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

描述（由申请人提供）：从糖到脂肪：转录因子XBP 1如何调节肝脏脂肪生成摘要膳食碳水化合物通过控制糖酵解和脂肪生成途径中关键酶的表达来调节肝脏脂肪生成。我们最近发现，转录因子XBP 1是ER跨膜激酶IRE 1下游未折叠蛋白反应（UPR）的关键调节因子，是肝脏从头脂肪酸合成所必需的，这一功能与其在UPR中的作用无关（1）。XBP 1蛋白表达在肝脏中由高碳水化合物饮食诱导，并直接控制参与脂肪酸和甾醇合成的关键基因的诱导。肝脏中可诱导的选择性XBP 1缺失导致显著的低胆固醇血症和继发于肝脏脂质产生减少的低胆固醇血症。值得注意的是，这种表型不伴有肝脂肪变性或蛋白分泌功能的显著损害。最近的数据表明，体内施用靶向野生型或高胆固醇血症载脂蛋白E（ApoE）缺陷小鼠的肝脏的脂质体封装的siXBP 1导致血清甘油三酯和胆固醇在48小时内显著降低，持续几乎2周。因此，XBP 1直接调节体内脂肪生成，其在脂肪生成中的功能似乎是非常重要的。我们最近发现，XBP 1直接调节PCSK 9的表达，这可能部分解释了其对血清胆固醇的影响。XBP 1加入了一个已经丰富的领域的转录调控蛋白在控制肝脏脂肪生成。我们的目标是将XBP 1置于广泛的现有肝脏脂肪生成知识的背景下。XBP 1如何作为脂肪生成基因的转录调节因子，与SREBP和ChREBP等因子相似或不同？XBP 1是否与其他转录激活因子或共激活因子协同作用调节脂肪生成基因的转录？在肝脏中激活IRE 1和诱导XBP 1的信号是什么，它们如何与诱导其他调节蛋白的信号相关？对于动脉粥样硬化模型，肝脏中XBP 1缺乏或XBP 1沉默的后果是什么？在这个修订的建议中，我们的目标是：1）进一步探索XBP 1诱导编码脂肪生成酶的基因转录的机制; 2）鉴定响应于碳水化合物喂养在肝脏中激活IRE 11和诱导XBP 1蛋白的细胞外和细胞内信号，并确定这些信号通过什么机制诱导XBP 1蛋白; 3）检查XBP 1在动脉粥样硬化的饮食和遗传模型中的作用。对XBP 1加速肝脏中脂肪酸和甾醇从头合成同时保持正常肝脏脂质组成的机制的更全面理解与治疗与血脂异常相关的疾病如动脉粥样硬化高度相关。 公共卫生相关性：我们最近发现，转录因子XBP 1，最为人所知的是未折叠蛋白质反应的关键调节因子，是肝脏中从头脂肪酸合成所必需的。肝脏中可诱导的选择性XBP 1缺失导致严重的低胆固醇血症和继发于肝脏脂质产生减少的低胆固醇血症。在这里，我们建议调查的机制，其中XBP 1加速从头脂肪酸和甾醇在肝脏中的合成，同时保持正常的肝脏脂质组成。这些知识与治疗与血脂异常相关的疾病如动脉粥样硬化高度相关。

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.