Novel Role of Hepatic SEL1L-HRD1 ERAD in Bile Acid Metabolism

肝脏SEL 1 L-HRD 1 ERAD在胆汁酸代谢中的新作用 总结 胆汁酸稳态受损有助于胆汁淤积性肝病和肝损伤的发病机制， 以及包括肥胖症和2型糖尿病在内的许多代谢性疾病。虽然先前的研究已经确定 作为胆汁酸代谢的几种关键调节剂，内质网（ER）稳态的作用仍然存在 基本上不清楚。Qi和Fang实验室正在努力探索两种生理作用， 使用细胞类型特异性敲除（KO）的相同蛋白质复合物的组分（分别为SEL 1 L和HRD 1） 小鼠模型。SEL 1 L和HRD 1蛋白形成ER相关蛋白降解的高度保守分支 （ERAD），一个质量控制过程，负责ER蛋白的募集和逆转录易位， 胞质蛋白酶体降解。在上一个资助周期，他们报告肝细胞SEL 1 L-HRD 1 ERAD 通过ER驻留转录因子CREBH与FGF 21基因转录相关。在初步数据中， 在这一更新的应用中，我们已经确定了胆汁酸合成中的一种新的反馈调节机制， “胆汁酸/SEL 1 L-HRD 1 ERAD/3β-羟基类固醇脱氢酶7型（HSD 3B 7）”轴，其补充了 典型的胆汁酸合成调节机制围绕着众所周知的“FXR-SHP-CYP 7A 1” 轴线HPD 3B 7是一种ER驻留跨膜蛋白，催化胆汁酸合成的早期步骤 胆固醇强调了我们研究的重要性，超过20个常染色体隐性HSD 3B 7突变， 在先天性胆汁酸合成缺陷1（CBAS 1）患者中发现， 以胆汁淤积性黄疸和脂质及脂溶性维生素吸收不良为特征的肝病。如果放任 如果不治疗，会导致肝功能衰竭，需要进行肝移植。在此更新应用程序中，我们将测试 假设胆汁酸诱导SEL 1 L-HRD 1 ERAD的表达和活性，从而控制胆汁 通过26 S蛋白酶体靶向HSD 3B 7蛋白降解，导致酸生物合成和肝损伤。我们 将以以下三个目的检验这一假设：（a）确定肝SEL 1 L-HRD 1的意义 ERAD在胆汁酸代谢和胆汁酸诱导的肝损伤中的作用，（B）从机制上描述了肝SEL 1 L- HRD 1 ERAD调节胆汁酸代谢和胆汁酸诱导的肝损伤，和（c）描绘病理性肝损伤， SEL 1 L-HRD 1 ERAD在携带HSD 3B 7突变的CBAS 1患者中的重要性和治疗潜力。 这项研究不仅将确定SEL 1 L-HRD 1 ERAD在肝脏中调节胆汁酸的重要性， 和胆固醇代谢，而且还揭示了一种新的调节机制，在维持胆汁酸 体内平衡 与人类健康的相关性：这项研究将揭示胆汁酸中新的信号通路和因子 内稳态，并提供与这一基本过程相关的疾病的重要见解。作为SEL 1 L- HRD 1 ERAD是ER稳态和胆汁酸生物合成的调节剂，该复合物可能是理想的 治疗肝损伤的靶点。

Novel Role of Hepatic SEL1L-HRD1 ERAD in Bile Acid Metabolism SUMMARY Impaired bile acid homeostasis contributes to the pathogenesis of cholestatic liver disease and liver injury as well as many metabolic diseases including obesity and type-2 diabetes. While prior studies have identified several critical regulators of bile acid metabolism, the role of endoplasmic reticulum (ER) homeostasis remains largely unclear. The Qi and Fang laboratories are leading the effort to explore the physiological roles of two components (SEL1L and HRD1, respectively) of the same protein complex using cell type-specific knockout (KO) mouse models. SEL1L and HRD1 proteins form a highly conserved branch of ER-associated protein degradation (ERAD), a quality-control process responsible for the recruitment and retrotranslocation of ER proteins for cytosolic proteasomal degradation. In the last funding cycle, they reported that hepatocyte SEL1L-HRD1 ERAD are linked to FGF21 gene transcription via the ER-resident transcription factor CREBH. In the preliminary data of this renew application, we have identified a novel feedback regulatory mechanism in bile acid synthesis, the “bile acids/SEL1L-HRD1 ERAD/3β-hydroxysteroid dehydrogenase type 7 (HSD3B7)” axis, which complements the canonical bile acid synthesis regulatory mechanism centered around the well-known “FXR-SHP-CYP7A1” axis. HSD3B7, an ER-resident transmembrane protein, catalyzes an early step in the synthesis of bile acids from cholesterol. Highlighting the importance of our study, over two-dozen autosomal-recessive HSD3B7 mutations have been identified in patients with congenital bile acid synthesis defect 1 (CBAS1), who develop progressive liver disease characterized by cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins. If left untreated, it would lead to liver failure requiring liver transplantation. In this renew application, we will test the hypothesis that bile acids induce the expression and activity of SEL1L-HRD1 ERAD, which in turn controls bile acid biosynthesis and hence liver injury by targeting HSD3B7 protein degradation by the 26S proteasome. We will test this hypothesis with the following three aims: (a) determine the significance of hepatic SEL1L-HRD1 ERAD in bile acid metabolism and bile acid-induced liver injury, (b) delineate mechanistically how hepatic SEL1L- HRD1 ERAD regulates bile acid metabolism and bile acid-induced liver injury, and (c) delineate the pathological importance and therapeutic potential of SEL1L-HRD1 ERAD in CBAS1 patients carrying HSD3B7 mutations. This study will not only establish the importance of SEL1L-HRD1 ERAD in the liver in the regulation of bile acid and cholesterol metabolism, but also reveals a novel regulator mechanism in the maintenance of bile acid homeostasis. RELEVANCE TO HUMAN HEALTH: This study will reveal novel signaling pathways and factors in bile acid homeostasis, and provide important insights into diseases associated with this fundamental process. As SEL1L- HRD1 ERAD is both a modulator of ER homeostasis and bile acid biosynthesis, this complex may be an ideal target for the treatment of liver injury.