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Background <p>Obesity and associated metabolic disorders remain major public health challenges worldwide. The regulation of lipid synthesis represents a promising therapeutic target, yet the precise mechanisms remain elusive.</p> Methods <p>RT-qPCR and western blot measured gene expression. Lipid droplets were evaluated by Nile Red staining. TC, HDL-C, LDL-C, TG and NEFA levels were detected by ELISA kits. The interaction between proteins or genes was analyzed by ChIP, Dual-luciferase reporter, and Co-IP assays. Subcellular localization was analyzed by nuclear/cytoplasmic fractionation and immunofluorescence.</p> Results <p>FOXO4 was downregulated after bariatric surgery and directly decreased the transcription of lipogenic enzymes ACACA and HMGCR. Nuclear localization of FOXO4 was regulated by a previously uncharacterized interplay between O-GlcNAcylation and phosphorylation. Specifically, O-GlcNAcylation at S261 promoted FOXO4 nuclear translocation and enhanced lipogenic gene expression, while PKCβII-mediated phosphorylation at T451 antagonized this modification. Functionally, FOXO4 deletion suppressed lipid synthesis under HFD conditions. OGA or PKCβII knockdown promoted lipid synthesis by regulating FOXO4.</p> Conclusion <p>Elevated OGA inhibited FOXO4’s nuclear translocation via O-GlcNAcylation, and subsequent PKCβII-mediated phosphorylation-induced degradation. This process decreased ACACA and HMGCR expression, thereby attenuating lipid synthesis.</p>

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PKCβ II antagonizes O-GlcNAcylated FOXO4 and inhibits lipid synthesis

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Hua Fu,
  • Yuqin Li,
  • Pengzhou Li,
  • Liyong Zhu,
  • Shaihong Zhu,
  • Guohui Wang

摘要

Background

Obesity and associated metabolic disorders remain major public health challenges worldwide. The regulation of lipid synthesis represents a promising therapeutic target, yet the precise mechanisms remain elusive.

Methods

RT-qPCR and western blot measured gene expression. Lipid droplets were evaluated by Nile Red staining. TC, HDL-C, LDL-C, TG and NEFA levels were detected by ELISA kits. The interaction between proteins or genes was analyzed by ChIP, Dual-luciferase reporter, and Co-IP assays. Subcellular localization was analyzed by nuclear/cytoplasmic fractionation and immunofluorescence.

Results

FOXO4 was downregulated after bariatric surgery and directly decreased the transcription of lipogenic enzymes ACACA and HMGCR. Nuclear localization of FOXO4 was regulated by a previously uncharacterized interplay between O-GlcNAcylation and phosphorylation. Specifically, O-GlcNAcylation at S261 promoted FOXO4 nuclear translocation and enhanced lipogenic gene expression, while PKCβII-mediated phosphorylation at T451 antagonized this modification. Functionally, FOXO4 deletion suppressed lipid synthesis under HFD conditions. OGA or PKCβII knockdown promoted lipid synthesis by regulating FOXO4.

Conclusion

Elevated OGA inhibited FOXO4’s nuclear translocation via O-GlcNAcylation, and subsequent PKCβII-mediated phosphorylation-induced degradation. This process decreased ACACA and HMGCR expression, thereby attenuating lipid synthesis.