LIPIN 1 AND CARDIAC METABOLISM IN THE CONTEXT OF LIPID OVERLOAD

脂质超载背景下的 LIPIN 1 和心脏代谢

• 批准号: 9304271
• 负责人: Brian N Finck
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304271
• 关键词: Alanine; Alleles; Attenuated; Automobile Driving; Biological Markers; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Nucleus; Cell Respiration; Cells; Chronic; Complex; Cytoplasm; DNA Binding; Development; Diabetes Mellitus; Diet; Diglycerides; Disease; Endoplasmic Reticulum; Energy Metabolism; Enzymes; Event; Exhibits; FRAP1 gene; Fatty Acids; Fatty acid glycerol esters; Fructose; Functional disorder; Gene Expression; Genetic Transcription; Glycerolipid Metabolism Pathway; Goals; Heart; Heart Diseases; Heart failure; High Fat Diet; Homeostasis; Impairment; Lead; Link; Lipids; Mediating; Membrane; Metabolic; Metabolism; Mitochondria; Molecular; Molecular Target; Mus; Mutate; Mutation; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Nuclear; Nutrient; Obesity; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Phosphatidic Acid; Phosphoric Monoester Hydrolases; Phosphorylation; Production; Proteins; Regulation; Reperfusion Injury; Role; Serine; Serine/Threonine Phosphorylation; Signal Transduction; Sirolimus; Testing; Tetracyclines; Transcription Coactivator; Transgenic Mice; Triglycerides; Work; cardiogenesis; design; diabetic; genetic manipulation; heart metabolism; human subject; insight; lipid metabolism; lipine; mouse model; new therapeutic target; non-diabetic; novel therapeutics; overexpression; prevent; promoter; public health relevance; response; trafficking; transcription factor; transcriptomics

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.

描述（由申请人提供）：脂质 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，脂质 1 在细胞核中发挥作用，通过与 DNA 结合的转录因子和共激活剂相互作用来调节编码线粒体酶的基因的表达。然而，脂质1可以在细胞内快速移位，并且在内质网（ER）膜上充当脂质磷酸酶，使磷脂酸（PA）去磷酸化形成二酰甘油（DAG）；甘油脂代谢和甘油三酯合成的关键步骤。有证据表明，脂质 1 的活性受到雷帕霉素复合物 1 (mTORC1) 分子靶标的丝氨酸/苏氨酸磷酸化以及细胞中脂肪酸和 PA 浓度的高度影响，它们共同调节脂质 1 的亚细胞定位这使得脂质 1 能够根据细胞的营养可用性调节合成代谢和分解代谢途径。我们假设慢性热量和脂质过量将导致脂质 1 的磷酸化和细胞质定位增加。我们还假设心脏脂质活性调节异常会促进甘油脂合成并抑制其促分解代谢作用，从而导致脂毒性心肌病的发生处于长期热量过剩的状态。该应用程序有三个主要目标。 1. 确定饮食营养控制对心肌细胞脂质 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. 评估改变的脂质1活性对缺血再灌注损伤反应的影响，缺血再灌注损伤在糖尿病心脏中受损。这些目标将通过使用多种心脏脂质 1 活性改变的转基因小鼠模型来实现。将通过使用复杂的功能表型分析、转录组学和脂质组学来评估调节心脏脂质 1 活性的效果。预计使用这些组学方法可以识别心脏特征，从而识别与肥胖心脏发育或防止功能障碍相关的生物标志物。总体目标是利用这些信息造福患有糖尿病心脏病的人类受试者。

项目成果

Regulation of Signaling and Metabolism by Lipin-mediated Phosphatidic Acid Phosphohydrolase Activity.

• DOI: 10.3390/biom10101386
• 发表时间: 2020-09-29
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Lutkewitte AJ;Finck BN
• 通讯作者: Finck BN

Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation.

糖皮质激素间歇性通过肌细胞自主 PGC1α-Lipin1 反式激活来协调与衰老相关的肌肉减少症的能量和质量的挽救。

• DOI: 10.1101/2023.10.16.562573
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Prabakaran,AshokDaniel;McFarland,Kevin;Miz,Karen;Durumutla,HimaBindu;Piczer,Kevin;ElAbdellaouiSoussi,Fadoua;Latimer,Hannah;Werbrich,Cole;Blair,NScott;Millay,DouglasP;Prideaux,Brendan;Finck,BrianN;Quattrocelli,Mattia
• 通讯作者: Quattrocelli,Mattia