Lmf1 in Lapse expression and lipid Metabolism

项目总结(见说明)： 脂蛋白脂酶(LPL)、肝脂酶(HL)和内皮脂酶(EL)长期以来被认为是 甘油三酯(TG)和胆固醇代谢中的重要生化角色。最近，这些脂肪酶 成为血浆甘油三酯和高密度脂蛋白胆固醇水平的一些最强的遗传决定因素 普通人口。LPL调节失调导致与代谢相关的病理变化 综合征，包括血脂异常、胰岛素抵抗、心肌病和β细胞功能障碍。虽然 LPL活性的大部分生理调节发生在翻译后水平，即潜在的 分子机制一直知之甚少。在当前的PPG周期中，我们发现了一个新的因素， 脂肪酶成熟因子1(LMF1)，促进脂肪酶的折叠、组装和分泌。而当 LMF1显然是脂肪酶表达所必需的，联合脂肪酶缺乏的代谢后果 成体生物体和Lmf1的分子功能仍未被探索。将追求三个目标： 解决这些问题。在目标1中，我们将生成并表征条件性和组织特异性敲除 用小鼠模型研究Lmf1在全身和脂肪代谢中的作用。扩大这些研究的范围 对于目标2中的人类，我们将通过以下方式确定与空腹或餐后血浆甘油三酯水平相关的变量 对不同人群的LMFI进行重新排序。此外，影响Lmf1的自然发生的变异 在近交系小鼠品系中的表达将被用来研究该蛋白在脂肪代谢和 相关特征。在目标3中，我们将通过鉴定蛋白质组来研究Lmf1功能的分子方面。 使用遗传和生化方法研究Lmf1相互作用因子。

PROJECT SUMMARY (See Instructions): Lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) have long been appreciated as important biochemical players in triglyceride (TG) and cholesterol metabolism. More recently, these lipases emerged as some ofthe strongest genetic determinants of plasma TG and HDL cholesterol levels in the general population. Dysregulation of LPL results in pathological changes associated with the Metabolic Syndrome, including dyslipidemia, insulin resistance, cardiomyopathy and beta-cell dysfunction. Although much ofthe physiological regulation of LPL activity occurs at the post-translational level, the underlying molecular mechanisms have been poorly understood. In the current PPG cycle we identified a novel factor, Lipase Maturation Factor 1 (Lmf1), which facilitates the folding, assembly and secretion of lipases. While Lmf1 is clearly required for lipase expression, the metabolic consequences of combined lipase deficiency in the adult organism, and the molecular function of Lmf1 remain unexplored. Three aims will be pursued to address these issues. In Aim 1, we will generate and characterize conditional and tissue-specific knock-out mouse models to investigate the role of Lmf1 in systemic and adipose metabolism. To extend these studies to humans in Aim 2, we will identify variants associated with fasting or postprandial plasma TG levels by resequencing LMFI in various populations. Furthermore, naturally occurring variants affecting Lmf1 expression in inbred mouse strains will be exploited to address the role of this protein in lipid metabolism and related traits. In Aim 3, we will investigate the molecular aspects of Lmf1 function by identifying the proteome of Lmf1-interacting factors using genetic and biochemical approaches.