Tags

Type your tag names separated by a space and hit enter

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.
Clin Sci (Lond). 2014 Oct; 127(7):507-18.CS

Abstract

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.

Authors+Show Affiliations

*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.†Liver Research Group, ANU Medical School at the Canberra Hospital, Garran, ACT, Australia.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.‡Pathology Department, St-Luc University Hospital, Université catholique de Louvain, Brussels, Belgium.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.†Liver Research Group, ANU Medical School at the Canberra Hospital, Garran, ACT, Australia.*Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24766485

Citation

Legry, Vanessa, et al. "Endoplasmic Reticulum Stress Does Not Contribute to Steatohepatitis in Obese and Insulin-resistant High-fat-diet-fed Foz/foz Mice." Clinical Science (London, England : 1979), vol. 127, no. 7, 2014, pp. 507-18.
Legry V, Van Rooyen DM, Lambert B, et al. Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. Clin Sci (Lond). 2014;127(7):507-18.
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. (2014). Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. Clinical Science (London, England : 1979), 127(7), 507-18. https://doi.org/10.1042/CS20140026
Legry V, et al. Endoplasmic Reticulum Stress Does Not Contribute to Steatohepatitis in Obese and Insulin-resistant High-fat-diet-fed Foz/foz Mice. Clin Sci (Lond). 2014;127(7):507-18. PubMed PMID: 24766485.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. AU - Legry,Vanessa, AU - Van Rooyen,Derrick M, AU - Lambert,Barbara, AU - Sempoux,Christine, AU - Poekes,Laurence, AU - Español-Suñer,Regina, AU - Molendi-Coste,Olivier, AU - Horsmans,Yves, AU - Farrell,Geoffrey C, AU - Leclercq,Isabelle A, PY - 2014/4/29/entrez PY - 2014/4/29/pubmed PY - 2014/10/1/medline SP - 507 EP - 18 JF - Clinical science (London, England : 1979) JO - Clin Sci (Lond) VL - 127 IS - 7 N2 - 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. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/24766485/Endoplasmic_reticulum_stress_does_not_contribute_to_steatohepatitis_in_obese_and_insulin_resistant_high_fat_diet_fed_foz/foz_mice_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20140026 DB - PRIME DP - Unbound Medicine ER -