# The Unfolded Protein Response in Fatty Liver

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $405,498

## Abstract

Project Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the
United States and is a major cause of cirrhosis, hepatocellular carcinoma and death. Although fatty liver
disease is associated with the metabolic syndrome, the pathogenesis remains poorly understood. In the
liver, the fidelity for protein folding is imperfect, and therefore excess misfolded or unfolded proteins may
accumulate, a condition termed ER stress. The Unfolded Protein Response (UPR) is a protective signaling
response present in all eukaryotic cells, and human and animal studies indicate that the UPR is important in
NAFLD and its progressive sub-type of non-alcoholic steatohepatitis (NASH). However, the role and
mechanisms of UPR signaling in the pathogenesis of NASH remains poorly understood. The UPR consists
of three pathways that are activated by the ER proteins IRE1α, PERK and ATF6. These proteins serve both
as sensors of ER stress and activators of their signaling pathways. In the canonical adaptive IRE1α
pathway, activated p-IRE1α splices XBP1 into the active transcription factor XBP1s, which then activates
protective downstream target genes. More recent data indicates that IRE1α has a major role in cell fate
determination, with both the adaptive XBP1 pathway, and apoptotic Regulated Ire1α-Dependent Decay
(RIDD) and TRAF2 pathways. In addition, IRE1α interacts with the UPR pathway involved with
eIF2α/ATF4/CHOP signaling and other cellular stress signaling pathways. Although dysregulation of liver
IRE1α and e-IF2α pathways have been associated with human NASH, the causative and mechanistic role
of IRE1α in the pathogenesis of steatohepatitis remain poorly understood. The long-term goals of these
studies are to enhance our understanding of the role of UPR signaling in the pathogenesis and progression
of NASH. The objectives of this grant proposal are to further define the role of hepatic IRE1α adaptive and
apoptotic signaling in the pathogenesis of non-alcoholic steatohepatitis. We have previously demonstrated
that when fed a high fat diet, mice with hepatocyte-specific deletion of Xbp1 have increased susceptibility to
develop NASH. We now propose three Specific Aims to further investigate the role of IRE1α signaling in the
pathogenesis of steatohepatitis: to determine that enhanced hepatic IRE1α signaling increases the
susceptibility to develop steatohepatitis using liver-specific XBP1(-/-) and liver-specific IRE1α(-/-) mice fed high
fat diets (Aim 1); to delineate the regulation of apoptosis by hepatic IRE1α via the TRAF2, eIF2α and RIDD
pathways (Aim 2); and to utilize liver-specific cell cultures and cultured hepatocytes to determine the role of
IRE1α signaling in cell fate determination during hepatocyte lipotoxicity (Aim 3). By better understanding
this IRE1α-mediated adaptive and apoptotic signaling in the liver, it may be possible to shift the balance of
cell fate determination away from apoptosis and tow...

## Key facts

- **NIH application ID:** 10375371
- **Project number:** 5R01DK121997-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Richard M Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,498
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375371

## Citation

> US National Institutes of Health, RePORTER application 10375371, The Unfolded Protein Response in Fatty Liver (5R01DK121997-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375371. Licensed CC0.

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