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.