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（ER相关降解（ERAD）、自噬和未折叠蛋白）来描述维持内质网（ER）稳态的潜在分子机制和生理意义。尽管最近的研究表明 UPR 在肥胖和 2 型糖尿病的发病机制中可能发挥作用，但脂肪细胞中 ER 稳态的维持和生理意义仍然存在。我们最近的数据表明，Sel1L 是哺乳动物 ERAD 中 E3 连接酶 Hrd1 的关键接头蛋白，在脂肪细胞和代谢调节中发挥着关键作用，脂肪细胞特异性 Sel1L 缺陷小鼠 (Sel1LΔadipo) 可以免受饮食诱导的肥胖影响。 UPR 和自噬升高，但与 WAT 中的炎症和细胞死亡无关。此外，我们的数据表明 Sel1L 对于脂蛋白的分泌至关重要。因此，我们的数据表明 Sel1L 在肥胖发病机制中的脂肪细胞功能中发挥着不可或缺的作用。我们对于 Sel1L 通过 Hrd1/ERAD 依赖和独立机制以及通过脂肪细胞中三个 ER 质量控制系统（Sel1L-Hrd1 ERAD、UPR 和自噬）之间的串扰使用一系列脂肪细胞特异性敲除小鼠模型以及体外机制研究，我们将在机制上确定 Se1L 如何调节脂肪细胞功能和代谢，并特别强调。目标 1 中的 Hrd1/ERAD 依赖性以及目标 2 中脂肪细胞中三个 ER 质量控制系统之间的串扰。对几种具有不同水平 ER 应激水平的脂肪细胞特异性双敲除小鼠模型的表征不仅将阐明关键 ER 质量控制机制之间的功能串扰，而且还将阐明 ER 稳态紊乱在肥胖和肥胖发病机制中的细胞和病理后果。最后，本研究可能鉴定出 Sel1L-Hrd1 ERAD 复合物的新型内源性底物，并建立 Sel1L-Hrd1 ERAD 和 ERAD 之间反馈调节环的新机制。 IRE1α信号与人类健康的相关性：蛋白质错误折叠会给细胞带来困扰，并且与多种人类疾病的发病机制有关，尽管经过近十年的努力，脂肪细胞内质网稳态在肥胖发病机制中的作用仍然模糊。我们的初步数据表明脂肪细胞 Sel1L 是 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其生理意义产生重大影响。饮食诱导肥胖背景下的内质网质量控制系统和脂肪细胞内质网稳态的维持。