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

描述(申请人提供)：从糖到脂肪：转录因子XBP1如何调节肝脏脂肪生成摘要饮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XBP1是肝脏从头合成脂肪酸所必需的，这一功能与其在UPR中的作用无关[1]。XBP1被认为是ER跨膜蛋白激酶IRE1下游未折叠蛋白反应(UPR)的关键调节因子。XBP1蛋白在肝脏中的表达是由高碳水化合物饮食诱导的，并直接控制与脂肪酸和甾醇合成有关的关键基因的诱导。肝脏中可诱导的、选择性的XBP1缺失导致显著的低胆固醇血症和继发性低甘油三酯血症，这是由于肝脏产生的脂质减少。值得注意的是，这种表型没有伴随肝脏脂肪变性或蛋白质分泌功能的显著损害。最近的数据表明，脂质体包裹的siXBP1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，可在48小时内显著降低血清甘油三酯和胆固醇，并持续近2周。因此，XBP1在体内直接调节脂肪生成，其在脂肪生成中的作用显得非常重要。我们最近发现，XBP1直接调节PCSK9的表达，这可能部分解释了它对血清胆固醇的影响。XBP1加入了控制肝脏脂肪生成的一个已经丰富的转录调控蛋白领域。我们的目标是将XBP1放在对肝脏脂肪生成的广泛现有知识的背景下。XBP1如何作为致脂基因的转录调节因子，这与SREBPs和ChREBP等因子相似还是不同？XBP1是否与其他转录激活剂或共激活剂协同作用来调节致脂基因的转录？在肝脏中激活IRE1并诱导XBP1的信号是什么，它们与诱导其他调节蛋白的信号有什么关系？XBP1缺乏或XBP1在肝脏中沉默对动脉粥样硬化模型的影响是什么？在这项修订的提案中，我们的目标是：1)进一步探讨XBP1诱导造脂酶基因转录的机制(S)；2)确定激活IRE11并诱导XBP1蛋白在肝脏中的细胞外和细胞内信号，以响应碳水化合物喂养，并建立这些信号诱导XBP1蛋白的机制；3)研究XBP1在饮食和动脉粥样硬化遗传模型中的作用。更全面地了解XBP1在保持正常肝脂成分的同时促进肝脏中从头合成脂肪酸和固醇的机制，对于治疗与血脂异常相关的疾病，如动脉粥样硬化，具有高度的相关性。 与公共健康相关：我们最近发现，转录因子XBP1是肝脏从头合成脂肪酸所必需的，XBP1是未折叠蛋白反应的关键调节因子。肝脏中可诱导的、选择性的XBP1缺失导致严重的低胆固醇血症和继发性低甘油三酯血症，这是由于肝脏产生的脂质减少。在这里，我们建议研究XBP1在保持正常肝脂组成的同时，加速肝脏中从头合成脂肪酸和甾醇的机制。这一知识与动脉粥样硬化等与血脂异常相关的疾病的治疗高度相关。

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.