1. Interaction of FOXO1 and SUMOylated PPARγ1 induced by hyperlipidemia and hyperglycemia favors vascular endothelial insulin resistance and dysfunction.
- Author
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Kong, Ying, Niu, Ailin, Yuan, Wanwan, Zhou, Yumeng, Xia, Min, Xiong, Xiaowei, Lu, Yanli, Yin, Tingting, Zhang, Yanan, Chen, Sheng, Huang, Qianqian, Zeng, Guohua, and Huang, Qiren
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INSULIN resistance , *HYPERGLYCEMIA , *PI3K/AKT pathway , *INSULIN sensitivity , *ENDOTHELIUM diseases , *HYPERLIPIDEMIA - Abstract
PPARγ1 and FOXO1 are the key transcription factors that regulate insulin sensitivity. We previously found that a small ubiquitin-related modifier of PPARγ1 at K77 (SUMOylation) favored endothelial insulin resistance (IR) induced by high fat/high glucose (HF/HG) administration. However, whether and how the crosstalk between SUMOylated PPARγ1 and FOXO1 would mediate the development of the endothelial IR and dysfunction remains unclear. Here, we emphasize how PPARγ1-K77 SUMOylation would interact with FOXO1 and participate in the development of the endothelial IR and dysfunction. Our results show that the combination of HF/HG and PPARγ1-K77 SUMOylation exhibits a synergistic deteriorative effect on the endothelial IR and dysfunction, presenting decreased NO levels and elevated ET-1 levels, weakened PI3K/Akt/eNOS signaling, and impaired endothelium-dependent vasodilation function. The further researches reveal that PPARγ1-K77 SUMOylation readily interacts with FOXO1, and FOXO1 occupies the PPAR response element (PPRE) which is supposed to be occupied by PPARγ, thus resulting in the decrease of PPARγ1 transcription activity and the mitigation of the PI3K/Akt signaling. Moreover, the mitigation of the PI3K/Akt signaling promotes in turn the accumulation of FOXO1 in the nucleus where FOXO1 interacts with the SUMOylated PPARγ1, thus exerting a positive feedback effect on IR pathogenesis. The findings uncover a novel association between PPARγ1-K77 SUMOylation and FOXO1, which contributes to our understanding of the pathogenesis of endothelial IR and dysfunction and provides novel pharmacological targets for diabetic angiopathy. [Display omitted] • PPARγ1-K77 SUMOylation combined with HF/HG exhibits a synergistic deteriorative effect on the endothelial IR and dysfunction. • PPARγ1-K77 SUMOylation impairs rats endothelium-dependent vasodilation. • FOXO1 blocks the PPRE binding site on PI3K and represses the PPARγ transcription activity via PPARγ1-K77 SUMOylation. • PPARγ1-K77 SUMOylation causes FOXO1 nuclear accumulation by negatively regulating FOXO1 phosphorylation via PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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