Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy
Open accessAbstract
Background & aims Metabolic stress during liver injury enhances autophagy and provokes stellate cell activation, with secretion of scar matrix. Conditions that augment protein synthesis increase demands on the endoplasmic reticulum (ER) folding capacity and trigger the unfolded protein response (UPR) to cope with resulting ER stress. Generation of reactive oxygen species (ROS) is a common feature of hepatic fibrogenesis, and crosstalk between oxidant stress and ER stress has been proposed. The aim of our study was to determine the impact of oxidant and ER stress on stellate cell activation.Methods Oxidant stress was induced in hepatic stellate cells using H2O2 in culture or by ethanol feeding in vivo, and the UPR was analyzed. Because the branch of the UPR mainly affected was IREα, we blocked this pathway in stellate cells and analyzed the fibrogenic response, together with autophagy and downstream MAPK signaling. The Nrf2 antioxidant response was also evaluated in stellate cells under oxidant stress conditions.Results H2O2 treatment in culture or ethanol feeding in vivo increased the UPR based on splicing of XBP1 mRNA, which triggered autophagy. The Nrf2-mediated antioxidant response, as measured by qRT-PCR of its target genes was also induced under ER stress conditions. Conversely, blockade of the IRE1α pathway in stellate cells significantly decreased both their activation and autophagic activity in a p38 MAPK-dependent manner, leading to a reduced fibrogenic response.Conclusions These data implicate mechanisms underlying protein folding quality control in regulating the fibrogenic response in hepatic stellate cells.
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HSC activation requires energy and relies on autophagy to release fatty acids through hydrolysis of retinyl esters, linked to endoplasmic reticulum stress.
“In addition to generation of intermediary metabolites through glycolysis, lipolysis, and glutaminolysis, the cells rely on activation of autophagy to release fatty acids through hydrolysis of retinyl esters (183) linked to endoplasmic reticulum stress (184).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [184]
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- Authors
- Hernández-Gea, V., Hilscher, M., Rozenfeld, R., Lim, M. P., Nieto, N., Werner, S., Devi, L. A., & Friedman, S. L.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- ETH Zurich (CH)
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 59
- Issue
- 1
- Pages
- 98-104
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC3686909
- OpenAlex
- W1978014906
- Cited by
- 236
- References
- 46
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 14 · 2023: 15 · 2022: 16 · 2021: 28 · 2020: 23 · 2019: 21 · 2018: 25 · 2017: 18 · 2016: 15 · 2015: 22 · 2014: 14 · 2013: 9
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Alcohol Abuse and Alcoholism (K05AA018408, R01AA020709, P20AA017067, AA020709)
- National Institute on Drug Abuse (K05DA019521, R37DA008863)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK056621, R01DK056621, DK 56621)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- endoplasmic reticulum stress, hepatic stellate cells, liver fibrosis, autophagy, unfolded protein response, IRE1α, XBP1 splicing, Nrf2 antioxidant response, reactive oxygen species, oxidative stress, p38 MAPK signaling, ethanol feeding, hydrogen peroxide, protein folding quality control
- MeSH terms
- Regulatory Factor X Transcription Factors, X-Box Binding Protein 1, Animals, Antioxidants, Autophagy, Cell Line, DNA-Binding Proteins, Endoribonucleases, Liver Cirrhosis, Mice, Inbred C57BL, RNA Splicing, Transcription Factors, Protein Serine-Threonine Kinases, Oxidative Stress, MAP Kinase Signaling System, NF-E2-Related Factor 2, Mice, Hepatic Stellate Cells, Unfolded Protein Response, Endoplasmic Reticulum Stress
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