Fine-tuning lipid metabolism by LSD1

描述(申请人提供)：固醇调节元件结合蛋白-1c(SREBP-1c)是成脂基因的关键转录激活因子。鉴于脂质平衡失调与人类主要疾病(如2型糖尿病)之间的密切联系，了解SREBP-1c依赖的转录调控不仅将为脂肪肝和血脂异常的发生提供新的分子控制，而且将为抗击这些疾病提供潜在的治疗机会。目前，调控核SREBP-1c激活和失活的途径还不是很清楚。最近的研究表明，依赖于NAD的蛋白脱乙酰酶SIRT1是SREBP-1c的负调控因子，提示SIRT1的表达或酶活性的调节可以影响脂质代谢。初步研究表明，赖氨酸特异的脱甲基酶-1(LSD1)是SIRT1的重要调节因子，控制着成脂基因的表达。令人惊讶的是，一种经常使用的小分子，它具有已知的脂代谢功能，显示出一种新的抑制LSD1活性的功能。因此，这一建议的中心假设是LSD1通过抑制SIRT1激活SREBP-1c介导的转录和脂肪生成。为了验证这一假说，提出了以下三个具体目标：1)确定LSD1在调节原代肝细胞和小鼠肝脏脂代谢中的作用；2)阐明LSD1调控SIRT1与新生脂肪生成相关的分子机制；以及3)靶向LSD1调节SREBP-1c活性/水平和新生脂肪生成。一系列的体外和体内实验被提出，以确定LSD1/SREBP通路在脂代谢中的调节机制和意义。这项建议的长期目标是确定LSD1在营养调节SREBP-1c功能和控制代谢紊乱条件下的脂平衡中的作用。这一应用不仅与公众健康密切相关，而且具有很高的创新性，将对脂类代谢领域产生重大影响。总之，拟议的研究将讨论LSD1和SREBP-1c在调节脂质平衡方面的分子联系，以及它在脂质平衡失调的疾病发展中的潜在作用，如肥胖症、2型糖尿病和心血管疾病。

DESCRIPTION (provided by applicant): Sterol regulatory element-binding protein-1c (SREBP-1c) is a key transcription activator of lipogenic genes. Given the close association between dysregulation of lipid homeostasis and major human diseases, such as type 2 diabetes, understanding the regulation of SREBP-1c-dependent transcription will provide not only novel insights into the molecular control of the development of fatty liver and dyslipidemia but also potential therapeutic opportunities for fighting these diseases. At present, the pathways that regulate nuclear SREBP-1c activation and inactivation are poorly defined. Recent studies have demonstrated the NAD-dependent protein deacetylase SIRT1 as a negative regulator of SREBP-1c, suggesting that modulation of SIRT1 expression or enzymatic activity can affect lipid metabolism. The preliminary data have shown that the lysine-specific demethylase-1 (LSD1) is a critical regulator of SIRT1 and controls the expression of lipogenic genes. Surprisingly, a frequently used small molecule, which has known functions on lipid metabolism, displayed a novel function of inhibiting LSD1 activity. Thus, the central hypothesis of this proposal is that LSD1 activates SREBP-1c-mediated transcription and lipogenesis by repressing SIRT1. The following three Specific Aims are proposed to test this hypothesis: 1) Determine the role of LSD1 in regulating lipid metabolism in primary hepatocytes and mouse livers in vivo; 2) Elucidate the molecular mechanisms of LSD1 regulation on SIRT1 in relevance to de novo lipogenesis; and 3) Target LSD1 for modulating SREBP-1c activity/level and de novo lipogenesis. A series of in vitro and in vivo experiments are proposed to determine the regulatory mechanisms and significance of the LSD1/SREBP pathway in lipid metabolism. The long-term objectives of this proposal are to determine the role of LSD1 in nutritional regulation of SREBP-1c function and in controlling lipid homeostasis in conditions of metabolic disorder. This application is not only significantly relevant to public health, but also highly innovative and will have major impacts to the field of lipid metabolism. Together, the proposed studies will address the molecular link between LSD1 and SREBP-1c in regulating lipid homeostasis and its potential role in the development of diseases with dysregulated lipid homeostasis, such as obesity, type 2 diabetes and cardiovascular diseases.