Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress.
Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress.
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DOI：
10.1042/bj20110373
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发表时间：
2011-09-01
期刊：
影响因子：
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通讯作者：
Delibegović M
中科院分区：
文献类型：
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作者：
Agouni A;Mody N;Owen C;Czopek A;Zimmer D;Bentires-Alj M;Bence KK;Delibegović M
肥胖与内质网(ER)应激反应信号的诱导和胰岛素抵抗有关。蛋白酪氨酸磷酸酶(PTP)-1B是肥胖和胰岛素敏感性的主要调节因子。本研究的目的是在体外和体内研究肝脏PTP1B在慢性(高脂饮食)和药物诱导(衣霉素、thapsigargin)ER应激反应信号中的作用。我们评估了内质网应激反应诱导对肝脏PTP1B表达的影响，以及在细胞和小鼠肝脏中肝PTP1B缺陷对内质网应激反应信号成分的影响。我们发现，在体外和体内，PTP1B蛋白和mRNA的表达水平随着急性和/或慢性内质网应激的反应而上调。在肝细胞系或小鼠肝脏中沉默PTP1B(L-PTP1B−/−)可防止药物和/或肥胖诱导的内质网应激。与对照组相比，高脂饮食诱导的−/−小鼠CHOP和BIP mRNA水平的升高被部分抑制，而ATF4、Gadd34、GRP94、ERDJ4mRNAs和ATF6蛋白的切割被完全抑制。L-PTP1B−/−小鼠还通过增加p85α结合增加了剪接XBP-1的核转位。我们证明，在肥胖和药物诱导的ER应激中，ER应激反应和肝脏PTP1B的表达是相互关联的，这可能是L-PTP1B−/−小鼠改善胰岛素敏感性和降低脂质积累的机制之一。
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 p85α 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.