Fine-tuning lipid metabolism by LSD1

通过 LSD1 微调脂质代谢

• 批准号: 8719984
• 负责人: Fajun James Yang
• 金额: $ 36.32万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719984
• 关键词: ADD-1 protein; Address; Affect; Applied Genetics; Binding Proteins; Biochemical; Cardiovascular Diseases; Cardiovascular system; Data; Deacetylase; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dyslipidemias; Enzymes; Fatty Acids; Fatty Liver; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health; Hepatic; Hepatocyte; Histones; Homeostasis; In Vitro; Knowledge; Link; Lipids; Liver; Liver diseases; Lysine; Mediating; Metabolic Diseases; Modeling; Molecular; Molecular Genetics; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutritional; Obese Mice; Obesity; Outcome; Pargyline; Pathway interactions; Physiological; Play; Proteins; Public Health; Publications; Rattus; Regulation; Reporting; Research; Response Elements; Resveratrol; Role; Series; Sterols; Testing; Therapeutic; Transcription Coactivator; Tranylcypromine; Work; base; fighting; functional outcomes; human disease; in vivo; inhibitor/antagonist; innovation; insight; lipid biosynthesis; lipid metabolism; mouse model; non-alcoholic fatty liver; novel; novel strategies; novel therapeutic intervention; prevent; promoter; research study; small molecule

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.

描述（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剂。鉴于脂质稳态失调与主要人类疾病（例如 2 型糖尿病）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发展的分子控制提供新的见解，而且还将为研究提供新的见解。对抗这些疾病的潜在治疗机会。目前，调节核 SREBP-1c 激活和失活的途径尚不清楚。最近的研究表明，NAD 依赖性蛋白脱乙酰酶 SIRT1 作为 SREBP-1c 的负调节因子，表明调节 SIRT1 表达或酶活性可以影响脂质代谢。初步数据表明，赖氨酸特异性去甲基化酶 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，一种常用的小分子，其已知的脂质代谢功能，显示出抑制LSD1活性的新功能。因此，该提议的中心假设是LSD1通过抑制SIRT1来激活SREBP-1c介导的转录和脂肪生成。提出以下三个具体目标来检验这一假设：1）确定LSD1在体内调节原代肝细胞和小鼠肝脏脂质代谢的作用； 2) 阐明LSD1对SIRT1的调控与脂肪从头生成相关的分子机制； 3) 用于调节 SREBP-1c 活性/水平和从头脂肪生成的靶标 LSD1。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。该提案的长期目标是确定 LSD1 在 SREBP-1c 功能的营养调节和代谢紊乱条件下控制脂质稳态中的作用。该应用不仅与公众健康密切相关，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 在调节脂质稳态方面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。