Hepatokine Control of Metabolic Crosstalk and Insulin Resistance

项目摘要 该项目的主要目标是了解NAD+依赖性脱乙酰酶SIRT1如何调节 肝脏分泌的肝细胞因子以及这一过程如何减缓非酒精性脂肪肝的进展 疾病（NAFLD）和肥胖。肥胖或超重影响大约70%的美国成年人， 增加了NAFLD和2型糖尿病的发病率。2型糖尿病是一种致命的疾病。 以外周胰岛素抵抗为特征的疾病，其使组织间通讯失调， 促进高血糖和血脂异常。然而，肝脏是否通过以下方式控制全身代谢： 作为内分泌器官通过分泌因子与其他代谢组织结合是一种新的 未开发的地区。我们的初步研究揭示了一系列新颖而令人兴奋的观察结果， 支持我们的假设肝脏中SIRT1的缺失导致肥胖表型，表现为脂肪增加 减少能量消耗。引人注目的是，基因表达谱分析确定成纤维细胞 生长因子21（FGF21）--一种由肝脏分泌的"瘦因子"（称为肝细胞因子）--是最显著的 肝脏特异性SIRT1敲除（SIRT1 LKO）小鼠肝脏中的下调基因。因此，我们的中央 假设肝脏SIRT1调节的肝细胞因子对NAFLD具有治疗意义， 肥胖通过自分泌调节肝脏脂质代谢和内分泌控制脂肪 组织功能因为在SIRT1 LKO小鼠中肝脏和循环中FGF 21的水平显著降低， 我们选择研究肝因子如FGF 21在SIRT 1作用中的作用。使用增益和损失函数 在小鼠模型中，将在三个特定目的中检验该中心假设：1）为了确定肝细胞是否具有肝细胞毒性， SIRT1通过刺激肝细胞因子FGF21，防止全身胰岛素抵抗和代谢紊乱。 2）阐明肝细胞来源的SIRT1 - 1基因表达的分子机制， FGF21信号传导发挥自分泌作用以改善肝脂肪变性;以及3）研究肝脂肪变性是否与FGF21信号传导有关。 SIRT 1诱导的FGF 21激素对米色脂肪细胞和白色人胰岛素抵抗具有内分泌作用 脂肪组织该项目是对单一组织或途径研究的创新性偏离，因此 可能揭示肝脏SIRT1缺陷单独引起肥胖的许多特征的机制。 该申请的创新方面还包括：SIRT1介导的SIRT1调控的新概念， 肝细胞因子代表了肝脏和脂肪组织通讯的分子基础， SIRT1通过脱乙酰化机制调节FGF21转录， RNA测序和代谢组学分析的技术创新。总的来说，完成这项提案将 不仅提供了对以前未被认识的肝脏在控制中的内分泌作用的基本见解， 此外，还将确定治疗NAFLD和肥胖症的新靶点。

Project Summary The major goal of this project is to understand how the NAD+-dependent deacetylase SIRT1 regulates hepatokines that are secreted by the liver and how this process slows the progression of non-alcoholic fatty liver disease (NAFLD) and obesity. Obesity or being overweight affects approximately 70% of U.S. adults and increases the prevalence of developing NAFLD and Type 2 diabetes. Type 2 diabetes is a life-threatening disease characterized by peripheral insulin resistance, which dysregulates inter-tissue communication to promote hyperglycemia and dyslipidemia. However, whether the liver controls systemic metabolism by functioning as an endocrine organ to engage other metabolic tissues through secreted factors is a novel and under-explored area. Our preliminary studies reveal a series of novel and exciting observations that support our hypothesis. The loss of SIRT1 in the liver leads to an obese phenotype manifested by increased fat mass and decreased energy expenditure. Strikingly, gene expression profiling analyses identify that fibroblast growth factor 21 (FGF21)—a “lean factor” secreted by the liver (called hepatokine)—is the most markedly downregulated gene in the liver of liver-specific SIRT1 knockout (SIRT1 LKO) mice. Thus, our Central Hypothesis is that hepatic SIRT1-regulated hepatokines have therapeutic implications for NAFLD and obesity through the autocrine regulation of hepatic lipid metabolism and endocrine control of adipose tissue function. Because hepatic and circulating levels of FGF21 are remarkably decreased in SIRT1 LKO mice, we choose to study the role of hepatokines such as FGF21 in SIRT1 action. Using gain- and loss-of-function mouse models, this central hypothesis will be tested in three Specific Aims: 1) To determine whether hepatic SIRT1, via stimulating the hepatokine FGF21, protects against whole-body insulin resistance and metabolic abnormalities in obesity; 2) To elucidate the molecular mechanisms by which the hepatocyte-derived SIRT1- FGF21 signaling exerts an autocrine effect to ameliorate hepatic steatosis; and 3) To investigate whether hepatic SIRT1-induced FGF21 hormone has an endocrine effect on beige adipocytes and insulin resistance in white adipose tissue. This project is an innovative departure from the study of a single tissue or pathway and thus is likely to reveal the mechanisms by which hepatic SIRT1 defects alone give rise to many features of obesity. Innovative aspects of the application also include: the novel concept that SIRT1-mediated regulation of hepatokines represents the molecular basis for liver and adipose tissue communication, the new mechanistic insight into that SIRT1 regulates FGF21 transcription via a mechanism involving deacetylation, and the technical innovation of RNA-sequencing and metabolomics analyses. Overall, accomplishing this proposal will not only provide fundamental insight into a previously unrecognized endocrine role of the liver in controlling systemic and adipose tissue metabolism but will also identify new targets for treating NAFLD and obesity.