Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes

Anit Shah; Ian Huck; Kaylia Duncan; Erica R. Gansemer; Kaihua Liu; Reed C. Adajar; Udayan Apte; Mark A. Stamnes; D. Thomas Rutkowski

doi:10.1097/HC9.0000000000000278

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Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes

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Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes

Anit Shah, Ian Huck, Kaylia Duncan, Erica R. Gansemer, Kaihua Liu, Reed C. Adajar, Udayan Apte, Mark A. Stamnes and D. Thomas Rutkowski

Hepatology communications, Vol.7(11), e0278

11/01/2023

DOI: 10.1097/HC9.0000000000000278

PMCID: PMC10578741

PMID: 37820274

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Abstract

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.

Details

Title: Subtitle: Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes
Creators: Anit Shah - University of Iowa
Ian Huck - University of Kansas Medical Center
Kaylia Duncan - University of Iowa
Erica R. Gansemer - University of Iowa
Kaihua Liu - University of Iowa
Reed C. Adajar - University of Iowa
Udayan Apte - University of Kansas Medical Center
Mark A. Stamnes - University of Iowa
D. Thomas Rutkowski - University of Iowa
Resource Type: Journal article
Publication Details: Hepatology communications, Vol.7(11), e0278
DOI: 10.1097/HC9.0000000000000278
PMID: 37820274
PMCID: PMC10578741
NLM abbreviation: Hepatol Commun
ISSN: 2471-254X
eISSN: 2471-254X
Language: English
Date published: 11/01/2023
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984482557702771

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