Fine-tuning lipid metabolism by LSD1

描述（由申请人提供）：甾醇调节元件结合蛋白1c （SREBP-1c）是脂肪生成基因的关键转录激活因子。鉴于脂质稳态失调与主要人类疾病（如2型糖尿病）之间的密切联系，了解srebp -1c依赖转录的调控不仅将为脂肪肝和血脂异常的分子控制提供新的见解，而且还将为对抗这些疾病提供潜在的治疗机会。目前，调控核SREBP-1c激活和失活的途径尚不明确。最近的研究表明，nad依赖性蛋白去乙酰化酶SIRT1是SREBP-1c的负调节因子，这表明SIRT1表达或酶活性的调节可以影响脂质代谢。初步数据表明，赖氨酸特异性去甲基酶-1 （LSD1）是SIRT1的关键调节因子，并控制脂肪生成基因的表达。令人惊讶的是，一种已知在脂质代谢中具有功能的常用小分子，显示出抑制LSD1活性的新功能。因此，本研究的中心假设是LSD1通过抑制SIRT1激活srebp -1c介导的转录和脂肪生成。我们提出以下三个具体目标来验证这一假设：1)在体内确定LSD1在调节原代肝细胞和小鼠肝脏脂质代谢中的作用；2)阐明LSD1调控SIRT1与新生脂肪生成相关的分子机制；3)靶LSD1调节SREBP-1c活性/水平和新生脂肪生成。我们提出了一系列体外和体内实验来确定LSD1/SREBP通路在脂质代谢中的调节机制和意义。本提案的长期目标是确定LSD1在代谢紊乱条件下对SREBP-1c功能的营养调节和控制脂质稳态中的作用。这一应用不仅与公共卫生具有重要意义，而且具有高度创新性，将对脂质代谢领域产生重大影响。总之，拟议的研究将探讨LSD1和SREBP-1c在调节脂质稳态中的分子联系及其在脂质稳态失调疾病（如肥胖、2型糖尿病和心血管疾病）发展中的潜在作用。

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. PUBLIC HEALTH RELEVANCE: Aberrant hepatic lipogenesis causes fatty liver and dyslipidemia, which are closely linked to human diseases, including type 2 diabetes, obesity, and cardiovascular complications. The proposed research will study the mechanisms and functions of the histone demethylase LSD1 in regulating de novo lipogenesis. Thus, the outcomes of this project have the potential to guide the development of novel therapeutic approaches, and will have a significant impact on the treatment of human diseases with dysregulated lipid homeostasis.