The Lipid Protein Family and Triglyceride Metabolism

项目2的目的是确定脂蛋白家族在甘油三酯代谢中的作用。 我们以前确定了脂蛋白-1的突变是脂肪肝营养不良突变体脂肪营养不良的原因 小鼠品系，并确定脂蛋白-1是脂肪组织发育、肥胖和 小鼠和人类的胰岛素敏感性最近，脂蛋白-1的两种不同的分子功能已经被发现。 表征了首先，lipin-1是一种磷脂酸磷酸酶-1（PAP 1），催化脂代谢的关键步骤。 甘油三酸酯生物合成，并占脂肪组织和骨骼肌中的所有PAP 1活性。第二、 lipin-1是过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR-alpha）和PPAR-gamma的转录共激活因子 在肝细胞和脂肪细胞中。我们还确定了另外两个lipin家族成员， 确定它们具有PAP 1活性，并在肝脏（脂蛋白-2）或骨骼（脂蛋白-3）中表现出显著表达。 我们推测，这三种脂蛋白中的每一种在甘油三酯中具有独特的组织特异性作用。 它们通过作为PAP 1酶和转录辅激活因子的作用来代谢。具体目标是： (1)确定小鼠lipin-1和人lipin-2点突变损害PAP 1的机制， 和/或辅激活因子的作用是引起脂肪代谢障碍和炎症性疾病，马吉德综合征， 分别(2)确定脂肪细胞中lipin-1辅激活因子与PAP 1功能的需求 分化、生理学和代谢，使用Lipin-1活性的遗传和化学操作。我们 将产生表达“仅辅激活因子”脂蛋白-1蛋白的培养细胞和小鼠， 在脂肪组织、肝脏、肌肉、神经和生殖系统中， 功能我们还将描述一种新的成脂化合物的机制， 项目3增强PAP 1活性，并确定其他前脂肪形成化合物对lipin-1的影响 辅激活因子和PAP 1活性。(3)建立lipin-2和lipin-3的生理作用。我们将产生 敲除小鼠模型并表征脂蛋白-2在肝脏脂质代谢和炎症中的作用， 以及脂蛋白-3在骨脂质代谢和调节全身性骨代谢的骨激素产生中的作用。 葡萄糖稳态脂蛋白功能的阐明可能会导致新的方法来调节 肥胖症、胰岛素敏感性和导致肥胖症、高脂血症和糖尿病的炎症。

The objective of Project 2 is to define the role of the lipin family of proteins in triglyceride metabolism. We previously identified mutations in lipin-1 as the cause of lipodystrophy in the fatty liver dystrophy mutant mouse strain, and established that lipin-1 is a determinant of adipose tissue development, obesity, and insulin sensitivity in mice and humans. Very recently, two distinct molecular functions for lipin-1 have been characterized. First, lipin-1 is a phosphatidate phosphatase-1 (PAP1) enzyme, catalyzing a key step in triglyceride biosynthesis, and accounting for all PAP1 activity in adipose tissue and skeletal muscle. Second, lipin-1 is a transcriptional coactivator of PPAR (peroxisome proliferator-activated receptor)-alpha and PPARgamma in hepatocytes and adipocytes. We have also identified two additional lipin family members and determined that they have PAP1 activity and exhibit prominent expression in liver (lipin-2) or bone (lipin-3). We hypothesize that each of the three lipin proteins has unique, tissue-specific roles in triglyceride metabolism through their actions as PAP1 enzymes and transcriptional coactivators. The Specific Aims are: (1) To determine the mechanisms by which point mutations in mouse lipin-1 and human lipin-2 impair PAP1 and/or coactivator function to cause lipodystrophy and the inflammatory disorder, Majeed syndrome, respectively. (2) To determine the requirement for lipin-1 coactivator versus PAP1 function in adipocyte differentiation, physiology, and metabolism using genetic and chemical manipulation of lipin-1 activity. We will generate cultured cells and mice that express "coactivator only" lipin-1 protein and determine ability of the mutant to complement lipin-1 deficiency in adipose tissue, liver, muscle, nerve, and reproductive function. We will also characterize the mechanism by which a novel adipogenic compound identified in Project 3 enhances PAP1 activity, and determine effects of other proadipogenic compounds on lipin-1 coactivator and PAP1 activity. (3) To establish the physiological roles of lipin-2 and lipin-3. We will generate knockout mouse models and characterize the role of lipin-2 in hepatic lipid metabolism and inflammation, and the role of lipin-3 in bone lipid metabolism and production of bone hormones that modulate systemic glucose homeostasis. The elucidation of lipin protein functions may lead to novel approaches for modulating adiposity, insulin sensitivity and inflammation contributing to obesity, hyperlipidemia, and diabetes.