Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were establi...Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.展开更多
AIMTo assess whether surrogate biomarkers of endotoxemia were correlated with the histological features of nonalcoholic fatty liver disease (NAFLD).METHODSOne hundred twenty-six NAFLD patients who had undergone percut...AIMTo assess whether surrogate biomarkers of endotoxemia were correlated with the histological features of nonalcoholic fatty liver disease (NAFLD).METHODSOne hundred twenty-six NAFLD patients who had undergone percutaneous liver biopsy were enrolled. Serum lipopolysaccharide (LPS)-binding protein (LBP) and anti-endotoxin core immunoglobulin G (EndoCab IgG) antibody concentrations at the time of liver biopsy were measured using the enzyme-linked immunosorbent assays to examine for relationships between biomarker levels and histological scores.RESULTSSerum LBP concentration was significantly increased in nonalcoholic steatohepatitis (NASH) patients as compared with nonalcoholic fatty liver (NAFL) subjects and was correlated with steatosis (r = 0.38, P < 0.0001) and ballooning scores (r = 0.23, P = 0.01), but not with the severity of lobular inflammation or fibrosis. Multivariate linear regression analysis revealed that LBP was associated with steatosis score and circulating C-reactive protein, aspartate aminotransferase, and fibrinogen levels. Serum EndoCab IgG concentration was comparable between NASH and NAFL patients. No meaningful correlations were detected between EndoCab IgG and histological findings.CONCLUSIONLBP/EndoCab IgG were not correlated with lobular inflammation or fibrosis. More accurate LPS biomarkers are required to stringently assess the contribution of endotoxemia to conventional NASH.展开更多
目的:检测杀菌性/通透性增加蛋白(BPI)和脂多糖结合蛋白(LBP)基因单个核苷酸多态性(SNP)的频率分布。方法:选择该院部分科室ICU病房并发全身性感染的患者112例,并以100名正常健康者为对照组,取外周血白细胞提取基因组DNA,用聚合酶链反应...目的:检测杀菌性/通透性增加蛋白(BPI)和脂多糖结合蛋白(LBP)基因单个核苷酸多态性(SNP)的频率分布。方法:选择该院部分科室ICU病房并发全身性感染的患者112例,并以100名正常健康者为对照组,取外周血白细胞提取基因组DNA,用聚合酶链反应-限制性内切酶长度多态性分析(RFLP-PCR)法检测BPI基因上Lys216G lu、PstⅠin intron 5和G545C、LBP基因上Cys98G ly和Leu436Pro共5个位点SNP。结果:全身性感染组BPI Lys216G lu G/G纯合子及G等位基因出现的频率明显高于对照组;死亡组BPI Lys216G lu G/G纯合子及G等位基因出现的频率也明显高于存活组。结论:BPI Lys216G lu SNP的差异可能是全身性感染患者易感原因之一。展开更多
Background:A specific feature of the autoimmune response in rheumatoid arthritis(RA)is the presence of anti-citrullinated protein antibodies(ACPAs)in patient sera.These antibodies can appear several years before disea...Background:A specific feature of the autoimmune response in rheumatoid arthritis(RA)is the presence of anti-citrullinated protein antibodies(ACPAs)in patient sera.These antibodies can appear several years before disease onset and are involved in the development of RA.Objective:We performed proteomic analysis by mass spectroscopy to identify novel citrullinated antigens and autoantibodies in RA patients.Methods:Polypeptides isolated from the sera of RA patients were identified by Orbitrap high-precision mass spectrometry and then citrulline-containing proteins were selected.The levels of ACPAs against these newly identified citrullinated autoantigens in sera of 100 RA patients and 50 healthy controls were determined by enzyme-linked immunosorbent assays.Results:A total of 135 proteins were identified in RA patients and the protein profile included 11 citrulline-containing antigens.Three of the 11 citrullinated proteins had been reported in previous studies.ACPAs against the novel citrullinated epitopes from these proteins were increased in sera from the RA patients compared with those from healthy controls.Autoantibodies against one of the citrullinated antigens,lipopolysaccharide-binding protein(LBP),was significantly increased in RA patients and associated with disease activities.The titer of anti-citrullinated LBP antibodies(anti-cLBP)was closely related to the infection incidence in RA patients.Conclusion:Serum protein analysis by high-precision proteomic technology is a feasible method to identify novel citrullinated epitopes in RA patients.Anti-cLBP antibodies are associated with disease severity and infection in RA patients.展开更多
基金supported by the National Natural Science Foundation of China(81971875,82300661)Natural Science Foundation of Anhui province(2308085QH246)+3 种基金Natural Science Foundation of the Anhui Higher Education Institutions(KJ2021A0205)Basic and Clinical Cooperative Research Program of Anhui Medical University(2019xkjT002,2019xkjT022,2022xkjT013)Talent Training Program,School of Basic Medical Sciences,Anhui Medical University(2022YPJH102)National College Students Innovation and Entrepreneurship Training Program of China(202210366024)。
文摘Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.
文摘AIMTo assess whether surrogate biomarkers of endotoxemia were correlated with the histological features of nonalcoholic fatty liver disease (NAFLD).METHODSOne hundred twenty-six NAFLD patients who had undergone percutaneous liver biopsy were enrolled. Serum lipopolysaccharide (LPS)-binding protein (LBP) and anti-endotoxin core immunoglobulin G (EndoCab IgG) antibody concentrations at the time of liver biopsy were measured using the enzyme-linked immunosorbent assays to examine for relationships between biomarker levels and histological scores.RESULTSSerum LBP concentration was significantly increased in nonalcoholic steatohepatitis (NASH) patients as compared with nonalcoholic fatty liver (NAFL) subjects and was correlated with steatosis (r = 0.38, P < 0.0001) and ballooning scores (r = 0.23, P = 0.01), but not with the severity of lobular inflammation or fibrosis. Multivariate linear regression analysis revealed that LBP was associated with steatosis score and circulating C-reactive protein, aspartate aminotransferase, and fibrinogen levels. Serum EndoCab IgG concentration was comparable between NASH and NAFL patients. No meaningful correlations were detected between EndoCab IgG and histological findings.CONCLUSIONLBP/EndoCab IgG were not correlated with lobular inflammation or fibrosis. More accurate LPS biomarkers are required to stringently assess the contribution of endotoxemia to conventional NASH.
文摘目的:检测杀菌性/通透性增加蛋白(BPI)和脂多糖结合蛋白(LBP)基因单个核苷酸多态性(SNP)的频率分布。方法:选择该院部分科室ICU病房并发全身性感染的患者112例,并以100名正常健康者为对照组,取外周血白细胞提取基因组DNA,用聚合酶链反应-限制性内切酶长度多态性分析(RFLP-PCR)法检测BPI基因上Lys216G lu、PstⅠin intron 5和G545C、LBP基因上Cys98G ly和Leu436Pro共5个位点SNP。结果:全身性感染组BPI Lys216G lu G/G纯合子及G等位基因出现的频率明显高于对照组;死亡组BPI Lys216G lu G/G纯合子及G等位基因出现的频率也明显高于存活组。结论:BPI Lys216G lu SNP的差异可能是全身性感染患者易感原因之一。
基金Peking University People's Hospital Research and Development Funds,Grant/Award Number:RDX2019-03National Natural Science Foundation of China,Grant/Award Numbers:81971520,U1903210,81671602Beijing Municipal Science and Technology Project,Grant/Award Numbers:Z191100006619112,Z191100006619110。
文摘Background:A specific feature of the autoimmune response in rheumatoid arthritis(RA)is the presence of anti-citrullinated protein antibodies(ACPAs)in patient sera.These antibodies can appear several years before disease onset and are involved in the development of RA.Objective:We performed proteomic analysis by mass spectroscopy to identify novel citrullinated antigens and autoantibodies in RA patients.Methods:Polypeptides isolated from the sera of RA patients were identified by Orbitrap high-precision mass spectrometry and then citrulline-containing proteins were selected.The levels of ACPAs against these newly identified citrullinated autoantigens in sera of 100 RA patients and 50 healthy controls were determined by enzyme-linked immunosorbent assays.Results:A total of 135 proteins were identified in RA patients and the protein profile included 11 citrulline-containing antigens.Three of the 11 citrullinated proteins had been reported in previous studies.ACPAs against the novel citrullinated epitopes from these proteins were increased in sera from the RA patients compared with those from healthy controls.Autoantibodies against one of the citrullinated antigens,lipopolysaccharide-binding protein(LBP),was significantly increased in RA patients and associated with disease activities.The titer of anti-citrullinated LBP antibodies(anti-cLBP)was closely related to the infection incidence in RA patients.Conclusion:Serum protein analysis by high-precision proteomic technology is a feasible method to identify novel citrullinated epitopes in RA patients.Anti-cLBP antibodies are associated with disease severity and infection in RA patients.
