FIG 10.

Model for the regulation of liver glucose and lipid homeostasis in the presence (left) or the absence (right) of Grb14. (Left) Grb14 binds to the activated insulin receptor, inhibiting its catalytic activity, and to p62. Hepatic glucose production (HGP) is regulated by the transcription factor FoxO1, which is phosphorylated and inactivated by Akt in an insulin-dependent manner. Lipogenesis is controlled by the transcription factor SREBP-1c, which is regulated at the transcriptional level by LXR, and at the transcriptional and the posttranslational levels by insulin through the Akt-mTORC1 pathway. Under basal physiological conditions, Nrf2 is degraded by the proteasome and is expressed at a low level. (Right) Grb14 depletion enhances insulin signaling, improving insulin-dependent inhibition of hepatic glucose production. The increased p62 availability upon liver Grb14 depletion combined with the phosphorylation of p62 by the activated mTORC1 stabilized Nrf2, leading to the repression of LXR activity and blocking SREBP-1c and lipogenic gene expression.