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因子。脂素1通过其双功能分子活动将线粒体代谢稳态与甘油脂代谢联系起来。我们已经证明，脂素1在细胞核中通过与dna结合的转录因子和辅激活因子相互作用来调节编码线粒体酶的基因的表达。然而，脂素1可以在细胞内快速转运，并在内质网（ER）膜上作为脂质磷酸酶，使磷脂酸（PA）去磷酸化，形成二酰基甘油（DAG）；甘油脂代谢和甘油三酯合成的关键步骤。有证据表明，脂素1的活性受到rapamycin复合物1 （mTORC1）分子靶点丝氨酸/苏氨酸磷酸化以及细胞内脂肪酸和PA浓度的高度影响，它们共同调节脂素1的亚细胞定位。这允许脂素1调节合成代谢和分解代谢途径取决于细胞的营养可用性。我们假设，慢性热量和脂质过剩将导致增加磷酸化和脂质1的细胞质定位。我们还假设心脏脂质活性调节的异常促进甘油脂合成并抑制其促分解代谢作用，从而导致慢性热量过剩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. 确定膳食营养调控对心肌细胞脂素1表达、活性和亚细胞定位的影响。2. 确定核和细胞质脂质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. 目的探讨脂素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改变心脏脂素1活性的各种转基因小鼠模型来实现。调节心脏脂素1活性的作用将通过使用复杂的功能表型、转录组学和脂质组学进行评估。这些-组学方法有望用于识别与肥胖心脏发育或保护功能障碍相关的生物标志物的心脏特征。总体目标将是利用这些信息使糖尿病心脏病患者受益。

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.