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XBP1，最著名的是内质网跨膜激酶IRE1下游未折叠蛋白反应（UPR）的关键调节因子，是肝脏中重新合成脂肪酸所必需的，这一功能与其在UPR中的作用无关(1)。高碳水化合物饮食可诱导肝脏中XBP1蛋白的表达，并直接控制参与脂肪酸和固醇合成的关键基因的诱导。肝脏中诱导的、选择性的XBP1缺失导致继发于肝脏脂质产生减少的显著的低胆固醇血症和低甘油三酯血症。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著损害。最近的数据表明，体内给药siXBP1脂质体靶向野生型或高胆固醇血症载脂蛋白（ApoE）缺乏小鼠的肝脏，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在体内直接调控脂肪生成，其在脂肪生成中的作用似乎非常显著。我们最近发现XBP1直接调控PCSK9的表达，这可能部分解释了其对血清胆固醇的影响。XBP1加入了一个已经丰富的转录调节蛋白领域，控制肝脏脂肪生成。我们的目标是将XBP1置于肝脏脂肪生成的广泛现有知识的背景下。XBP1如何作为脂肪生成基因的转录调节因子，它与srebp和ChREBP等因子相似或不同？XBP1是否与其他转录激活因子或辅激活因子协同作用以调节脂质基因的转录？肝脏中激活IRE1和诱导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？肝脏XBP1缺乏或XBP1沉默对动脉粥样硬化模型有什么影响？在这篇修改后的提案中，我们的目标是：1)进一步探索XBP1诱导脂肪生成酶编码基因转录的机制；2)确定肝脏对碳水化合物摄食反应中激活IRE11和诱导XBP1蛋白的细胞外和细胞内信号，并确定这些信号诱导XBP1蛋白的机制；3)研究XBP1在动脉粥样硬化饮食和遗传模型中的作用。更全面地了解XBP1加速肝脏中脂肪酸和固醇合成的机制，同时保持正常的肝脂质组成，与治疗与血脂异常相关的动脉粥样硬化等疾病高度相关。

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.