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{"title":"Enhancement of post-receptor insulin signaling by trivalent chromium in hepatoma cells is associated with differential inhibition of specific protein-tyrosine phosphatases","authors":"Barry J. Goldstein, Li Zhu, Richard Hager, Assaf Zilbering, Yanjie Sun, John B. Vincent","doi":"10.1002/jtra.1050","DOIUrl":null,"url":null,"abstract":"<p>Various molecular forms of chromium have been implicated in the regulation of glucose metabolism, and chromium deficiency can be associated with insulin resistance and impaired glucose tolerance. Protein-tyrosine phosphatases (PTPases), which negatively regulate signaling through the insulin receptor, are potential targets of chromium action, since this transition metal may inhibit catalysis at the thiol-dependent active sites of these enzymes. Treatment of cultured rat hepatoma cells with 0.1 mM CrCl<sub>3</sub> for 16 h increased the insulin-stimulated tyrosine phosphorylation of high M<sub>r</sub> insulin receptor substrate (IRS) proteins by 49% to 7.3-fold over basal (n = 7; <i>P</i>= 0.03), without altering basal insulin receptor or IRS tyrosine phosphorylation or insulin-stimulated receptor autophosphorylation, suggesting a post-receptor effect of chromium on signal transduction. PTPase activity in cell extracts of CrCl<sub>3</sub>-treated hepatoma cells before or after insulin stimulation was unchanged, indicating that if chromium acted via cellular PTPases, the effect was reversible and limited to the in vivo state. Chromium (Cr<sup>+3</sup>) ion and two organic derivatives, an oligopeptide chromium complex from bovine liver (Cr-pep), and a synthetic multinuclear complex of chromium with carboxylate ligands (Sm-Cr) were also tested for their direct in vitro inhibition of the enzymatic activity of LAR and PTP1B, two structurally variant PTPases that have been implicated in regulation of the insulin signaling pathway. PTP1B (rat and human) was strongly inhibited by CrCl<sub>3</sub> to 21–33% of control (n = 4–6; <i>P</i>< 0.001). In contrast, LAR activity was actually enhanced by CrCl<sub>3</sub> to 47% above the control value (n = 12; <i>P</i>< 0.001). The Cr-pep and Sm-Cr complexes had no effect on PTP1B and LAR activity at the tested concentrations using the <i>p</i>NPP assay. These data suggest that the metabolic effects of chromium may be mediated by inhibition of PTP1B, a PTPase that negatively modulates insulin signaling, consistent with other recent studies implicating PTP1B in the regulation of the dephosphorylation of post-insulin receptor substrate proteins. J. Trace Elem. Exp. Med. 14:393–404, 2001. © 2001 Wiley-Liss, Inc.</p>","PeriodicalId":101243,"journal":{"name":"The Journal of Trace Elements in Experimental Medicine","volume":"14 4","pages":"393-404"},"PeriodicalIF":0.0000,"publicationDate":"2001-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jtra.1050","citationCount":"25","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Trace Elements in Experimental Medicine","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jtra.1050","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
Various molecular forms of chromium have been implicated in the regulation of glucose metabolism, and chromium deficiency can be associated with insulin resistance and impaired glucose tolerance. Protein-tyrosine phosphatases (PTPases), which negatively regulate signaling through the insulin receptor, are potential targets of chromium action, since this transition metal may inhibit catalysis at the thiol-dependent active sites of these enzymes. Treatment of cultured rat hepatoma cells with 0.1 mM CrCl3 for 16 h increased the insulin-stimulated tyrosine phosphorylation of high Mr insulin receptor substrate (IRS) proteins by 49% to 7.3-fold over basal (n = 7; P = 0.03), without altering basal insulin receptor or IRS tyrosine phosphorylation or insulin-stimulated receptor autophosphorylation, suggesting a post-receptor effect of chromium on signal transduction. PTPase activity in cell extracts of CrCl3 -treated hepatoma cells before or after insulin stimulation was unchanged, indicating that if chromium acted via cellular PTPases, the effect was reversible and limited to the in vivo state. Chromium (Cr+3 ) ion and two organic derivatives, an oligopeptide chromium complex from bovine liver (Cr-pep), and a synthetic multinuclear complex of chromium with carboxylate ligands (Sm-Cr) were also tested for their direct in vitro inhibition of the enzymatic activity of LAR and PTP1B, two structurally variant PTPases that have been implicated in regulation of the insulin signaling pathway. PTP1B (rat and human) was strongly inhibited by CrCl3 to 21–33% of control (n = 4–6; P < 0.001). In contrast, LAR activity was actually enhanced by CrCl3 to 47% above the control value (n = 12; P < 0.001). The Cr-pep and Sm-Cr complexes had no effect on PTP1B and LAR activity at the tested concentrations using the p NPP assay. These data suggest that the metabolic effects of chromium may be mediated by inhibition of PTP1B, a PTPase that negatively modulates insulin signaling, consistent with other recent studies implicating PTP1B in the regulation of the dephosphorylation of post-insulin receptor substrate proteins. J. Trace Elem. Exp. Med. 14:393–404, 2001. © 2001 Wiley-Liss, Inc.
肝癌细胞中三价铬受体后胰岛素信号的增强与特异性蛋白酪氨酸磷酸酶的差异抑制有关
铬的各种分子形式都与葡萄糖代谢的调节有关,铬缺乏可能与胰岛素抵抗和葡萄糖耐量受损有关。蛋白酪氨酸磷酸酶(PTPases)通过胰岛素受体负调控信号,是铬作用的潜在靶标,因为这种过渡金属可能抑制这些酶的硫醇依赖活性位点的催化作用。用0.1 mM CrCl3处理培养的大鼠肝癌细胞16小时后,胰岛素刺激的高Mr胰岛素受体底物(IRS)蛋白酪氨酸磷酸化增加了49%至7.3倍(n = 7;P= 0.03),没有改变基础胰岛素受体或IRS酪氨酸磷酸化或胰岛素刺激受体自磷酸化,提示铬对信号转导的受体后效应。胰岛素刺激前后,crcl3处理的肝癌细胞提取物中PTPase活性不变,表明如果铬通过细胞PTPase起作用,则其作用是可逆的,并且仅限于体内状态。铬(Cr+3)离子和两种有机衍生物,来自牛肝脏的寡肽铬配合物(Cr-pep)和铬与羧酸配体的合成多核配合物(Sm-Cr)也测试了它们对LAR和PTP1B酶活性的直接体外抑制,这两种结构变异的ptpase参与胰岛素信号通路的调节。CrCl3强烈抑制PTP1B(大鼠和人)至对照组的21-33% (n = 4-6;术中;0.001)。相比之下,CrCl3实际上提高了LAR活性,比对照值高出47% (n = 12;术中;0.001)。在pNPP检测浓度下,Cr-pep和Sm-Cr复合物对PTP1B和LAR活性没有影响。这些数据表明,铬的代谢作用可能是通过抑制PTP1B介导的,PTP1B是一种负性调节胰岛素信号的ptp酶,这与近期其他研究表明PTP1B参与胰岛素受体后底物蛋白去磷酸化的调节一致。J. Trace Elem。中华医学杂志,2001,14(2):393 - 404。©2001 Wiley-Liss, Inc。
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