title: Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress.
abstract: 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.
authors: Institute of Biological and Environmental Sciences, College of Life Sciences and Medicine, University of Aberdeen, UK.
authors: Abdelali
authors: A
authors: Agouni
authors: Nimesh
authors: N
authors: Mody
authors: Carl
authors: C
authors: Owen
authors: Alicja
authors: A
authors: Czopek
authors: Derek
authors: D
authors: Zimmer
authors: Mohamed
authors: M
authors: Bentires-Alj
authors: Kendra K
authors: KK
authors: Bence
authors: Mirela
authors: M
authors: Delibegović
references: Dev Cell. 2002 Apr;2(4):497-503
references: 11970899
references: J Biochem. 2004 Jul;136(1):89-96
references: 15269244
references: J Biol Chem. 2003 Oct 31;278(44):43095-101
references: 12941932
references: Mol Cell Endocrinol. 2009 Aug 13;307(1-2):89-98
references: 19524131
references: Science. 1999 Mar 5;283(5407):1544-8
references: 10066179
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Biochim Biophys Acta. 2005 Dec 30;1754(1-2):108-17
references: 16198645
references: Science. 2004 Oct 15;306(5695):457-61
references: 15486293
references: Mol Cell Endocrinol. 2003 May 30;203(1-2):155-68
references: 12782412
references: Nat Rev Drug Discov. 2002 Sep;1(9):696-709
references: 12209150
references: Nature. 2006 Dec 14;444(7121):860-7
references: 17167474
references: Nature. 2009 Jul 23;460(7254):534-7
references: 19543265
references: J Biol Chem. 2011 Mar 18;286(11):9225-35
references: 21216966
references: Dev Cell. 2008 Dec;15(6):795-6
references: 19081067
references: Biochem Biophys Res Commun. 2007 Nov 23;363(3):626-32
references: 17897622
references: Nature. 2008 Jul 24;454(7203):455-62
references: 18650916
references: J Biol Chem. 2004 Nov 26;279(48):49689-93
references: 15465829
references: J Biol Chem. 2005 Apr 8;280(14):14189-202
references: 15684420
references: Science. 2006 Aug 25;313(5790):1137-40
references: 16931765
references: Mol Cell Biol. 2000 Aug;20(15):5479-89
references: 10891488
references: Dev Cell. 2003 Feb;4(2):265-71
references: 12586069
references: Cell Metab. 2008 Jun;7(6):520-32
references: 18522833
references: J Biol Chem. 2010 Feb 26;285(9):6198-207
references: 19996103
references: Trends Biochem Sci. 2010 Aug;35(8):442-9
references: 20381358
references: Mol Cell Biol. 2003 Nov;23(21):7448-59
references: 14559994
references: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G852-8
references: 16603729
references: Mol Cell. 2003 Mar;11(3):619-33
references: 12667446
references: Dev Cell. 2007 Sep;13(3):351-64
references: 17765679
references: Mol Cell. 2000 Nov;6(5):1099-108
references: 11106749
references: Antioxid Redox Signal. 2007 Dec;9(12):2277-93
references: 17979528
references: Dev Cell. 2002 Apr;2(4):489-95
references: 11970898
references: J Clin Metab Diabetes. 2010 May;1(1):27-33
references: 21533018
references: Dev Cell. 2007 Sep;13(3):365-76
references: 17765680
references: Nat Med. 2010 Apr;16(4):438-45
references: 20348923
references: Nat Med. 2006 Aug;12(8):917-24
references: 16845389
references: Cell. 1992 Feb 7;68(3):545-60
references: 1739967
references: Diabetes. 2009 Mar;58(3):590-9
references: 19074988
references: J Biochem. 2009 Dec;146(6):743-50
references: 19861400
references: Mol Cell Biol. 2007 Nov;27(21):7727-34
references: 17724080
references: J Biol Chem. 2008 May 23;283(21):14230-41
references: 18281274
references: J Biol Chem. 2005 Oct 7;280(40):33917-25
references: 16107336
references: Biochem Biophys Res Commun. 2010 May 28;396(2):467-71
references: 20417620
references: Mol Biol Cell. 1999 Nov;10(11):3787-99
references: 10564271
references: J Lipid Res. 2007 Sep;48(9):1905-14
references: 17699733
references: Nat Med. 2010 Apr;16(4):429-37
references: 20348926
references: J Clin Invest. 2009 May;119(5):1201-15
references: 19363290
references: Nature. 2002 Jan 3;415(6867):92-6
references: 11780124
references: Diabetes. 2010 Jan;59(1):6-16
references: 19808896