LIPIN 1 AND CARDIAC METABOLISM IN THE CONTEXT OF LIPID OVERLOAD

描述(申请人提供)：脂蛋白1是一种重要的中间代谢调节剂。脂蛋白1通过其双功能分子活性将线粒体代谢动态平衡与甘油脂代谢联系起来。我们已经证明，Lipin 1通过与DNA结合的转录因子和共激活因子相互作用，在细胞核内调节线粒体酶编码基因的表达。然而，脂类1可以在细胞内快速转运，也可以作为内质网(ER)膜上的一种脂磷酸酶，使磷脂酸(PA)脱磷形成甘油二酯(DAG)，这是甘油代谢和甘油三酯合成的关键步骤。有证据表明，Lipin 1的活性受雷帕霉素复合体1分子靶点(MTORC1)的丝氨酸/苏氨酸磷酸化以及细胞内脂肪酸和PA浓度的共同影响，共同调节Lipin 1的亚细胞定位。这使得Lipin 1可以根据细胞的营养供应来调节合成代谢和分解代谢途径。我们假设慢性热量和脂肪过量将导致Lipin 1的磷酸化和细胞质定位增加。我们还假设心脏脂肪活性的调节异常促进甘油脂的合成并抑制其促分解代谢作用，从而导致在慢性热量过多状态下发展的脂毒性心肌病。这个应用程序有三个主要目标。1.探讨膳食营养调控对心肌细胞脂蛋白1表达、活性及亚细胞定位的影响。2.确定胞核和胞浆Lipin 1活性的遗传改变是否会调节脂中毒性心肌病，并影响心脏的脂代谢、信号转导和功能。3.观察脂类1活性改变对糖尿病心脏缺血再灌注损伤反应的影响。这些目标将通过使用各种心脏脂蛋白1活性改变的转基因小鼠模型来实现。调节心脏脂蛋白1活性的效果将通过复杂的功能表型、转录组学和脂质组学进行评估。这些组学方法的使用有望识别心脏信号，以识别与肥胖心脏发育或保护功能障碍相关的生物标记物。然后，首要目标将是利用这些信息造福于患有糖尿病心脏病的受试者。

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.