Lipocalin 2 as a regulator of phospholipid metabolism in adipose mitochondrial bioenergetics

脂质运载蛋白 2 作为脂肪线粒体生物能学中磷脂代谢的调节剂

• 批准号: 10376484
• 负责人: XIAOLI CHEN
• 金额: $ 36.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376484
• 关键词: Adipocytes; Adipose tissue; Aging; Anabolism; Architecture; Binding; Binding Proteins; Bioenergetics; Brown Fat; Cardiolipins; Cell Aging; Crista ampullaris; Data; Diabetes Mellitus; Electron Microscopy; Endoplasmic Reticulum; Energy Metabolism; Exhibits; Functional disorder; Glucose Intolerance; Grant; Health; Homeostasis; Impairment; In Vitro; Inflammasome; Inflammation; Insulin Resistance; Investigation; Knockout Mice; Knowledge; LCN2 gene; Lead; Link; Lipid Binding; Lipids; Mediating; Membrane; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Obesity; Pathology; Phenotype; Phosphatidic Acid; Phospholipid Metabolism; Phospholipids; Play; Process; Protein Import; Publishing; Regulation; Respiration; Role; Site; Thermogenesis; Transgenic Mice; age related; blood glucose regulation; diet-induced obesity; improved; in vivo; lipidomics; loss of function; mitochondrial dysfunction; mitochondrial membrane; mitochondrial metabolism; novel; overexpression; trafficking

Phospholipids, particularly cardiolipin (CL) and phosphatidic acid (PA) are known as critical regulators of mitochondrial membrane architecture and dynamics. Endoplasmic reticulum (ER) is the major site of phospholipid biosynthesis for mitochondria; ER-mitochondria contact sites or so-called Mitochondria-ER Associated Membranes (MAMs) serve as the platforms for phospholipid exchange between ER and mitochondria. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial architecture and function. As such, maintaining metabolic homeostasis of phospholipids at MAMs is essential for the normal architecture and functioning of mitochondria. However, we have little or no knowledge on how phospholipid biosynthesis and exchange at the MAMs is regulated in adipocytes and what factors are involved in these regulatory processes. We have been characterizing the metabolic role of lipocalin 2 (Lcn2) as a critical regulator of thermogenic adipocyte activation and mitochondrial respiration. Lcn2 KO mice exhibit impaired thermogenesis as well as exacerbated diet-induced obesity and insulin resistance. Notably, deletion of Lcn2 disrupts mitochondrial architecture, dysregulates mitochondrial dynamics, and impairs mitochondrial respiration in brown and beige adipocytes, whereas overexpression of Lcn2 in adipose tissue promotes thermogenesis, increases mitochondrial metabolism of brown adipose tissue, and activates beiging of white adipose tissue without thermogenic stimulation. Most intriguingly, we discovered that Lcn2 is localized at MAMs in adipocytes, and Lcn2 has ability to strongly and selectively bind phosphatidic acid (PA). We hypothesize that Lcn2 plays a key role as a novel PA binding protein in the regulation of PA transport through MAM providing the precursor for CL biosynthesis, thereby maintaining mitochondrial phospholipid homeostasis and health. We proposed three Aims to 1) characterize the role of Lcn2 in PA transport, 2) determine the role of Lcn2 in CL biosynthesis, and 3) determine the role of Lcn2 in MAM function and mitochondrial dynamics in thermogenic adipocytes. We believe that this project will open a novel avenue to understand the molecular mechanisms for the dysregulation of mitochondrial bioenergetics in thermogenic adipocytes in obesity and during aging.

磷脂，特别是心磷脂（CL）和磷脂酸（PA）被认为是线粒体膜结构和动力学的关键调节剂。内质网（ER）是线粒体磷脂生物合成的主要场所; ER-线粒体接触位点或所谓的线粒体-ER相关膜（MAMs）充当ER和线粒体之间磷脂交换的平台。MAM功能障碍干扰磷脂代谢，从而破坏线粒体结构和功能。因此，维持磷脂在MAMs的代谢稳态对于线粒体的正常结构和功能是必不可少的。然而，我们对脂肪细胞中MAMs处的磷脂生物合成和交换是如何调节的以及这些调节过程涉及哪些因素知之甚少或一无所知。我们一直在表征脂质运载蛋白2（Lcn 2）作为产热脂肪细胞活化和线粒体呼吸的关键调节剂的代谢作用。Lcn 2 KO小鼠表现出产热受损以及饮食诱导的肥胖和胰岛素抵抗加剧。值得注意的是，Lcn 2的缺失破坏棕色和米色脂肪细胞中的线粒体结构，使线粒体动力学失调，并损害线粒体呼吸，而Lcn 2在脂肪组织中的过表达促进产热，增加棕色脂肪组织的线粒体代谢，并在没有产热刺激的情况下激活白色脂肪组织的米色化。最有趣的是，我们发现Lcn 2定位于脂肪细胞中的MAMs，并且Lcn 2具有强烈和选择性结合磷脂酸（PA）的能力。我们假设Lcn 2作为一种新型PA结合蛋白，通过MAM提供CL生物合成的前体，在调节PA转运中发挥关键作用，从而维持线粒体磷脂稳态和健康。我们提出了三个目标：1）表征Lcn 2在PA转运中的作用，2）确定Lcn 2在CL生物合成中的作用，3）确定Lcn 2在产热脂肪细胞中MAM功能和线粒体动力学中的作用。我们相信，这个项目将打开一个新的途径，了解在肥胖和衰老过程中产热脂肪细胞线粒体生物能量失调的分子机制。