ER stress-mediated FoxO1 induces impaired insulin signaling and hepatic steatosis in aging process

Dysregulated forkhead box O1 (FoxO1) is involved in hepatic insulin resistance with aging in rat. It has been reported that endoplasmic reticulum (ER) stress causes de novo lipogenesis by increasing hepatic insulin resistance. However, the precise role of FoxO1 in the ERstress-inducedinsulinresistanceandhepaticlipogenesishas not been elucidated. We demonstrate that FoxO1 transcription factor regulates PPARγ-induced lipid accumulation under ER stress conditions in aged rat. We also investigated the effect of FoxO1 on lipid metabolism in aged liver. Here, we showed increased glucose tolerance and hepatic steatosis in aged liver. In addition, hepatic insulin signaling was increased and induced activation of FoxO1, which was negatively regulated by IRS/Akt. The protein level of PPARγ, a lipogenic transcription factor, was increased in aged liver. Therefore, we further investigated whether FoxO1 mediates PPARγ-induced hepatic steatosis by insulin signaling by ER stress in AC2F hepatocytes. Interestingly, FoxO1 adenovirus notably increased mRNA expression of genes related to lipogenesis. Furthermore, FoxO1 regulated binding of the PPARγ promoter and PPARγ transcriptional activity in AC2F hepatocytes, which might be mediated to induce hepatic steatosis in aging. We conclude that ER stress-mediated FoxO1 induces hepatic steatosis, in part, by PPARγ activation and thereby increasing lipogenic gene transcription.