# Elucidating the role of ATF6α as a critical pro-fibrogenic transcription factor in Hepatic Stellate Cells

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $118,875

## Abstract

Cirrhosis is a global health crisis that develops in response to chronic liver injury. Liver injury activates Hepatic
Stellate Cells (HSCs) which differentiate into fibrogenic myofibroblasts. Fibrogenic HSCs produce and secrete
vast amounts of matrix proteins that deposit into the extracellular space leading to fibrosis, and if unchecked,
cirrhosis. While fibrosis is reversible upon removal of injurious stimuli, no therapies effectively promote fibrosis
regression. Production of matrix proteins by fibrogenic HSCs leads to excess proteins in the endoplasmic
reticulum (ER), placing stress on the ER. ER stress initiates the Unfolded Protein Response (UPR), a signaling
cascade allowing HSCs to adapt to increased protein load and facilitate efficient protein folding and secretion.
If ER stress is unresolved, UPR signaling switches from adaptive to pro-apoptotic. We propose that targeting
mechanisms facilitating HSC adaptation to ER stress would promote HSC apoptosis and limit
fibrogenesis, leading to fibrosis regression in vivo. Preliminary data shows that Activating Transcription
Factor 6α (ATF6α), a transcription factor and effector of the UPR, is crucial for HSC activation and survival in
vitro and fibrogenesis in vivo; however, the mechanisms underlying this role are unknown. RNAseq performed
on ATF6αΔ/Δ HSCs isolated from mice following 4 weeks of CCl4 injection revealed dysregulation of genes
involved in ossificaiton, protein degradation, apoptotic signaling, chromatin remodeling, and cellular response
to starvation compared to HSCs isolated from WT mice. We hypothesize that ATF6α activates
profibrogenic transcriptional programs to promote adaption of fibrogenic HSCs to ER stress and HSC
survival. Aim 1 will investigate the role of the ATF6α-regulated genes involved in ossification identified by our
RNAseq on HSCs isolated from mice with CCl4-induced fibrosis. We will additionally use RNAseq/ATACseq to
understand the short-term transcriptional impact of ATF6α deletion in HSCs. These analyses will reveal
ATF6α-dependent changes in the transcriptional and chromatin landscapes that drive fibrogenesis. Aim 2 will
study how ATF6α promotes HSC survival through ER-phagy: selective autophagic degradation of the ER. ER-
phagy is critical for secretory cell survival but its role in HSCs and fibrogenesis is unknown. We show that ER-
phagic flux increases in activated HSCs. Furthermore, ER-phagy receptors are upregulated in cirrhotic livers
and activated HSCs, and this upregulation is ATF6α-dependent. Aim 2 will study how ER-phagy maintains ER
function and promotes HSC survival to drive fibrogenesis, how ATF6α promotes ER-phagic flux in activated
HSCs, and the mechanisms by which key ER-phagy receptors target unfolded and misfolded proteins for
degradation. Together, the proposed studies will establish ATF6α as a key profibrotic transcription
factor in HSCs, provide insight into fibrogenic transcription regulated by ATF6α during fibrogenesis,
and identify a...

## Key facts

- **NIH application ID:** 10526974
- **Project number:** 1R03DK129326-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jessica L Maiers
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $118,875
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526974

## Citation

> US National Institutes of Health, RePORTER application 10526974, Elucidating the role of ATF6α as a critical pro-fibrogenic transcription factor in Hepatic Stellate Cells (1R03DK129326-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10526974. Licensed CC0.

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