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Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes
BACKGROUND: In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet, ER stress in the liver is uniquely accompanied by the suppression of metabolic gene...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578741/ https://www.ncbi.nlm.nih.gov/pubmed/37820274 http://dx.doi.org/10.1097/HC9.0000000000000278 |
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author | Shah, Anit Huck, Ian Duncan, Kaylia Gansemer, Erica R. Liu, Kaihua Adajar, Reed C. Apte, Udayan Stamnes, Mark A. Rutkowski, D. Thomas |
author_facet | Shah, Anit Huck, Ian Duncan, Kaylia Gansemer, Erica R. Liu, Kaihua Adajar, Reed C. Apte, Udayan Stamnes, Mark A. Rutkowski, D. Thomas |
author_sort | Shah, Anit |
collection | PubMed |
description | BACKGROUND: In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet, ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which are largely unknown. METHODS: Here, we combined in silico machine learning, in vivo liver-specific deletion of the master regulator of hepatocyte differentiation HNF4α, and in vitro manipulation of hepatocyte differentiation state to determine how the UPR regulates hepatocyte identity and toward what end. RESULTS: Machine learning identified a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. CONCLUSIONS: Together, our findings suggest that the UPR regulates hepatocyte identity through HNF4α to protect ER homeostasis even at the expense of liver function. |
format | Online Article Text |
id | pubmed-10578741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-105787412023-10-17 Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes Shah, Anit Huck, Ian Duncan, Kaylia Gansemer, Erica R. Liu, Kaihua Adajar, Reed C. Apte, Udayan Stamnes, Mark A. Rutkowski, D. Thomas Hepatol Commun Original Article BACKGROUND: In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet, ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which are largely unknown. METHODS: Here, we combined in silico machine learning, in vivo liver-specific deletion of the master regulator of hepatocyte differentiation HNF4α, and in vitro manipulation of hepatocyte differentiation state to determine how the UPR regulates hepatocyte identity and toward what end. RESULTS: Machine learning identified a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. CONCLUSIONS: Together, our findings suggest that the UPR regulates hepatocyte identity through HNF4α to protect ER homeostasis even at the expense of liver function. Lippincott Williams & Wilkins 2023-10-12 /pmc/articles/PMC10578741/ /pubmed/37820274 http://dx.doi.org/10.1097/HC9.0000000000000278 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Article Shah, Anit Huck, Ian Duncan, Kaylia Gansemer, Erica R. Liu, Kaihua Adajar, Reed C. Apte, Udayan Stamnes, Mark A. Rutkowski, D. Thomas Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title | Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title_full | Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title_fullStr | Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title_full_unstemmed | Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title_short | Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
title_sort | interference with the hnf4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578741/ https://www.ncbi.nlm.nih.gov/pubmed/37820274 http://dx.doi.org/10.1097/HC9.0000000000000278 |
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