# Novel role of hepatic SEL1L-HRD1 ERAD in bile acid metabolism

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $696,090

## Abstract

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 f...

## Key facts

- **NIH application ID:** 10992891
- **Project number:** 7R01DK120330-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Deyu Fang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $696,090
- **Award type:** 7
- **Project period:** 2023-11-30 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992891

## Citation

> US National Institutes of Health, RePORTER application 10992891, Novel role of hepatic SEL1L-HRD1 ERAD in bile acid metabolism (7R01DK120330-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10992891. Licensed CC0.

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