# Elucidating the Role and Regulation of Proteostasis in Hepatic Fibrogenesis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $445,621

## Abstract

Liver cirrhosis is a major health crisis caused by chronic liver injury. Liver injury leads to fibrosis which impairs
liver function and can progress to cirrhosis and end-stage liver disease if unchecked. Fibrosis can reverse with
removal of the injury; however, no therapeutics effectively targeted fibrosis. The major fibrogenic cells in the liver
are hepatic stellate cells (HSCs), which produce and secrete matrix proteins into the extracellular space to drive
fibrogenesis. Production of matrix proteins in fibrogenic HSCs exceeds the folding capacity of the endoplasmic
reticulum (ER), leading to ER stress and induction of the Unfolded Protein Response (UPR). The UPR propa-
gates signaling cascades to increase protein folding demands, restore proteostasis, and promote cell survival
(adaptive UPR); however prolonged ER stress leads to apoptosis. We propose that targeting the adaptive
UPR in HSCs is an effective anti-fibrotic strategy, through disrupting proteostasis, promting apoptosis,
and limiting fibrogenesis. A major effector of the adaptive UPR is ATF6α. We found that ATF6α is necessary
and sufficient to promote HSC activation in vitro, and HSC-specific loss of ATF6α limited fibrogenesis in vivo;
however, the pro-fibrotic mechanisms downstream of ATF6α are unclear. To gain insight into these mechanisms,
we performed RNAseq on HSCs isolated from fibrotic Atf6aHSCΔ/Δ mice, revealing disruption of several pathways
compared to Atf6afl/fl HSCs, including pathways crucial for maintaining proteostasis through autophagy, protein
secretion, and cell survival. We hypothesize that ATF6α drives fibrogenesis through regulating proteosta-
sis in fibrogenic HSCs. Based on RNAseq as well as proteomics data from patient derived HSCs, this proposal
will focus on how ATF6α regulates proteostasis to drive fibrogenesis through three distinct mechanisms: protein
degradation, regulation of pro-survival signals, and protein trafficking. Degrading misfolded proteins is crucial for
relieving ER stress. Misfolded proteins in the ER can undergo ER-to-lysosomal associated degradation (ER-
LAD), with ERLAD receptors targeting misfolded proteins for lysosomal degradation. ERLAD activity and ERLAD
receptors increased in fibrogenic HSCs in an ATF6α-dependent manner. Aim 1 will study how ATF6α regulates
ERLAD to reduce ER stress and promote HSC survival and fibrogenesis. Second, ATF6α is crucial for survival
of secretory cells, and we show that ATF6α induces expression of GADD45A, a protein which binds to and
regulates several kinases. We show that GADD45A loss limits HSC activation in vitro, thus Aim 2 will study how
ATF6α regulates GADD45A expression and association with pro-survival kinases to promote HSC survival and
fibrogenesis in vitro and in vivo. Finally, we identified a potential role for ATF6α in procollagen I secretion through
SORT1. Aim 3 will utilize a combination of in vitro mechanistic studies, proteomics, and in vivo studies to reveal
how ATF6α regulation of S...

## Key facts

- **NIH application ID:** 10866564
- **Project number:** 5R01DK136812-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jessica L Maiers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,621
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866564

## Citation

> US National Institutes of Health, RePORTER application 10866564, Elucidating the Role and Regulation of Proteostasis in Hepatic Fibrogenesis (5R01DK136812-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866564. Licensed CC0.

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