Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress

Abdelali Agouni, Nimesh Mody, Carl Owen, Alicja Czopek, Derek Zimmer, Mohamed Bentires-Alj, Kendra K Bence, Mirela Delibegović

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)369-78
Number of pages10
JournalBiochemical Journal
Issue number2
Publication statusPublished - 1 Sept 2011

Keywords / Materials (for Non-textual outputs)

  • Activating Transcription Factor 6
  • Animals
  • Cell Nucleus
  • Class Ia Phosphatidylinositol 3-Kinase
  • DNA-Binding Proteins
  • Endoplasmic Reticulum
  • Endoribonucleases
  • Eukaryotic Initiation Factor-2
  • Gene Deletion
  • Gene Knockdown Techniques
  • Glucose
  • Hep G2 Cells
  • Homeostasis
  • Humans
  • Lipid Metabolism
  • Liver
  • Mice
  • Obesity
  • Organ Specificity
  • Protein Transport
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger
  • Signal Transduction
  • Stress, Physiological
  • Thapsigargin
  • Transcription Factors
  • Tunicamycin


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