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

肝脏SEL1L-Hrd1 ERAD在胆汁酸代谢中的新作用 摘要 胆汁酸平衡受损在胆汁淤积性肝病和肝损伤的发病机制中起重要作用 以及包括肥胖和2型糖尿病在内的许多代谢性疾病。虽然之前的研究已经确定 胆汁酸代谢的几个关键调节者，内质网(ER)稳态的作用仍然存在 很大程度上还不清楚。齐和方实验室正在带头探索两个基因的生理作用 使用细胞类型特异性基因敲除(KO)的相同蛋白质复合体的组成部分(分别为SEL1L和Hrd1) 老鼠模型。SEL1L和Hrd1蛋白构成ER相关蛋白降解的一个高度保守的分支 (ERAD)，这是一个质量控制过程，负责内质网蛋白质的招募和反向转位 胞浆蛋白酶体降解。在上一个资助周期中，他们报告了肝细胞SEL1L-Hrd1 ERAD 通过内质网驻留转录因子CREBH与FGF21基因转录相关。在初步数据中 在这一新的应用中，我们发现了胆汁酸合成中的一种新的反馈调节机制，即 胆汁酸/SEL1L-Hrd1ERAD/3β-羟基类固醇脱氢酶7型(HSD3B7)轴，补充 经典的胆汁酸合成调控机制以众所周知的“FXR-SHP-CYP7A1”为中心 轴心。HSD3B7，一种内质网驻留的跨膜蛋白，催化胆汁酸合成的早期步骤 胆固醇。突显我们研究的重要性的是，超过24个常染色体隐性HSD3B7突变 已在先天性胆汁酸合成缺陷1(CBAS1)患者中发现，这些患者发展为进展性 以胆汁淤积性黄疸和脂类及脂溶维生素吸收不良为特征的肝病。如果离开 如果不进行治疗，它将导致肝功能衰竭，需要肝移植。在此续订应用程序中，我们将测试 胆汁酸诱导SEL1L-Hrd1 ERAD表达和活性进而控制胆汁的假说 通过26S蛋白酶体靶向HSD3B7蛋白的降解，酸的生物合成，从而导致肝脏损伤。我们 我将通过以下三个目的来检验这一假设：(A)确定肝脏SEL1L-Hrd1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)从机制上描绘了肝脏SEL1L-1是如何- Hrd1 ERAD调节胆汁酸代谢和胆汁酸诱导的肝损伤，以及(C)描绘病理 SEL1L-Hrd1 ERAD在携带HSD3B7突变的CBAS1患者中的重要性和治疗潜力 这项研究不仅将确定肝脏中SEL1L-Hrd1 ERAD在胆汁酸调节中的重要性 和胆固醇代谢，也揭示了胆汁酸维持的一种新的调节机制 动态平衡。 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素 动态平衡，并对与这一基本过程相关的疾病提供重要见解。作为SEL1L- Hrd1 ERAD既是内质网稳态的调节剂，也是胆汁酸生物合成的调节剂，这一复合体可能是理想的 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.