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 language | English |
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Pages (from-to) | 369-78 |
Number of pages | 10 |
Journal | Biochemical Journal |
Volume | 438 |
Issue number | 2 |
DOIs | |
Publication status | Published - 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