Novel roles for Maf1 as a central regulator of lipid homeostasis

描述（由申请人提供）：哺乳动物Maf 1最初被鉴定为RNA聚合酶III转录基因的转录抑制因子，研究集中在检查其在抑制RNA聚合酶III依赖性靶标中的作用。我们的工作令人惊讶地发现Maf 1还能够直接抑制RNA pol II基因，尽管人们对这些特定基因靶点知之甚少。此外，我们还发现Maf 1在维持C.线虫、小鼠和人类细胞培养物。这些结果是第一个定义Maf 1在多细胞生物体中的特定生理作用。Maf 1部分通过抑制脂质生物合成基因的表达来负调节脂质积累。我们假设Maf 1是维持机体脂质稳态的中心节点。我们提出的研究将从三个方面来确定Maf 1在脂质代谢中的机制作用。我们将首先利用我们的蠕虫模型系统，并使用这些发现来指导小鼠实验。这种双系统方法将允许我们：（1）通过鉴定哪些组织对Maf 1功能重要并鉴定Maf 1表达的细胞自主和/或非自主效应来确定Maf 1表达在维持脂质稳态中的生理影响;（2）通过鉴定Maf 1的进化上保守的脂质途径基因靶标来测试Maf 1如何调节细胞内脂质稳态，从生物化学上评估这些基因对Maf 1脂质表型的影响，并检查Maf 1克服饮食引起的细胞内脂质增加的能力;（3）确定Maf 1如何影响细胞内脂质的增加。 Maf 1活性被调节以维持细胞内脂质稳态。这些研究的结果将揭示Maf 1如何整合到体内脂质代谢的生物控制中，并确定控制Maf 1在脂质稳态中功能的机制。这些研究将定义脂质代谢中的重要新参与者，并将对我们未来了解Maf 1在糖尿病，肥胖和癌症等人类疾病中发挥的作用至关重要，这些疾病显示出突出的脂质失调表型。

DESCRIPTION (provided by applicant): Mammalian Maf1 was initially identified as a transcriptional repressor of RNA polymerase III-transcribed genes and studies have focused on examining its role in repressing RNA pol III-dependent targets. Our work surprisingly revealed that Maf1 is also able to directly repress RNA pol II genes, although little is known regarding these specific gene targets. Furthermore, we have importantly identified a novel and conserved function for Maf1 in the maintenance of intracellular lipid pools in C. elegans, mice, and human cell culture. These results are the first to define a specific physiologic role for Maf1 in a multicellular organism. Maf1 negatively regulates lipid accumulation, in part, by repressing the expression of lipid biosynthesis genes. We hypothesize that Maf1 is a central node in the maintenance of organismal lipid homeostasis. Our proposed studies will define the mechanistic role of Maf1 in lipid metabolism in three aims. We will initially exploit our worm model system and use these findings to direct experiments in the mouse. This dual system approach will allow us to: (1) Define the physiological impact of Maf1 expression in maintaining lipid homeostasis by identifying which tissues are important for Maf1 function and identify cell autonomous and/or non-autonomous effects of Maf1 expression; (2) test how Maf1 regulates intracellular lipid homeostasis by the identification of evolutionarily conserved lipid pathway gene targets of Maf1, assess biochemically the impact of these genes on Maf1 lipid phenotypes, and examine the ability of Maf1 to override increases in intracellular lipids resulting from diet; (3) Identify how Maf1 activity is regulated to maintain intracellular lipid homeostasis. The results of these studie will reveal how Maf1 integrates into organismal control of lipid metabolism in vivo and identify the mechanisms that control this Maf1 function in lipid homeostasis. These studies will define an important new player in lipid metabolism and will be critical towards our future understanding of the role that Maf1 plays in human diseases such as diabetes, obesity, and cancer, which display prominent lipid dysregulation phenotypes.