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

• 批准号: 9792378
• 负责人: Deyu Fang
• 金额: $ 53.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-26 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792378
• 关键词: Adipocytes; Cell Nucleus; Cells; Communication; Complex; Cues; Cyclic AMP-Responsive DNA-Binding Protein; Data; Diabetes Mellitus; Endoplasmic Reticulum; Energy Metabolism; Exhibits; Fasting; Female infertility; Gene Expression; Genes; Genetic Transcription; Growth; Growth Factor; Health; Hepatic; Hepatocyte; Homeostasis; Hormones; Immune; Knockout Mice; Laboratories; Link; Liver; Liver Circulation; Membrane; Metabolic; Metabolism; Microarray Analysis; Molecular; Mus; Neurons; Nuclear; Nuclear Receptors; Obesity; Organ; PPAR alpha; Pancreas; Pathogenesis; Pathway interactions; Peptides; Phenocopy; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Process; Proteins; Proteomics; Qi; Regulation; Resource Sharing; Role; Side; Signal Transduction; Starvation; System; Testing; Transgenic Mice; base; cDNA Arrays; cell type; comparative; feeding; fibroblast growth factor 21; in vivo; insulin sensitivity; interest; loss of function; misfolded protein; mouse model; multicatalytic endopeptidase complex; novel; nutrient metabolism; promoter; protein complex; protein degradation; recruit; role model; screening; transcription factor; transcriptome sequencing; ubiquitin-protein ligase

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.

肝脏 SEL1L-HRD1 ERAD 在 FGF21 基因转录中的新作用 概括 肝脏通过器官间通讯来调节生长和全身能量稳态 生长因子、激素和肽的分泌。成纤维细胞生长因子 21 (FGF21) 是一种源自肝脏的、 空腹诱导的激素，对生长、营养代谢和胰岛素敏感性具有广泛影响。气和 Fang实验室分别对SEL1L和HRD1的生理作用感兴趣，重点关注 不同的细胞类型。它们以其内质网中的 SEL1L-HRD1 蛋白复合物而闻名 (ER) 相关降解 (ERAD)，负责 ER 招募和逆转录转位的过程 胞质蛋白酶体降解的蛋白质。此外，研究表明SEL1L可能具有HRD1- 独立功能，反之亦然。在这项研究中，两个实验室正在合作定义 肝细胞中的 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起来 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 表现出惊人相似的表型，包括生长迟缓和女性不孕症，且显着升高 肝脏和循环中的 FGF21 水平。从机制上讲，我们独立识别了急诊室住院医生 转录因子 CREBH 作为 ER 膜上的 SEL1L/HRD1 和 FGF21 之间可能的分子联系 在细胞核中。基于这些强有力的初步数据，我们将检验肝脏 SEL1L 或 HRD1 的假设 作为 ERAD 复合物发挥作用，并至少部分控制全身能量代谢 通过 CREBH-FGF21 轴。为此，我们计划独立和协作测试以下内容 目标：目标 1 确定肝脏 SEL1L-HRD1 ERAD 是否通过调节来调节全身代谢 FGF21 水平；目标 2 证明肝脏 SEL1L-HRD1 ERAD 是否调节 FGF21 基因 通过靶向 CREBH 进行蛋白酶体降解来进行转录。这项研究不仅将确定重要性 SEL1L-HRD1 ERAD 在肝脏中调节全身能量代谢的作用，同时也揭示了一种新的机制 肝脏“ERAD-CREBH-FGF21”轴直接将 ER 蛋白周转与 FGF21 基因转录联系起来 全身代谢调节。 与人类健康的相关性：FGF21 是一种重要的代谢肝因子，控制全身 能量代谢和胰岛素敏感性。本研究将定义 SEL1L- 的病理生理学意义 肝细胞中的 HRD1 ERAD 并确定直接连接功能的新型肝“ERAD-CREBH-FGF21”轴 ER 蛋白降解机制对 FGF21 基因转录和全身代谢调节的影响。