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

Abstract

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.

• Authors: Fang Liu, Shirui Chen, Xinyue Ming, Huijuan Li, Zhaoming Zeng, Yuncheng Lv
• Journal: Journal of Zhejiang University. Science. B (J Zhejiang Univ Sci B) Vol. 24 Issue 11 Pg. 998-1013 (Nov 15 2023) ISSN: 1862-1783 [Electronic] China
• Vernacular Title: 玉竹黄酮通过促进HNF1b蛋白的SUMO化修饰抑制sortilin介导的脂质积累及动脉粥样硬化.
• PMID: 37961802 (Publication Type: Journal Article)

Chemical References

• sortilin
• Hepatocyte Nuclear Factor 1-beta
• Flavones
• Lipids

Topics

• Mice
• Animals
• Polygonatum (metabolism)
• Sumoylation
• Hepatocyte Nuclear Factor 1-beta (genetics, metabolism)
• Atherosclerosis (drug therapy, metabolism)
• Flavones
• Lipids