行动，有助于脂毒性心肌病的发展，在国家的慢性热量过剩。这个应用程序有三个主要目标。1.确定膳食营养调控对心肌细胞脂蛋白1表达、活性和亚细胞定位的影响。2.确定细胞核和细胞质lipin 1活性的遗传改变是否会调节脂毒性心肌病并影响心脏脂质代谢、信号传导和功能。3.目的探讨脂蛋白1活性改变对糖尿病心脏缺血再灌注损伤的影响。这些目标将通过使用具有改变的心脏lipin 1活性的各种转基因小鼠模型来实现。调节心脏脂蛋白1活性的作用将通过复杂的功能表型、转录组学和脂质组学来评估。预期使用这些组学方法来鉴定用于鉴定与肥胖心脏中的功能障碍的发育或保护相关的生物标志物的心脏特征。最终的目标将是利用这些信息使患有糖尿病心脏病的人类受试者受益。

DESCRIPTION (provided by applicant): Lipin 1 is emerging as a critical regulator of intermediary metabolism. Lipin 1 connects mitochondrial metabolic homeostasis to glycerolipid metabolism through its bi-functional molecular activities. We have shown that lipin 1 acts in the nucleus to regulate the expression of genes encoding mitochondrial enzymes by interacting with DNA-bound transcription factors and coactivators. However, lipin 1 can rapidly translocate within the cell and also acts as a lipid phosphatase at the endoplasmic reticulum (ER) membrane to dephosphorylate phosphatidic acid (PA) to form diacylglycerol (DAG); a key step in glycerolipid metabolism and triglyceride synthesis. Evidence has emerged that lipin 1 activity is highly influenced via serine/threonine phosphorylation by the molecular target of rapamycin complex 1 (mTORC1) and by the concentration of fatty acids and PA in the cell, which together regulate the sub-cellular localization of lipin 1. This allows lipin 1 to regulate both anabolic an catabolic pathways depending upon the nutrient availability of the cell. We hypothesize that chronic caloric and lipid excess will lead to increased phosphorylation and cytoplasmic localization of lipin 1. We also hypothesize that abnormalities in the regulation of cardiac lipin activity promote glycerolipid synthesis and inhibit its pro-catabolic actions, contributing to the lipotoxic cardiomyopathy that develops in states of chronic caloric excess. There are three primary goals of this application. 1. To determine the effects of dietary nutrient manipulation on cardiac myocyte lipin 1 expression, activity, and sub-cellular localization. 2. To determine whether genetic alterations in nuclear and cytoplasmic lipin 1 activity will modulate lipotoxic cardiomyopathy and impact cardiac lipid metabolism, signaling, and function. 3. To evaluate the effects of altered lipin 1 activity on the response to ischemia-reperfusion injury, which is impaired in diabetic heart. These goals will be achieved by using a variety of transgenic mouse models with altered cardiac lipin 1 activity. The effects of modulating cardiac lipin 1 activity wil be assessed by using sophisticated functional phenotyping, transcriptomics, and lipidomics. The use of these -omic approaches is anticipated to identify a cardiac signature for identifying biomarkers linked to development or protection from dysfunction in obese hearts. The overarching goal will then be to use this information to benefit human subjects with diabetic heart disease.