Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a ‘pathological’ response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.
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June 25 2014
Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice
Vanessa Legry;
Vanessa Legry
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Derrick M. Van Rooyen;
Derrick M. Van Rooyen
†Liver Research Group, ANU Medical School at the Canberra Hospital, Garran, ACT, Australia
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Barbara Lambert;
Barbara Lambert
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Christine Sempoux;
Christine Sempoux
‡Pathology Department, St-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium
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Laurence Poekes;
Laurence Poekes
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Regina Español-Suñer;
Regina Español-Suñer
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Olivier Molendi-Coste;
Olivier Molendi-Coste
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Yves Horsmans;
Yves Horsmans
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Geoffrey C. Farrell;
Geoffrey C. Farrell
†Liver Research Group, ANU Medical School at the Canberra Hospital, Garran, ACT, Australia
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Isabelle A. Leclercq
*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
Correspondence: Professor Isabelle A. Leclercq (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 07 2014
Revision Received:
April 17 2014
Accepted:
April 25 2014
Accepted Manuscript online:
April 25 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (7): 507–518.
Article history
Received:
January 07 2014
Revision Received:
April 17 2014
Accepted:
April 25 2014
Accepted Manuscript online:
April 25 2014
Citation
Vanessa Legry, Derrick M. Van Rooyen, Barbara Lambert, Christine Sempoux, Laurence Poekes, Regina Español-Suñer, Olivier Molendi-Coste, Yves Horsmans, Geoffrey C. Farrell, Isabelle A. Leclercq; Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. Clin Sci (Lond) 1 October 2014; 127 (7): 507–518. doi: https://doi.org/10.1042/CS20140026
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