Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes Export

@article{Feng:2008p819, abstract = {TNF-like weak inducer of apoptosis (TWEAK), a relatively new member of the TNF superfamily, is an important immune/inflammatory regulator that has different functional properties from that of other members of this superfamily. We report herein that TWEAK induces cellular insulin resistance in both human hepatocellular carcinoma cell lines (Huh7 and HepG2) and primary rat hepatocytes by inhibiting both early insulin receptor (IR) signaling events and the downstream actions of insulin. TWEAK profoundly inhibited insulin-induced Akt phosphorylation in both a concentration- and time-dependent manner. This inhibitory effect occurred via mechanisms that involved the TWEAK receptor Fn14 and the activation of the canonical and noncanonical nuclear factor-kappaB signaling pathways. Furthermore, TWEAK significantly inhibited IRbeta autophosphorylation and IR substrate-1 activation, with concomitant increases in serine phosphorylation of IR substrate-1. Moreover, insulin-induced reduction of gluconeogenic enzyme gene expression and increases in glycogen synthesis in hepatocytes were significantly attenuated by TWEAK treatment. Therefore, these findings not only reveal a novel pathophysiological function of TWEAK/Fn14 but also uncover a new player that may contribute to the development of cellular insulin resistance in hepatocytes.}, author = {Feng, Feng and Wang, Lijun and Albanese, Nathaniel and Holmes, Andrew and Xia, Pu}, citeulike-article-id = {3046190}, citeulike-linkout-0 = {http://endo.endojournals.org/cgi/content/full/149/4/1505}, citeulike-linkout-1 = {http://dx.doi.org/10.1210/en.2007-1119}, doi = {10.1210/en.2007-1119}, journal = {Endocrinology}, keywords = {adaptor, b, c-akt, carboxykinase, cell, dose-response, drug, factor, factors, file-import-08-07-27, glucose-6-phosphatase, gtp, hepatocytes, humans, insulin, line, necrosis, nf-kappa, phosphoenolpyruvate, phosphorylation, proteins, proto-oncogene, receptor, receptors, relationship, resistance, signal, transducing, tumor}, local-url = {file://localhost/Users/ken/Documents/Papers/2008/Feng/Endocrinology\%202008\%20Feng.pdf}, month = {Apr}, number = {4}, pages = {1505--13}, posted-at = {2008-07-27 14:46:03}, priority = {2}, title = {Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes}, url = {http://dx.doi.org/10.1210/en.2007-1119}, volume = {149}, year = {2008} }

TY - JOUR ID - Feng:2008p819 L3 - citeulike-article-id:3046190 N2 - TNF-like weak inducer of apoptosis (TWEAK), a relatively new member of the TNF superfamily, is an important immune/inflammatory regulator that has different functional properties from that of other members of this superfamily. We report herein that TWEAK induces cellular insulin resistance in both human hepatocellular carcinoma cell lines (Huh7 and HepG2) and primary rat hepatocytes by inhibiting both early insulin receptor (IR) signaling events and the downstream actions of insulin. TWEAK profoundly inhibited insulin-induced Akt phosphorylation in both a concentration- and time-dependent manner. This inhibitory effect occurred via mechanisms that involved the TWEAK receptor Fn14 and the activation of the canonical and noncanonical nuclear factor-kappaB signaling pathways. Furthermore, TWEAK significantly inhibited IRbeta autophosphorylation and IR substrate-1 activation, with concomitant increases in serine phosphorylation of IR substrate-1. Moreover, insulin-induced reduction of gluconeogenic enzyme gene expression and increases in glycogen synthesis in hepatocytes were significantly attenuated by TWEAK treatment. Therefore, these findings not only reveal a novel pathophysiological function of TWEAK/Fn14 but also uncover a new player that may contribute to the development of cellular insulin resistance in hepatocytes. IS - 4 JF - Endocrinology EP - 13 TI - Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes VL - 149 SP - 1505 KW - adaptor KW - b KW - c-akt KW - carboxykinase KW - cell KW - dose-response KW - drug KW - factor KW - factors KW - file-import-08-07-27 KW - glucose-6-phosphatase KW - gtp KW - hepatocytes KW - humans KW - insulin KW - line KW - necrosis KW - nf-kappa KW - phosphoenolpyruvate KW - phosphorylation KW - proteins KW - proto-oncogene KW - receptor KW - receptors KW - relationship KW - resistance KW - signal KW - transducing KW - tumor AU - Feng, Feng AU - Wang, Lijun AU - Albanese, Nathaniel AU - Holmes, Andrew AU - Xia, Pu PY - 2008/Apr// UR - http://dx.doi.org/10.1210/en.2007-1119 ER -