Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes.
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.
Feng
Feng
F
Signal Transduction Laboratory, Centenary Institute, Locked Bag 6, Newtown, New South Wales 2042, Australia.
Wang
Lijun
L
Albanese
Nathaniel
N
Holmes
Andrew
A
Xia
Pu
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D004305:Dose-Response Relationship, Drug; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D016328:NF-kappa B / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D000074049:Cytokine TWEAK; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; D048069:Tumor Necrosis Factors; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)