From Sugar to Fat: How Transcription Factor XBP1 Regulates Hepatic Lipogenesis

从糖到脂肪：转录因子 XBP1 如何调节肝脏脂肪生成

• 批准号: 8308665
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 33.59万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308665
• 关键词: Atherosclerosis; Carbohydrates; Cholesterol; Data; Diet; Dietary Carbohydrates; Disease; Dyslipidemias; Encapsulated; Enzymes; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genes; Genetic Models; Genetic Transcription; Goals; Hepatic; Hour; Knowledge; Lipids; Liposomes; Liver; Modeling; Mus; Pathway interactions; Phenotype; Phosphotransferases; Production; Proteins; Role; Secondary to; Serum; Signal Transduction; Sterols; Transcription Coactivator; Transcription Regulatory Protein; Triglycerides; abstracting; extracellular; feeding; genetic regulatory protein; hypocholesterolemia; in vivo; lipid biosynthesis; protein expression; public health relevance; response; secretory protein; sugar; transcription factor

DESCRIPTION (provided by applicant): From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis Abstract Dietary carbohydrates regulate hepatic lipogenesis by controlling the expression of critical enzymes in glycolytic and lipogenic pathways. We have recently discovered that the transcription factor XBP1, best known as a key regulator of the Unfolded Protein Response (UPR) downstream of the ER transmembrane kinase IRE1, is required for de novo fatty acid synthesis in the liver, a function unrelated to its role in the UPR (1). XBP1 protein expression is induced in the liver by a high carbohydrate diet and directly controls the induction of critical genes involved in fatty acid and sterol synthesis. Inducible, selective deletion of XBP1 in liver results in marked hypocholesterolemia and hypotriglyceridaemia secondary to decreased production of lipids from the liver. Notably, this phenotype is not accompanied by hepatic steatosis or significant compromise in protein secretory function. Recent data demonstrate that in vivo administration of liposome encapsulated siXBP1 targeted to liver of wildtype or hypercholesterolemic apolipoproteinE (ApoE) deficient mice results in significant reductions in serum triglycerides and cholesterol within 48 hours that persist for almost 2 weeks. Hence, XBP1 directly regulates lipogenesis in vivo and its function in lipogenesis appears to be highly significant. Our recent discovery that XBP1 directly regulates the expression of PCSK9 may partly explain its effect on serum cholesterol. XBP1 joins an already rich field of transcriptional regulatory proteins in the control of hepatic lipogenesis. Our goal here is to place XBP1 in the context of the extensive existing knowledge of hepatic lipogenesis. How does XBP1 act as a transcriptional regulator of lipogenic genes and is this similar to or different than factors such as SREBPs and ChREBP? Does XBP1 act synergistically with other transcriptional activators or coactivators to regulate the transcription of lipogenic genes? What are the signals that activate IRE1 and induce XBP1 in liver and how do they relate to signals that induce other regulatory proteins? What are the consequences of XBP1 deficiency or XBP1 silencing in the liver for models of atherosclerosis? In this revised proposal, our goals are to 1) further explore the mechanism(s) by which XBP1 induces the transcription of genes encoding lipogenic enzymes; 2) Identify the extracellular and intracellular signals that activate IRE11 and induce XBP1 protein in liver in response to carbohydrate feeding and establish by what mechanisms these signals induce XBP1 protein and; 3) Examine the role of XBP1 in dietary and genetic models of atherosclerosis. A more complete understanding of the mechanisms by which XBP1 accelerates de novo fatty acid and sterol synthesis in the liver while preserving normal hepatic lipid composition is highly relevant to the treatment of diseases such as atherosclerosis that are associated with dyslipidemia. PUBLIC HEALTH RELEVANCE: We have recently discovered that the transcription factor XBP1, best known as a key regulator of the Unfolded Protein Response, is required for de novo fatty acid synthesis in the liver. Inducible, selective deletion of XBP1 in liver results in profound hypocholesterolemia and hypotriglyceridaemia secondary to decreased production of lipids from the liver. Here we propose to investigate the mechanisms by which XBP1 accelerates de novo fatty acid and sterol synthesis in the liver while preserving normal hepatic lipid composition. This knowledge is highly relevant to the treatment of diseases such as atherosclerosis that are associated with dyslipidemia.

描述（由申请人提供）：从糖到脂肪：转录因子XBP1如何调节肝脂肪生成抽象的饮食碳水化合物来调节肝脂肪生成，通过控制糖溶解和脂源途径中关键酶的表达。我们最近发现，转录因子XBP1是ER跨膜激酶IRE1下游展开的蛋白质反应（UPR）的关键调节剂，是肝脏中从头脂肪酸合成所必需的，这是与其在UPR（1）中无关的函数。 XBP1蛋白的表达是通过高碳水化合物饮食在肝脏中诱导的，并直接控制诱导参与脂肪酸和固醇合成的关键基因。 XBP1在肝脏中的诱导性缺失导致降低脂质产生脂质的降低降脂脂血症和低甘露糖伊血症。值得注意的是，这种表型不伴有肝脂肪变性或蛋白质分泌功能的显着妥协。最近的数据表明，在体内施用脂质体封装的SIXBP1靶向于野生型或高胆固醇血症的载脂蛋白（APOE）缺陷小鼠的肝脏导致血清甘时甘油三酸酯和胆固醇在48小时内持续了近2周，导致血清甘油三酸酯和胆固醇的大幅降低。因此，XBP1直接调节体内脂肪形成，其在脂肪生成中的功能似乎非常重要。我们最近发现XBP1直接调节PCSK9的表达可能部分解释了其对血清胆固醇的影响。 XBP1在控制肝脂肪生成的控制中加入了已经丰富的转录调节蛋白领域。我们的目标是将XBP1放置在广泛的肝脂肪生成知识的背景下。 XBP1如何充当脂肪生成基因的转录调节剂，这与Srebps和Chrebp等因素相似或不同？ XBP1是否与其他转录激活剂或共激活剂协同作用以调节脂肪生成基因的转录？激活IRE1并在肝脏中诱导XBP1的信号是什么？它们与诱导其他调节蛋白的信号有何关系？动脉粥样硬化模型中XBP1缺乏症或XBP1沉默的后果是什么？在这项修订的建议中，我们的目标是1）进一步探索XBP1诱导编码脂肪酶的基因转录的机制； 2）确定激活IRE11的细胞外和细胞内信号，并诱导肝脏中的XBP1蛋白，以响应碳水化合物的摄食，并通过这些机制诱导XBP1蛋白的机制建立； 3）检查XBP1在动脉粥样硬化的饮食和遗传模型中的作用。对XBP1在肝脏中加速从头脂肪酸和固醇合成的机制的更完整理解，同时保存正常的肝脂质组成与与血脂异常有关的疾病（例如动脉粥样硬化）的治疗高度相关。 公共卫生相关性：我们最近发现，转录因子XBP1（最著名的是展开的蛋白质反应的关键调节剂）是肝脏中从头脂肪酸合成所必需的。 XBP1在肝脏中的诱导性缺失会导致肝脏降低脂质产生的降低降降脂质素血症和低甘油糖酵母。在这里，我们建议研究XBP1在肝脏中加速从头脂肪酸和固醇合成的机制，同时保留正常的肝脂质组成。这些知识与与血脂异常有关的疾病（例如动脉粥样硬化）的治疗高度相关。