Obesity is associated with induction of the ER (endoplasmic reticulum)-stress response signalling and insulin resistance. PTP1B (protein tyrosine phosphatase 1B) is a major regulator of adiposity and insulin sensitivity. The aim of the present study was to investigate the role of L-PTP1B (liver-specific PTP1B) in chronically HFD (high-fat diet) and pharmacologically induced (tunicamycin and thapsigargin) ER-stress response signalling in vitro and in vivo. We assessed the effects of ER-stress response induction on hepatic PTP1B expression, and consequences of hepatic-PTP1B deficiency, in cells and mouse liver, on components of ER-stress response signalling. We found that PTP1B protein and mRNA expression levels were up-regulated in response to acute and/or chronic ER stress, in vitro and in vivo. Silencing PTP1B in hepatic cell lines or mouse liver (L-PTP1B−/−) protected against induction of pharmacologically induced and/or obesity-induced ER stress. The HFD-induced increase in CHOP (CCAAT/enhancer-binding protein homologous protein) and BIP (binding immunoglobulin protein) mRNA levels were partially inhibited, whereas ATF4 (activated transcription factor 4), GADD34 (growth-arrest and DNA-damage-inducible protein 34), GRP94 (glucose-regulated protein 94), ERDJ4 (ER-localized DnaJ homologue) mRNAs and ATF6 protein cleavage were completely suppressed in L-PTP1B−/− mice relative to control littermates. L-PTP1B−/− mice also had increased nuclear translocation of spliced XBP-1 (X box-binding protein-1) via increased p85α binding. We demonstrate that the ER-stress response and L-PTP1B expression are interlinked in obesity- and pharmacologically induced ER stress and this may be one of the mechanisms behind improved insulin sensitivity and lower lipid accumulation in L-PTP1B−/− mice.
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Research Article|
August 12 2011
Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress
Abdelali Agouni;
Abdelali Agouni
*Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB25 2ZD, U.K.
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Nimesh Mody;
Nimesh Mody
*Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB25 2ZD, U.K.
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Carl Owen;
Carl Owen
*Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB25 2ZD, U.K.
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Alicja Czopek;
Alicja Czopek
*Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB25 2ZD, U.K.
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Derek Zimmer;
Derek Zimmer
†Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Mohamed Bentires-Alj;
Mohamed Bentires-Alj
‡Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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Kendra K. Bence;
Kendra K. Bence
†Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Mirela Delibegović
Mirela Delibegović
1
*Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen AB25 2ZD, U.K.
1To whom correspondence should be addressed (email m.delibegovic@abdn.ac.uk).
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Publisher: Portland Press Ltd
Received:
February 28 2011
Revision Received:
May 13 2011
Accepted:
May 24 2011
Accepted Manuscript online:
May 24 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (2): 369–378.
Article history
Received:
February 28 2011
Revision Received:
May 13 2011
Accepted:
May 24 2011
Accepted Manuscript online:
May 24 2011
Citation
Abdelali Agouni, Nimesh Mody, Carl Owen, Alicja Czopek, Derek Zimmer, Mohamed Bentires-Alj, Kendra K. Bence, Mirela Delibegović; Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem J 1 September 2011; 438 (2): 369–378. doi: https://doi.org/10.1042/BJ20110373
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