Department of Food Science & Technology, College of Natural Resources and Life Science, Pusan National University, Miryang-Si, Gyeongsangnam-Do, 50463, Republic of Korea.
J Mol Med (Berl). 2024 Oct;102(10):1267-1284. doi: 10.1007/s00109-024-02480-2. Epub 2024 Aug 28.
Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice.
内质网（ER）应激通过增加从头脂肪生成导致肝脂肪变性。叉头框 O6（FoxO6）是一种转录因子，介导胰岛素信号转导至葡萄糖和脂质代谢。因此，失调的 FoxO6 参与肝脂肪生成。本研究阐明了 FoxO6 在体内和体外 ER 应激诱导的肝脂肪变性中的作用。在过表达组成型激活 FoxO6 等位基因的小鼠和 FoxO6 敲除小鼠中监测肝 ER 应激反应和β-氧化。对于体外研究，用高葡萄糖处理过表达组成型激活 FoxO6 和 FoxO6-siRNA 的肝细胞，并测量脂质代谢改变。ER 应激诱导的 FoxO6 激活抑制体内肝β-氧化。组成型激活 FoxO6 等位基因显著降低过氧化物酶体增殖物激活受体 α（PPARα）的表达和转录活性。相反，FoxO6-siRNA 和 FoxO6-KO 小鼠中抑制β-氧化基因的表达减少。我们的数据表明，FoxO6 诱导的肝脂质积累受胰岛素信号的负调控。高葡萄糖处理作为高血糖状态导致 ER 应激诱导基因的表达，而在肝细胞中 FoxO6 激活则恶化了这种情况。然而，高葡萄糖介导的 ER 应激通过 PPARα 和 FoxO6 之间的相互作用抑制β-氧化基因表达，这与体内研究的结果一致——脂质分解代谢也受 FoxO6 调节。此外，胰岛素抵抗通过 FoxO6 和 PPARα 之间的相互作用抑制 b-氧化促进肝脂肪变性，这由于高血糖诱导的 ER 应激，损害了胰岛素信号。关键信息：我们最初的目的是在分子水平上阐明 PPARα 和转录因子 FoxO6 通路的调节之间的相互关系与脂质代谢有关。高葡萄糖促进 FoxO6 激活诱导肝脂肪变性的证据。胰岛素信号转导中 PPARα 激活的作用。FoxO6 在 FoxO6 过表达小鼠中通过失活 PPARα 发挥关键作用，导致肝脂质积累。
