Sterol Regulatory Element Binding Proteins in regulation of lipid metabolism

甾醇调节元件结合蛋白在脂质代谢调节中的作用

• 批准号: 8897433
• 负责人: Timothy F Osborne
• 金额: $ 51.61万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897433
• 关键词: ADD-1 protein; Area; Award; BHLH Protein; Binding; Binding Proteins; Biological Models; Biological Process; Cell physiology; Cholesterol; Chromosomes; Clinical effectiveness; Combined Modality Therapy; Complex; Cultured Cells; DNA; Data; Dietary Intervention; Drug usage; Family; Foundations; Funding; Future; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Grant; Health; Hepatic; Homeostasis; Homologous Gene; Human; Hyperlipidemia; In Vitro; Ingestion; Intervention; Investigation; Isomerism; Laboratories; Lipids; Liver; Location; Lovastatin; Mammals; Manuscripts; Membrane Protein Traffic; Metabolic Control; Metabolic Diseases; Metabolism; MicroRNAs; Modeling; Molecular; Monitor; Mus; Nuclear; Nuclear Receptors; Nutritional; Operon; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiological Processes; Population; Process; Protein Binding; Protein Isoforms; Proteins; Protocols documentation; Publications; Publishing; Refractory; Regimen; Regulation; Regulator Genes; Regulatory Element; Role; SRE-1 binding protein; SRE-2 binding protein; Site; Sterols; Testing; Therapeutic; Transcript; Work; cell growth; clinical investigation; clinically relevant; clinically significant; combat; combinatorial; dietary supplements; ezetimibe; feeding; flexibility; genome-wide; genome-wide analysis; human NR5A2 protein; in vivo; in vivo Model; insulin signaling; knockout animal; lipid biosynthesis; lipid metabolism; mouse model; programs; promoter; protein expression; protein metabolism; receptor; response; trafficking; transcription factor

DESCRIPTION (provided by applicant): The sterol regulatory element binding proteins (SREBPs) have been studied as key modulators of lipid metabolism but emerging data indicate they are involved in additional cellular pathways and processes. In mammals, there are three major SREBP isoforms encoded by two unlinked genes. The SREBP-1 gene has two isomers that only differ at their amino-terminal regions. The SREBP-2 gene encodes a single protein. SREBP-1 and 2 are regulated differently in the liver, SREBP-1c is activated by insulin signaling and is a major driver of the de novo lipogenesis program. SREBP-2 is activated by cholesterol depletion and is a major driver of cholesterol synthesis when hepatic sterol levels are low or subject to pharmacologic blockade by statin treatment. In a recent study, we described an SREBP regulated micro-RNA (miR) cluster that encodes three distinct miRs that are processed from a single SREBP regulated primary transcript. We went on to show that each miR negatively regulates expression of a different protein involved in the complex membrane-trafficking and proteolytic maturation pathway that controls the level of active nuclear SREBPs. This "miR operon" functions in a positive regulatory loop that increases SREBP activity. Studies in Aim 1 will enhance our understanding of this regulatory mechanism through genetic and pharmacologic manipulation in vivo. We explore another key signature feature of the SREBPs in Aim 2, which is they do not activate transcription efficiently alone and work in a concerted fashion with additional transcription factors that bind to adjacent DNA sites to stimulate target gene expression. This feature provides modular and dynamic flexibility for SREBPs and allows them to function in combinatorial regulatory processes to integrate lipid synthesis with other key cellular physiologic processes. Most of this work in the past has been focused on isolated gene-promoters taking advantage of cultured cells and in vitro approaches. In our preliminary studies, we performed genome- wide binding studies for both SREBP-2 and one of its key hepatic partner proteins, LRH-1, and in Aim 2 we propose to take advantage of these studies to exploit key genetic models and a robust feeding protocol to explore SREBP-LRH-1 action in vivo.

描述（由申请人提供）：已将固醇调节元件结合蛋白（SREBP）作为脂质代谢的关键调节剂进行了研究，但新出现的数据表明它们参与了其他细胞途径和过程。在哺乳动物中，有三种主要的SREBP亚型由两个不连锁的基因编码。SREBP-1基因有两种异构体，仅在其氨基末端区域不同。SREBP-2基因编码单一蛋白质。SREBP-1和2在肝脏中的调节不同，SREBP-1c被胰岛素信号激活，是从头脂肪生成程序的主要驱动力。SREBP-2被胆固醇消耗激活，并且当肝固醇水平低或受到他汀类药物治疗的药理学阻断时，SREBP-2是胆固醇合成的主要驱动因素。在最近的一项研究中，我们描述了一个SREBP调节的micro-RNA（miR）簇，它编码三个不同的miR，这些miR是从一个SREBP调节的初级转录本加工而来的。我们继续表明，每个miR负调控参与复杂的膜运输和蛋白水解成熟途径的不同蛋白质的表达，该途径控制活性核SREBP的水平。这种“miR操纵子”在增加SREBP活性的正调控环中起作用。目标1的研究将通过体内遗传和药理学操作增强我们对这种调节机制的理解。我们探索了Aim 2中SREBP的另一个关键特征，即它们不能单独有效地激活转录，而是与结合到相邻DNA位点的额外转录因子以协同方式工作以刺激靶基因表达。这一特征为SREBP提供了模块化和动态的灵活性，并允许它们在组合调节过程中发挥作用，以将脂质合成与其他关键的细胞生理过程整合在一起。在过去，大部分的工作都集中在利用培养细胞和体外方法分离基因启动子。在我们的初步研究中，我们对SREBP-2及其关键肝伴侣蛋白之一LRH-1进行了全基因组结合研究，并且在目的2中，我们提出利用这些研究来利用关键遗传模型和稳健的喂养方案来探索SREBP-LRH-1在体内的作用。