Lipid Storage and the Metablic Syndrome

项目总结(见说明)： 脂肪储存对代谢动态平衡至关重要，并影响代谢综合征的组成部分， 包括内脏肥胖、胰岛素抵抗和血脂异常。其目的是进一步阐明 Lipin-1在脂肪组织和肌肉中脂质合成、储存和脂质信号传递中的作用，并鉴定 影响脂肪组织质量和功能的新基因。我们之前的研究表明，Lipin-1 是脂肪组织发育、胰岛素敏感性和能量代谢的决定因素。利平-I是一名 磷脂酸盐磷酸酶(PAP)，将磷脂酸盐转化为二酰甘醇，占所有 脂肪组织和肌肉中的PAP活性。此外，它还是一种转录共激活因子，影响 脂代谢基因在肝脏中的表达。具体目标是：(1)确定Lipin-1是如何调制的 磷脂酸盐水平调节脂肪生成并影响骨骼肌中的胰岛素敏感性。在 没有脂类-1，磷脂酸盐在组织中积累，这可能会激活信号转导通路 和/或改变线粒体或内质网的膜特性。我们假设磷脂酸盐水平 脂蛋白-1对PPAR-γ表达和脂肪细胞分化的影响及胰岛素 肌肉的敏感性。我们将研究脂类-1和磷脂酸盐水平的失调是如何导致 改变脂肪组织、肌肉和肝脏的新陈代谢。(2)评价脂蛋白-1在他汀类药物诱导中的作用 肌肉毒性。人类LPINI无义突变会导致儿童肌病，而错义突变会 与他汀类药物引起的肌病有关。我们将检验这样一种假设，即脂类-1活性受损和 他汀类药物的作用相互作用，损害线粒体的功能。我们将从功能上表征突变的Lipin-1 蛋白质，评估脂-1缺乏对他汀类药物诱导的小鼠肌肉毒性的影响，并评估一种 他汀类药物诱导的肌病患者LPINI突变的队列研究。(3)识别和描述 新的肥胖基因的分子功能。我们假设改变肥胖症的基因变异 活体将揭示脂肪组织功能的新基因。我们将研究7个候选基因的功能 使用体外和体内方法，通过小鼠的网络建模确定在脂肪细胞功能中的作用。

PROJECT SUMMARY (See instructions): Lipid storage is critical for metabolic homeostasis, and influences components ofthe metabolic syndrome, including visceral obesity, insulin resistance, and dyslipidemia. The objectives are to further elucidate the function of lipin-1 in lipid synthesis, storage, and lipid signaling in adipose tissue and muscle, and to identify novel genes that influence adipose tissue mass and function. Our previous studies demonstrated that lipin-1 is a determinant of adipose tissue development, insulin sensitivity, and energy metabolism. Lipin-I is a phosphatidate phosphatase (PAP) enzyme that converts phosphatidate to diacylglyerol, and accounts for all PAP activity in adipose tissue and muscle. In addition, it is a transcriptional coactivator that influences expression of lipid metabolism genes in liver. The specific aims are: (1) Determine how lipin-1 modulation of phosphatidate levels regulates adipogenesis and influences insulin sensitivity in skeletal muscle. In the absence of lipin-1, phosphatidate accumulates in tissues, which may activate signal transduction pathways and/or alter mitochondrial or ER membrane properties. We hypothesize that phosphatidate levels determined by lipin-1 influence expression of PPARgamma and adipocyte differentiation, and insulin sensitivity in muscle. We will investigate how dysregulation of lipin-1 and phosphatidate levels contribute to altered metabolism in adipose tissue, muscle, and liver. (2) Evaluate the role of lipin-1 in statin-induced myotoxicity. Human LPINI nonsense mutations cause childhood myopathy, and missense mutations have been associated with statin-induced myopathy. We will test the hypothesis that impaired lipin-1 activity and statin action interact to impair mitochondrial function. We will functionally characterize mutant lipin-1 proteins, evaluate effects of lipin-1 deficiency on statin-induced myotoxicity in the mouse, and evaluate a cohort of subjects with statin-induced myopathy for LPINI mutations. (3) Identify and characterize the molecular function of novel adiposity genes. We hypothesize that genetic variations that alter adiposity in vivo will reveal novel genes in adipose tissue function. We will investigate the function of 7 candidate genes identified by network modeling in the mouse for roles in adipocyte function using in vitro and in vivo methods.