Sortilin-induced lipid accumulation and atherogenesis are suppressed by HNF1b SUMOylation promoted by flavone of Polygonatum odoratum / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

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.

The rs4430796 SNP of the HNF1ß gene associates with type 2 diabetes in older adults

SUMMARY INTRODUCTION: The impact of type 2 diabetes mellitus raises interest in understanding its evolutionary-genetic basis, to unveil yet unknown pathways that may have immediate medical relevance. The HNF1β gene (hepatocyte nuclear factor-1 beta) is a transcription factor expressed in tissues such as liver, kidney, genital tract and pancreas that is known to be essential for insulin secretion and glucose balance. We tested the association of allelic variants produced by the HNF1β gene (rs4430796) variation with the clinical and biochemical profile of elderly Brazilian outpatients with metabolic disorders. MATERIAL AND METHODS: Anthropometry, blood pressure, glycaemia, lipemia and other parameters were assessed in 184 Brazilians aged 60 or older in clinical care settings. Alleles were determined by amplification of the polymorphic site by real time polymerase chain reaction. RESULTS: Analysing variables across the genotypes, a statistically significant difference was noticed in the allele frequencies among diabetic patients, with 30.8% of the A homozygous bearing the condition compared to a prevalence of 12.2% between G homozygotes. CONCLUSION: Our results corroborate the possible protective property of the GG genotype from the rs4430796 variation (already presented in the literature) against occurrence of diabetes mellitus, which appears applicable to elderly individuals as well, even in the context of multiple metabolic disorders so typical in older Brazilians.