Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HN...Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.展开更多
目的探讨跨膜蛋白4超级家族5（transmembrane 4 superfamily member 5,TM4SF5）基因多态性、栽脂蛋白E（ApoE）基因多态性和阿尔茨海默病（AD）的相关性。方法通过使用TaqMan—PCR法检测单核苷酸多态性（SNP）方法，在376例日本人AD患...目的探讨跨膜蛋白4超级家族5（transmembrane 4 superfamily member 5,TM4SF5）基因多态性、栽脂蛋白E（ApoE）基因多态性和阿尔茨海默病（AD）的相关性。方法通过使用TaqMan—PCR法检测单核苷酸多态性（SNP）方法，在376例日本人AD患者，包括323例迟发型AD（I。OAD）、53例早发型AD（EOAD）和377例非痴呆对照组中观察TM4SF5基因rs4790230（-791T／C）、rs746988（＋1528T／c）、rs2302328（＋11228c／A）及APOE基因的多态性分布，并分析与AD的相关性。结果（1）TM4SF5基因rs4790230（-791T／C）c／c纯合子频率在EOAD中明显高于对照组（0．70比0．52，P值为0．017）；rs2302328（＋11228C／A）携带A等位基因者频率在总AD中略高于对照组（0．88比0．84，P值为0．05）；（2）进一步在非APOE4携带者中分析显示rs4790230（-791T／C）c／c纯合子频率在EOAD中仍明显高于对照组（0．85比0．53，P〈0．001）；（3）单倍型分析显示病例组C—C—A型与C—T—A型频率分别高于时照组（0．29比0．21；0．35比0．16；P〈0．001）；病例组C—T—C型频率低于对照组（0．12比0．28；P〈0．001）。结论TM4SF5基因rs4790230（-791T／C）多态位点独立于APOE与EOAD存在相关性，三位点单倍型C—C—A型与C—T—A型增加了AD的发病风险。展开更多
文摘Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
文摘目的探讨跨膜蛋白4超级家族5（transmembrane 4 superfamily member 5,TM4SF5）基因多态性、栽脂蛋白E（ApoE）基因多态性和阿尔茨海默病（AD）的相关性。方法通过使用TaqMan—PCR法检测单核苷酸多态性（SNP）方法，在376例日本人AD患者，包括323例迟发型AD（I。OAD）、53例早发型AD（EOAD）和377例非痴呆对照组中观察TM4SF5基因rs4790230（-791T／C）、rs746988（＋1528T／c）、rs2302328（＋11228c／A）及APOE基因的多态性分布，并分析与AD的相关性。结果（1）TM4SF5基因rs4790230（-791T／C）c／c纯合子频率在EOAD中明显高于对照组（0．70比0．52，P值为0．017）；rs2302328（＋11228C／A）携带A等位基因者频率在总AD中略高于对照组（0．88比0．84，P值为0．05）；（2）进一步在非APOE4携带者中分析显示rs4790230（-791T／C）c／c纯合子频率在EOAD中仍明显高于对照组（0．85比0．53，P〈0．001）；（3）单倍型分析显示病例组C—C—A型与C—T—A型频率分别高于时照组（0．29比0．21；0．35比0．16；P〈0．001）；病例组C—T—C型频率低于对照组（0．12比0．28；P〈0．001）。结论TM4SF5基因rs4790230（-791T／C）多态位点独立于APOE与EOAD存在相关性，三位点单倍型C—C—A型与C—T—A型增加了AD的发病风险。
