Insulin resistance disrupts the interaction between AKT and the NMDA receptor and the inactivation of the CaMKIV/CREB pathway in minimal hepatic encephalopathy

Abstract

Hepatic cirrhosis-induced Minimal hepatic encephalopathy (MHE) has been characterized for cognitive dysfunction and central nervous system (CNS) insulin resistance (IR) has been acknowledged to be closely correlated with cognitive impairment while hepatic cirrhosis has been recognized to induce IR. Thus, this study aimed to investigate whether CNS IR occurred in MHE and induced MHE, as well as the underlying mechanism. We found IR in the MHE rats, an especially decreased level of the insulin receptor (InsR), and an increased serine phosphorylation of IRS1 in CNS. PI3K/AKT pathway signaling to the phosphorylation of N-Methyl-D-Aspartate receptors (NMDA receptors, NRs, NR1/NR2B) and downstream activation of the CaMKIV/CREB pathway and final production of neurotrophic factors were triggered by insulin, but impaired in the MHE rats. Additionally, CNS IR, memory impairment, the desensitization of the PI3K/AKT/NMDA receptor (NR)/CaMKIV/CREB pathway and decreased production of BDNF/NT3 in MHE rats were improved by rosiglitazone (RSG). These results suggested that IR, which induces the deficits in the insulin-mediated PI3K/AKT/NR/CaMKIV/CREB/ neurotrophin pathway and subsequent memory decline, contributes to the pathogenesis of MHE.