Effects of apolipoprotein E on regulating insulin sensitivity via regulating insulin receptor signalosome in caveolae.

Although impaired insulin signaling at a post-receptor level was a well-established key driver of insulin resistance, the role of surface abnormal insulin receptor (INSR) location in insulin resistance pathogenesis tended to be ignored and its molecular mechanisms remained obscure. Herein, this study aimed to investigate hepatic apolipoprotein E (APOE) impaired cellular insulin action via reducing cell surface INSR, especially in caveolae. Downregulation of APOE enhanced the caveolae translocation of INSR and glucose transporter 2 (GLUT2), and improved hepatic cells' sensitivity to insulin. Consistently, mice with selective suppression of liver tissue APOE showed lower fasting insulin and fasting glucose levels, better homeostatic model assessment (HOMA) index (HOMA-IS, HOMA-IR, HOMA- β) and quantitative insulin sensitivity check index (QUICKI). Furthermore, the co-localization of INSR and CAV1 in the liver of these mice were more substantial than controls. APOE might adversely set the basal gain of INSR signaling implied that APOE could be a new endogenous INSR regulator. [Display omitted] • Apolipoprotein E was indeed involved in the regulation of insulin signaling. • Down-regulation of apolipoprotein E enhanced insulin signaling on glucose metabolism. • Insulin-sensitizing effect of apolipoprotein E downregulation might be traced to the enhanced caveolae INSR activation. • Knockout of hepatic apolipoprotein E in mice reduced in vivo GSIS due to improved insulin sensitivity and HOMA index. • The co-localization between INSR and CAV1 was more evident in the apolipoprotein E KO mice. [ABSTRACT FROM AUTHOR]