Novel Role of Hepatic SEL1L-HRD1 ERAD in FGF21 Gene Transcription

肝脏SEL1L-Hrd1 ERAD在FGF21基因转录中的新作用 摘要 肝脏通过器官间通讯调节生长和全身能量动态平衡。 分泌生长因子、激素和多肽。成纤维细胞生长因子21(FGF21)是一种来源于肝脏、 禁食诱导的激素，对生长、营养代谢和胰岛素敏感性有广泛的影响。气和 Fang实验室对SEL1L和Hrd1的生理作用分别感兴趣，重点是 不同的细胞类型。它们最为人所知的是内质网中的SEL1L-Hrd1蛋白复合体 (ER)相关退化(ERAD)，这是一个负责ER招募和后移位的过程 胞浆蛋白酶体降解的蛋白质。此外，研究表明，SEL1L可能具有Hrd1- 独立的功能，反之亦然。在这项研究中，这两个实验室联手定义了 肝细胞表达SEL1L和Hrd1。值得注意的是，我们实验室最近的研究独立地将两者联系在一起 SEL1L和Hrd1至FGF21的表达。事实上，肝细胞特异性缺失SEL1L或Hrd1的小鼠 表现出惊人的相似表型，包括生长迟缓和女性不孕症，并明显升高 FGF21在肝脏和循环中的水平。从机制上讲，我们独立地确定了ER驻留人员 转录因子CREBH可能是ER膜上SEL1L/Hrd1与FGF21之间的分子连接 在原子核中。基于这些强大的初步数据，我们将检验肝脏SEL1L或Hrd1的假设 作为ERAD复合体发挥作用，共同控制全身能量代谢至少部分 穿过CREBH-FGF21轴。为此，我们计划独立和协作测试以下各项 目的：目的1确定肝脏SEL1L-Hrd1 ERAD是否通过调节调节系统代谢 目的2证实肝脏SEL1L-Hrd1 ERAD是否调控FGF21基因 针对蛋白酶体降解的靶向CREBH转录。这项研究不仅将确立 SEL1L-Hrd1 ERAD在肝脏中对全身能量代谢的调节，也揭示了一种新的 肝脏“ERAD-CREBH-FGF21”轴直接将ER蛋白周转与FGF21基因转录联系起来 全身性代谢调节。 与人类健康的相关性：FGF21是一种重要的代谢肝素，控制全身 能量代谢和胰岛素敏感性。本研究将明确SEL1L-1的病理生理学意义。 Hrd1 ERAD在肝细胞中的表达及鉴定与其功能直接相关的新的肝脏“ERAD-CREBH-FGF21”轴 ER蛋白降解机制对FGF21基因转录和系统代谢调节的影响。

Novel Role of Hepatic SEL1L-HRD1 ERAD in FGF21 Gene Transcription SUMMARY The liver regulates growth and systemic energy homeostasis through inter-organ communication via the secretion of growth factors, hormones and peptides. Fibroblast growth factor 21 (FGF21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism and insulin sensitivity. The Qi and Fang laboratories have been interested in the physiological roles of SEL1L and HRD1, respectively, focusing on different cell types. They are best known for their SEL1L-HRD1 protein complex in the endoplasmic reticulum (ER)-associated degradation (ERAD), a process responsible for the recruitment and retrotranslocation of ER proteins for cytosolic proteasomal degradation. In addition, studies have suggested that SEL1L may have HRD1- independent functions, and vice versa. In this study, the two laboratories are teaming up to define the role of SEL1L and HRD1 in hepatocytes. Remarkably, recent studies from our laboratories independently linked both SEL1L and HRD1 to FGF21 expression. Indeed, mice with hepatocyte-specific deletion of SEL1L or HRD1 exhibit strikingly similar phenotypes including growth retardation and female infertility with markedly elevated FGF21 levels in the liver and circulation. Mechanistically, we independently identified the ER-resident transcription factor CREBH as a possible molecular link between SEL1L/HRD1 on the ER membrane and FGF21 in the nucleus. Based on these strong preliminary data, we will test the hypothesis that hepatic SEL1L or HRD1 functions as an ERAD complex and together, controls systemic energy metabolism at least in part through the CREBH-FGF21 axis. To this end, we plan to independently and collaboratively test the following Aims: Aim 1 to determine whether hepatic SEL1L-HRD1 ERAD regulates systemic metabolism via modulation of FGF21 levels; and Aim 2 to demonstrate whether hepatic SEL1L-HRD1 ERAD regulates FGF21 gene transcription by targeting CREBH for proteasomal degradation. This study will not only establish the importance of SEL1L-HRD1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD-CREBH-FGF21” axis directly linking ER protein turnover to FGF21 gene transcription and systemic metabolic regulation. RELEVANCE TO HUMAN HEALTH: FGF21 is an important metabolic hepatokine that controls systemic energy metabolism and insulin sensitivity. This study will define the pathophysiological significance of SEL1L- HRD1 ERAD in hepatocytes and identify a novel hepatic “ERAD-CREBH-FGF21” axis directly linking the function of ER protein degradation machinery to FGF21 gene transcription and systemic metabolic regulation.