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.
Obesity has become markedly more prevalent over the past two decades in most developed countries. It is estimated that about two-thirds of the U.S. population is overweight or obese with 300 million obese adults worldwide. Alarmingly, over two- thirds of U.S. children are also overweight or obese. The incidence of type-II diabetes during this time period has also significantly increased. This is thought to be a direct result of he obesity epidemic. Obesity is a key factor in the development of diabetes, cardiovascular diseases and cancer. The worldwide obesity epidemic continues to increase, which demands an urgent need to delineate the mechanisms capable of curbing the development of obesity and the progression of metabolic syndromes and potentially fatal health conditions that accompany increased adiposity. This is essential for the design of new therapeutic approaches to intervene in this process. However, the molecular events that connect obesity, lipid deregulation and human diseases, such as metabolic syndromes and cancer, are still unclear. Fundamental questions are: what are the molecular players and events that regulate total adiposity in an organism? What are the key targets of the pathways that control metabolism and the maintenance of lipid homeostasis? The studies we propose will address these key questions and provide new insight into the molecular events that link lipid metabolism and disease.
