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 Bentirez-Alj, K. K. Bence, Mirela Delibegovic

Research output: Contribution to journalArticle

83 Citations (Scopus)
6 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)369-378
Number of pages10
JournalBiochemical Journal
Volume438
Issue number2
Early online date24 May 2011
DOIs
Publication statusPublished - 2011

Keywords

  • endoplasmic reticulum (ER) stress
  • insulin resistance
  • metabolic syndrome
  • obesity
  • protein tyrosine phosphatase 1B (PTP1B)

Fingerprint Dive into the research topics of 'Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress'. Together they form a unique fingerprint.

  • Cite this