The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease (original) (raw)

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Department of Pharmacology and Toxicology

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Southwest Environmental Health Sciences Center, College of Pharmacy, University of Arizona

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Tucson, Arizona 85721

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Biology Centre ASCR, Institute of Plant Molecular Biology

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Ceske Budejovice 37001

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Czech Republic

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Department of Pharmacology and Toxicology

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Department of Pharmacology and Toxicology

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Department of Pharmacology and Toxicology

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Department of Pharmacology and Toxicology

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Southwest Environmental Health Sciences Center, College of Pharmacy, University of Arizona

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Tucson, Arizona 85721

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Department of Pharmacology and Toxicology

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Southwest Environmental Health Sciences Center, College of Pharmacy, University of Arizona

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Tucson, Arizona 85721

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1To whom correspondence should be addressed at Department of Pharmacology and Toxicology, University of Arizona, 1703 East Mabel Street, PO Box 210207, Tucson, AZ 85721. Fax:

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Accepted:

24 September 2013

Published:

04 October 2013

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April D. Lake, Petr Novak, Rhiannon N. Hardwick, Brieanna Flores-Keown, Fei Zhao, Walter T. Klimecki, Nathan J. Cherrington, The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease, Toxicological Sciences, Volume 137, Issue 1, January 2014, Pages 26–35, https://doi.org/10.1093/toxsci/kft230
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Abstract

Nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to severe, nonalcoholic steatohepatitis (NASH) in 7%–14% of the U.S. population through a second “hit” in the form of increased oxidative stress and inflammation. Endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR) are triggered when high levels of lipids and misfolded proteins alter ER homeostasis creating a lipotoxic environment within NAFLD livers. The objective of this study was to determine the coordinate regulation of ER stress–associated genes in the progressive stages of human NAFLD. Human liver samples categorized as normal, steatosis, NASH (Fatty), and NASH (Not Fatty) were analyzed by individual Affymetrix GeneChip Human 1.0 ST microarrays, immunoblots, and immunohistochemistry. A gene set enrichment analysis was performed on autophagy, apoptosis, lipogenesis, and ER stress/UPR gene categories. An enrichment of downregulated genes in the ER stress–associated lipogenesis and ER stress/UPR gene categories was observed in NASH. Conversely, an enrichment of upregulated ER stress–associated genes for autophagy and apoptosis gene categories was observed in NASH. Protein expression of the adaptive liver response protein STC2 and the transcription factor X-box binding protein 1 spliced (XBP-1s) were significantly elevated among NASH samples, whereas other downstream ER stress proteins including CHOP, ATF4, and phosphorylated JNK and eIF2α were not significantly changed in disease progression. Increased nuclear accumulation of total XBP-1 protein was observed in steatosis and NASH livers. The findings reveal the presence of a coordinated, adaptive transcriptional response to hepatic ER stress in human NAFLD.

© The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Topic:

• apoptosis
• signal transduction
• transcription, genetic
• immunohistochemistry
• inflammation
• stress response
• autophagy
• endoplasmic reticulum
• genes
• heat-shock proteins
• lipids
• liver
• stress
• transcription factor
• steatohepatitis, non-alcoholic
• non-alcoholic fatty liver disease
• cyclophosphamide, doxorubicin, prednisone, and vincristine
• lipogenesis
• unfolded protein response
• fatty degeneration
• x-box binding protein 1

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