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

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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.