Sortilin-induced lipid accumulation and atherogenesis are suppressed by HNF1b SUMOylation promoted by flavone of Polygonatum odoratum  

作　　者：Fang LIU Shirui CHEN Xinyue MING Huijuan LI Zhaoming ZENG Yuncheng LV 

机构地区：[1]Guangxi Key Laboratory of Diabetic Systems Medicine&Institute of Basic Medical Sciences,Faculty of Basic Medical Sciences,Guilin Medical University,Guilin,541199,China [2]Hunan Mingshun Pharmaceutical Co.,Ltd.,Shaodong,422800,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2023年第11期998-1013,共16页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region,China (No.2019JJA140728);the Horizontal Cooperation Project with Hunan Mingshun Pharmaceutical Co.,Ltd. (No.2021GLHX02);the Guangxi Province Postgraduate Co-training Base for Cooperative Innovation in Basic Medicine of Guilin Medical University (No.Gui Xue Wei[2020]7).

摘　　要：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.

关 键 词：ATHEROSCLEROSIS Lipid accumulation Hepatocyte nuclear factor 1β(HNF1b) Flavone of Polygonatum odoratum SUMOYLATION 

分 类 号：R543.5[医药卫生—心血管疾病]