Novel roles for Maf1 as a central regulator of lipid homeostasis

描述(申请人提供)：哺乳动物Maf1最初被鉴定为RNA聚合酶III转录基因的转录抑制因子，研究重点是研究它在抑制RNA PolIII依赖靶标中的作用。我们的工作令人惊讶地发现，Maf1也能够直接抑制RNA polII基因，尽管对这些特定的基因靶点知之甚少。此外，我们重要地确定了Maf1在线虫、小鼠和人类细胞培养中维持细胞内脂质池中的一种新的和保守的功能。这些结果首次确定了Maf1在多细胞生物体中的特定生理作用。Maf1通过抑制脂类生物合成基因的表达，对脂类的积累起负向调节作用。我们假设Maf1是维持生物体内脂平衡的中心节点。我们提出的研究将从三个方面定义Maf1在脂质代谢中的机制作用。我们将首先开发我们的蠕虫模型系统，并使用这些发现来指导在小鼠身上的实验。这种双重系统方法将使我们能够：(1)通过确定哪些组织对Maf1功能重要，并确定Maf1表达的细胞自主和/或非自主影响，来确定Maf1表达在维持脂质稳态方面的生理影响；(2)通过鉴定进化上保守的Maf1的脂质途径基因靶标，测试Maf1如何调节细胞内的脂质稳态，从生化角度评估这些基因对Maf1脂类表型的影响，并检查Maf1抑制饮食导致的细胞内脂质增加的能力；(3)确定Maf1如何调节细胞内的脂质平衡 Maf1活性受到调节，以维持细胞内脂类平衡。这些研究的结果将揭示Maf1如何整合到体内脂肪代谢的生物控制中，并确定在脂质平衡中控制Maf1功能的机制。这些研究将确定脂代谢中一个重要的新参与者，并将对我们未来了解Maf1在糖尿病、肥胖症和癌症等人类疾病中所起的作用至关重要，这些疾病表现出突出的脂质调节失调表型。

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.