Fine-tuning lipid metabolism by LSD1

描述（由申请方提供）：固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2型糖尿病等主要人类疾病之间的密切关系，了解SREBP-1c依赖性转录的调节不仅将为脂肪肝和血脂异常的分子控制提供新的见解，而且还为对抗这些疾病提供潜在的治疗机会。目前，调节核SREBP-1c激活和失活的途径还不清楚。最近的研究表明，NAD依赖性蛋白脱乙酰酶SIRT 1作为SREBP-1c的负调节因子，表明SIRT 1表达或酶活性的调节可以影响脂质代谢。初步数据表明，赖氨酸特异性脱甲基酶-1（LSD 1）是SIRT 1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，一种常用的小分子，其对脂质代谢具有已知的功能，显示出抑制LSD 1活性的新功能。因此，该提议的中心假设是LSD 1通过抑制SIRT 1激活SREBP-1c介导的转录和脂肪生成。提出了以下三个具体目的来检验这一假设：1）确定LSD 1在体内调节原代肝细胞和小鼠肝脏中脂质代谢的作用; 2）阐明LSD 1调节SIRT 1与新生脂肪生成相关的分子机制; 3）靶向LSD 1调节SREBP-1c活性/水平和新生脂肪生成。本研究拟通过一系列的体内外实验来探讨LSD 1/SREBP通路在脂质代谢中的调控机制和意义。该提案的长期目标是确定LSD 1在营养调节SREBP-1c功能和控制代谢紊乱条件下脂质稳态中的作用。这一应用不仅与公众健康密切相关，而且具有高度的创新性，将对脂质代谢领域产生重大影响。总之，拟议的研究将解决LSD 1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（如肥胖症，2型糖尿病和心血管疾病）发展中的潜在作用。 公共卫生相关性：异常的肝脏脂肪生成导致脂肪肝和血脂异常，这与人类疾病密切相关，包括2型糖尿病、肥胖和心血管并发症。该研究将研究组蛋白去甲基化酶LSD 1在调节从头脂肪生成中的机制和功能。因此，该项目的结果有可能指导新的治疗方法的开发，并将对脂质稳态失调的人类疾病的治疗产生重大影响。

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.