Fine-tuning lipid metabolism by LSD1

通过 LSD1 微调脂质代谢

• 批准号: 8216239
• 负责人: Fajun James Yang
• 金额: $ 36.14万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216239
• 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. 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.

描述（由申请人提供）：固醇调节元素结合蛋白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）之间的密切关联，了解SREBP-1C依赖性转录的调节不仅会提供对脂肪肝和血脂异常发展的分子控制的新见解。与这些疾病作斗争的潜在治疗机会。目前，调节核SREBP-1C激活和失活的途径的定义很差。最近的研究表明，NAD依赖性蛋白脱乙酰基酶SIRT1是SREBP-1C的负调节剂，表明SIRT1表达或酶促活性的调节会影响脂质代谢。初步数据表明，赖氨酸特异性脱甲基-1（LSD1）是SIRT1的关键调节剂，并控制脂肪生成基因的表达。令人惊讶的是，一种在脂质代谢上已知功能的经常使用的小分子表现出抑制LSD1活性的新功能。因此，该提案的中心假设是LSD1通过抑制SIRT1激活SREBP-1C介导的转录和脂质形成。提出了以下三个特定目的来检验这一假设：1）确定LSD1在调节脂质代谢中的作用，体内原发性肝细胞和小鼠肝脏中的作用； 2）阐明了与从头脂质发生有关的SIRT1调节LSD1调节的分子机制； 3）用于调节SREBP-1C活性/水平和从头脂肪生成的目标LSD1。提出了一系列体外和体内实验，以确定LSD1/SREBP途径在脂质代谢中的调节机制和重要性。该提案的长期目标是确定LSD1在SREBP-1C功能的营养调节中的作用以及在代谢障碍条件下控制脂质稳态方面的作用。该应用不仅与公共卫生相关，而且具有高度创新性，并且会对脂质代谢领域产生重大影响。总之，拟议的研究将解决LSD1和SREBP-1C之间的分子联系，以调节脂质稳态及其在脂质稳态失调的疾病发展中的潜在作用，例如肥胖，2型糖尿病和心血管疾病。 公共卫生相关性：异常的肝脂肪生成会引起脂肪肝和血脂异常，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。拟议的研究将研究组蛋白去甲基酶LSD1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型治疗方法的发展，并将对脂质稳态失调的人类疾病的治疗产生重大影响。