The Role of Sel1L and ER Quality Control in Adipocytes

Sel1L 和 ER 质量控制在脂肪细胞中的作用

• 批准号: 9321525
• 负责人: Ling Qi
• 金额: $ 14.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321525
• 关键词: Accounting; Adaptor Signaling Protein; Adipocytes; Affect; Autophagocytosis; Cell Death; Cells; Complex; Coupled; Data; Dependency; Diet; Endoplasmic Reticulum; Ensure; Feedback; Generations; Goals; Health; Homeostasis; Hypertriglyceridemia; In Vitro; Inflammation; Insulin Resistance; Knockout Mice; Link; MAPK8 gene; Maintenance; Metabolic; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Patients; Phenotype; Physiological; Play; Proteins; Proteomics; Quality Control; Regulation; Role; Signal Transduction; System; Testing; Time; adipocyte biology; adiponectin; endoplasmic reticulum stress; gain of function; human disease; in vivo; insight; lipid metabolism; lipoprotein lipase; loss of function; metabolic phenotype; mouse model; novel; overexpression; promoter; protein aggregate; protein function; protein misfolding; response; sensor; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Our long-term goal is to delineate the underlying molecular mechanisms and physiological significance of the maintenance of endoplasmic reticulum (ER) homeostasis by three key quality-control systems, ERassociated degradation (ERAD), autophagy and unfolded protein response (UPR). Although recent studies have implied a possible role of UPR in the pathogenesis of obesity and type-2 diabetes, the maintenance and physiological significance of ER homeostasis in adipocytes remains enigma. Our recent data demonstrate that Sel1L, a key adaptor protein for the E3 ligase Hrd1 in mammalian ERAD, plays a critical role in adipocytes and metabolic regulation. Adipocyte-specific Sel1L-deficient mice (Sel1LΔadipo) are protected against diet-induced obesity with elevated UPR and autophagy, but uncoupled from inflammation and cell death in WAT. Moreover, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), which may account for postprandial hypertriglyceridemia of Sel1LΔadipo mice. Thus, our data point to an indispensable role of Sel1L in adipocyte function in the pathogenesis of obesity. However, underlying molecular mechanism(s) by which Sel1L affects adipocyte function and obesity remain largely unclear. We hypothesize that Sel1L regulates adipocyte function and metabolism via both Hrd1/ERAD-dependent and -independent mechanisms, and via the crosstalk among three ER qualitycontrol systems (Sel1L-Hrd1 ERAD, UPR and autophagy) in adipocytes. Using an array of adipocytespecific knockout mouse models coupled with in vitro mechanistic studies, we will determine mechanistically how Se1L regulates adipocyte function and metabolism with a particular emphasis on Hrd1/ERAD dependency in Aim 1 and on the crosstalk among three ER quality-control systems in adipocytes in Aim 2. The generation and characterization of several adipocyte-specific double knockout mouse models with various levels of ER stress will elucidate not only the functional crosstalk among key ER quality-control machineries, but also the cellular and pathological consequences of perturbed ER homeostasis in the pathogenesis of obesity and type-2 diabetes. Finally, this study may identify a novel endogenous substrate of the Sel1L-Hrd1 ERAD complex and establish a novel mechanism underlying a feedback regulatory loop between Sel1L-Hrd1 ERAD and IRE1αsignaling. RELEVANCE TO HUMAN HEALTH: Protein misfolding is detrimental to the cell and has been linked to the pathogenesis of several human diseases. Despite nearly a decade of effort, the role of ER homeostasis in adipocytes in the pathogenesis of obesity remains vague. Our preliminary data point to adipocyte Sel1L as a key regulator in ER homeostasis and metabolism. A successful completion of this study will have a powerful impact on our understanding of the physiological significance of ER quality-control systems and the maintenance of ER homeostasis in adipocytes in the context of diet-induced obesity.

 描述（由申请人提供）：我们的长期目标是通过三个关键的质量控制系统，内质网（ER）相关降解（ERAD），自噬和未折叠蛋白反应（UPR），描述维持内质网（ER）稳态的潜在分子机制和生理意义。虽然最近的研究表明UPR可能在肥胖和2型糖尿病的发病机制中发挥作用，但脂肪细胞ER稳态的维持和生理意义仍然是个谜。我们最近的数据表明，Sel 1 L，E3连接酶Hrd 1在哺乳动物ERAD中的关键衔接蛋白，在脂肪细胞和代谢调节中起着关键作用。脂肪细胞特异性Sel 1 L缺陷小鼠（Sel 1 L Δadipo）可通过升高的UPR和自噬防止饮食诱导的肥胖，但与WAT中的炎症和细胞死亡脱钩。此外，我们的数据表明，Sel 1 L的脂蛋白脂酶（LPL）的分泌的关键要求，这可能解释Sel 1 L Δadipo小鼠的餐后高脂血症。因此，我们的数据点Sel 1 L在脂肪细胞的功能在肥胖症的发病机制中的不可或缺的作用。然而，Sel 1 L影响脂肪细胞功能和肥胖的潜在分子机制仍不清楚。我们推测Sel 1 L通过Hrd 1/ERAD依赖性和非依赖性机制以及脂肪细胞中三种内质网质量控制系统（Sel 1 L-Hrd 1 ERAD、UPR和自噬）之间的相互作用来调节脂肪细胞的功能和代谢。使用一系列的脂肪细胞特异性基因敲除小鼠模型，再加上在体外机制的研究，我们将确定机械硒1 L如何调节脂肪细胞的功能和代谢，特别强调Hrd 1/ERAD依赖性的目的1和三个ER质量控制系统之间的串扰在脂肪细胞的目的2。产生和表征的几个脂肪细胞特异性双敲除小鼠模型与不同水平的ER压力将阐明不仅关键的ER质量控制机制之间的功能串扰，但也在肥胖症和2型糖尿病的发病机制ER稳态扰动的细胞和病理后果。最后，本研究为Sel 1 L-Hrd 1 ERAD复合物的内源性底物的鉴定和Sel 1 L-Hrd 1 ERAD与IRE 1 α β信号之间的反馈调节回路的建立提供了新的机制。与人类健康的关系：蛋白质错误折叠对细胞有害，并与几种人类疾病的发病机制有关。尽管近十年的努力，ER稳态在脂肪细胞中的作用在肥胖的发病机制仍然模糊。我们的初步数据表明，脂肪细胞Sel 1 L作为ER稳态和代谢的关键调节因子。这项研究的成功完成将对我们理解ER质量控制系统的生理意义和饮食诱导肥胖背景下脂肪细胞ER稳态的维持产生强大的影响。