Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.

Détails

ID Serval
serval:BIB_5B7F02BC9E6A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.
Périodique
Clinical Science
Auteur(s)
Legry V., Van Rooyen D.M., Lambert B., Sempoux C., Poekes L., Español-Suñer R., Molendi-Coste O., Horsmans Y., Farrell G.C., Leclercq I.A.
ISSN
1470-8736 (Electronic)
ISSN-L
0143-5221
Statut éditorial
Publié
Date de publication
2014
Peer-reviewed
Oui
Volume
127
Numéro
7
Pages
507-518
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Blood Glucose, DNA-Binding Proteins/genetics, Diet, High-Fat, Endoplasmic Reticulum Stress, Fatty Liver/metabolism, Fatty Liver/pathology, Female, Insulin Resistance, Male, Mice, Mice, Inbred NOD, Mice, Obese, Non-alcoholic Fatty Liver Disease, Phenotype
Pubmed
Web of science
Création de la notice
16/01/2015 13:14
Dernière modification de la notice
20/08/2019 15:14
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