Forkhead box protein O1 (FoxO1) knockdown accelerates the eicosapentaenoic acid (EPA)-mediated <i>Selenop</i> downregulation independently of sterol regulatory element-binding protein-1c (SREBP-1c) in H4IIEC3 hepatocytes

Abstract

Selenoprotein P is upregulated in type 2 diabetes, causing insulin and exercise resistance. We have previously reported that eicosapentaenoic acid (EPA) negatively regulates Selenop expression by suppressing Srebf1 in H4IIEC3 hepatocytes. However, EPA downregulated Srebf1 long before downregulating Selenop. Here, we report additional novel mechanisms for the Selenop gene regulation by EPA. EPA upregulated Foxo1 mRNA expression, which was canceled with the ERK1/2 inhibitor, but not with the PKA inhibitor. Foxo1 knockdown by siRNA initiated early suppression of Selenop, but not Srebf1, by EPA. However, EPA did not affect the nuclear translocation of the FoxO1 protein. Neither ERK1/2 nor PKA inhibitor affected FoxO1 nuclear translocation. In summary, FoxO1 knockdown accelerates the EPA-mediated Selenop downregulation independent of SREBP-1c in hepatocytes. EPA upregulates Foxo1 mRNA via the ERK1/2 pathway without altering its protein and nuclear translocation. These findings suggest redundant and conflicting transcriptional networks in the lipid-induced redox regulation.

Lipoteichoic acid restrains macrophage senescence via β‐catenin/FOXO1/REDD1 pathway in age‐related osteoporosis

“…The expression of FOXO1 was significantly decreased in the liver (Tomobe et al, 2013) and aorta (Zhu et al, 2021) Interestingly, no significant alteration of FOXO1 mRNA level was observed in the process (Figure 2e). We hypothesized that the changes of FOXO1 protein level were due to post-translational modifications, including phosphorylation and dephosphorylation (Kamoshita et al, 2022). The transcriptional function of FOXO1 is regulated by phosphorylation, and the nuclear localization of dephosphorylated FOXO1 is a key step in stimulating the downstream target gene transcription (Zhang et al, 2021).…”