# Cholestasis and the Unfolded Protein Response

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $355,500

## Abstract

PROJECT SUMMARY
Cholestatic liver diseases are highly prevalent causes of progressive liver disease in the United States with a
significant morbidity and mortality. Unfortunately, current medical therapies frequently do not prevent disease
progression and are not curative. Over the past decade, the Unfolded Protein Response (UPR), an adaptive
cellular response to Endoplasmic Reticulum (ER) stress, has been implicated in the pathogenesis of many liver
diseases. However, the role of the UPR in hepatic bile acid toxicity and cholestatic liver injury remains poorly
understood. The Inositol-Requiring Enzyme 1α/X-box binding protein 1 (IRE1α/Xbp1) pathway is a highly
evolutionarily conserved signaling pathway of the UPR that is both protective to the liver and is important in the
regulation of lipid metabolism. The central hypothesis of this proposal is that hepatic IRE1α/XBP1s signaling
regulates bile acid metabolism, and that bile acid signaling further regulates the IRE1α/XBP1s pathway. We
show preliminary data demonstrating that the hepatic IRE1α/Xbp1 pathway is activated by cholestasis, is an
important protective response to reduce cholestatic liver injury and regulates bile acid metabolism. Therefore,
we will determine the role of the hepatic IRE1α/XBP1 pathway in the regulation of cholestatic liver
injury (Specific Aim 1A) and bile acid synthesis (Specific Aim 1B). Hepatic FXR/SHP signaling is an
essential bile acid-responsive pathway that regulates many genes and physiologic processes involved in bile
acid metabolism. In preliminary studies, we demonstrated that the IRE1α/XBP1s pathway is regulated by the
FXR/SHP signaling pathway. Thus, we will define the regulatory mechanisms of FXR/SHP signaling on
the hepatic IRE1α/Xbp1s pathway (Specific Aim 2). Finally, FGF19 is an ileal hormone produced in
response to bile acids that regulates bile acid synthesis and other hepatic processes. Therefore, we will
characterize the regulation of the IRE1α/Xbp1 pathway by FGF19 signaling (Specific Aim 3). Our long-
term goal is to further develop a line of research characterizing the mechanisms by which the IRE1α/XBP1s
and other UPR signaling pathways reduce liver injury during cholestasis and other forms of liver disease. This
proposal utilizes state-of-the-art mouse genetics, molecular biology, proteomics and physiologic techniques to
further determine the protective role of the IRE1α/XBP1, FXR/SHP and FGF15/19 signaling pathways in bile
acid injury and cholestasis. These investigations may help identify novel regulatory mechanisms of bile acid
metabolism and IRE1α/XBP1 signaling that can be used to target new therapies for the treatment of
cholestatic liver disease and other hepatic disorders.

## Key facts

- **NIH application ID:** 9984338
- **Project number:** 5R01DK093807-08
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Richard M Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,500
- **Award type:** 5
- **Project period:** 2012-09-26 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984338

## Citation

> US National Institutes of Health, RePORTER application 9984338, Cholestasis and the Unfolded Protein Response (5R01DK093807-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984338. Licensed CC0.

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