Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.
Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.
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作者：
Delibegovic M;Zimmer D;Kauffman C;Rak K;Hong EG;Cho YR;Kim JK;Kahn BB;Neel BG;Bence KK
蛋白酪氨酸磷酸酶PTP1B是胰岛素信号传导的负调节剂;因此，PTP1B缺陷的小鼠对胰岛素过敏。由于PTP1B −/−小鼠的脂肪储存减少，PTP1B直接调节葡萄糖稳态的程度尚不清楚。之前，我们发现脑特异性PTP1B −/−小鼠可以防止高脂饮食诱导的肥胖和葡萄糖耐受不良，而肌肉特异性PTP1B −/−小鼠的胰岛素敏感性增加与肥胖的变化无关。在这里，我们研究了肝脏PTP1B在葡萄糖稳态和脂质代谢中的作用。研究设计和方法-我们分析了肝脏特异性PTP1B −/−和PTP1Bfl/fl对照小鼠的体重/肥胖、胰岛素敏感性、葡萄糖耐量和脂质代谢，这些小鼠喂食普通饲料或高脂饲料。与正常同窝出生的小鼠相比，肝脏特异性PTP1B −/−小鼠表现出改善的葡萄糖稳态和脂质谱，与肥胖的变化无关。肝脏特异性PTP1B −/−小鼠增加了肝脏胰岛素信号传导，降低了致炎基因PEPCK和G-6-β的表达，增强了胰岛素诱导的肝脏葡萄糖生成抑制，并改善了葡萄糖耐量。肝脏特异性PTP1B −/−小鼠表现出降低的甘油三酯和胆固醇水平以及脂肪生成基因SREBP、FAS和ACC的表达减少。肝脏特异性PTP1B缺失还在体内保护免受高脂饮食诱导的内质网应激反应，如p38 MAPK、JNK、PERK、和eIF2 α的表达以及转录因子C/EBP同源蛋白和剪接的X盒结合蛋白1的表达降低。结论-肝脏PTP1B在葡萄糖和脂质代谢中起重要作用，与肥胖的改变无关。抑制外周组织中的PTP1B可能有助于治疗代谢综合征和降低除糖尿病外的心血管风险。
OBJECTIVE—The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B are hypersensitive to insulin. Because PTP1B−/− mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously, we showed that brain-specific PTP1B−/− mice are protected against high-fat diet–induced obesity and glucose intolerance, whereas muscle-specific PTP1B−/− mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose homeostasis and lipid metabolism. RESEARCH DESIGN AND METHODS—We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B−/− and PTP1Bfl/fl control mice, fed a chow or high-fat diet. RESULTS—Compared with normal littermates, liver-specific PTP1B−/− mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B−/− mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B−/− mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and ACC. Liver-specific PTP1B deletion also protects against high-fat diet–induced endoplasmic reticulum stress response in vivo, as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2α and lower expression of the transcription factors C/EBP homologous protein and spliced X box-binding protein 1. CONCLUSIONS—Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in addition to diabetes.