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

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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

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Endoplasmic Reticulum Stress
Liver
Obesity
Insulin
Nutrition
Messenger RNA
Fats
Insulin Resistance
Tunicamycin
Thapsigargin
High Fat Diet
Proteins
Lipids
Adiposity
Hepatocytes
Cell Line

Keywords

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

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Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. / Agouni, Abdelali; Mody, Nimesh; Owen, Carl; Czopek, Alicja; Zimmer, Derek; Bentirez-Alj, Mohamed; Bence, K. K.; Delibegovic, Mirela.

In: Biochemical Journal, Vol. 438, No. 2, 2011, p. 369-378.

Research output: Contribution to journalArticle

Agouni, Abdelali ; Mody, Nimesh ; Owen, Carl ; Czopek, Alicja ; Zimmer, Derek ; Bentirez-Alj, Mohamed ; Bence, K. K. ; Delibegovic, Mirela. / Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. In: Biochemical Journal. 2011 ; Vol. 438, No. 2. pp. 369-378.
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AU - Czopek, Alicja

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AU - Bentirez-Alj, Mohamed

AU - Bence, K. K.

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KW - insulin resistance

KW - metabolic syndrome

KW - obesity

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