Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase.
Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702 and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment. Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver.
['Liu|Jinghui|J|', 'Xu|Chun|C|', 'Zhang|Shaofeng|S|', 'Li|Haoyan|H|', 'Chen|Kele|K|', 'Huang|Pu|P|', 'Guo|Zonglou|Z|', 'Xu|Lihong|L|']
D000818:Animals D002460:Cell Line D051273:Glucose Transporter Type 2 D006006:Glycogen Synthase D006801:Humans D007328:Insulin D055504:Insulin Receptor Substrate Proteins D008099:Liver D008387:Marine Toxins D051379:Mice D008813:Mice, Inbred ICR D052998:Microcystins D010766:Phosphorylation D015398:Signal Transduction
microcystin-LR insulin receptor substrate 1 glycogen synthase S6K1