Obesity is associated with induction of endoplasmic reticulum (ER)-stress response signalling and insulin resistance. Protein tyrosine phosphatase (PTP)-1B is a major regulator of adiposity and insulin sensitivity. The aim of this study was to investigate the role of liver-PTP1B in chronically- (high-fat diet) and pharmacologically-induced (tunicamycin, 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- and/or obesity-induced ER-stress. High-fat diet-induced increase in CHOP and BIP mRNA levels were partially inhibited, whereas ATF4, GADD34, GRP94, ERDJ4 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 via increased p85a binding. We demonstrate that the ER-stress response and liver-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.
- endoplasmic reticulum (ER) stress
- insulin resistance
- metabolic syndrome
- protein tyrosine phosphatase 1B (PTP1B)
Agouni, A., Mody, N., Owen, C., Czopek, A., Zimmer, D., Bentirez-Alj, M., Bence, K. K., & Delibegovic, M. (2011). Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochemical Journal, 438(2), 369-378. https://doi.org/10.1042/BJ20110373