| Autor: |
Liu F; Guangxi Key Laboratory of Diabetic Systems Medicine & Institute of Basic Medical Sciences, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541199, China., Chen S; Guangxi Key Laboratory of Diabetic Systems Medicine & Institute of Basic Medical Sciences, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541199, China., Ming X; Guangxi Key Laboratory of Diabetic Systems Medicine & Institute of Basic Medical Sciences, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541199, China., Li H; Guangxi Key Laboratory of Diabetic Systems Medicine & Institute of Basic Medical Sciences, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541199, China., Zeng Z; Hunan Mingshun Pharmaceutical Co., Ltd., Shaodong 422800, China. anthony0723@163.com, zzhg88@163.com., Lv Y; Guangxi Key Laboratory of Diabetic Systems Medicine & Institute of Basic Medical Sciences, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541199, China. anthony0723@163.com. |
| Abstrakt: |
This study aims to investigate the impact of hepatocyte nuclear factor 1β (HNF1b) on macrophage sortilin-mediated lipid metabolism and aortic atherosclerosis and explore the role of the flavone of Polygonatum odoratum (PAOA-flavone)-promoted small ubiquitin-related modifier (SUMO) modification in the atheroprotective efficacy of HNF1b. HNF1b was predicted to be a transcriptional regulator of sortilin expression via bioinformatics, dual-luciferase reporter gene assay, and chromatin immunoprecipitation. HNF1b overexpression decreased sortilin expression and cellular lipid contents in THP-1 macrophages, leading to a depression in atherosclerotic plaque formation in low-density lipoprotein (LDL) receptor-deficient (LDLR -/- ) mice. Multiple SUMO1-modified sites were identified on the HNF1b protein and co-immunoprecipitation confirmed its SUMO1 modification. The SUMOylation of HNF1b protein enhanced the HNF1b-inhibited effect on sortilin expression and reduced lipid contents in macrophages. PAOA-flavone treatment promoted SUMO-activating enzyme subunit 1 (SAE1) expression and SAE1-catalyzed SUMOylation of the HNF1b protein, which prevented sortilin-mediated lipid accumulation in macrophages and the formation of atherosclerotic plaques in apolipoprotein E-deficient (ApoE -/- ) mice. Interference with SAE1 abrogated the improvement in lipid metabolism in macrophage cells and atheroprotective efficacy in vivo upon PAOA-flavone administration. In summary, HNF1b transcriptionally suppressed sortilin expression and macrophage lipid accumulation to inhibit aortic lipid deposition and the development of atherosclerosis. This anti-atherosclerotic effect was enhanced by PAOA-flavone-facilitated, SAE1-catalyzed SUMOylation of the HNF1b protein. |
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