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
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
Objectives: To determine the anthropometric indices, lipopolysaccharide-binding proteins (LBP), and lipid profile in patients with metabolic endotoxemia. Methods: The study comprised of 47 patients with metabolic endo...Objectives: To determine the anthropometric indices, lipopolysaccharide-binding proteins (LBP), and lipid profile in patients with metabolic endotoxemia. Methods: The study comprised of 47 patients with metabolic endotoxemia (the metabolic endotoxemia group) and 43 controls (the control group). Patients in the metabolic endotoxemia group were categorized further into three subgroups including the normal weight group (n=8), the overweight group (n=12) and the obese group (n=27). Height, weight, waist, and hip circumference were measured, and waist-hip ratio (WHR) and body mass index (BMI) were calculated. LBP was determined by ELISA and total cholesterol, triglycerides, high density lipoprotein by the respective enzymatic colorimetric methods. In addition, low density lipoprotein and very low density lipoprotein were determined by Friedewald's formula. Results: The mean waist circumference (WC), hip circumference (HC), BMI, total cholesterol, low density lipoprotein, and LBP of the metabolic endotoxemia group were significantly higher (P<0.05) than those of the control group. WHR, TG, high density lipoprotein and very low density lipoprotein of the metabolic endotoxemia group were not significantly different (P>0.05) from those of the control group. The mean WC, HC, WHR, and BMI of the obese group with metabolic endotoxemia were significantly higher (P<0.05) than those of the overweight group and the normal weight group with metabolic endotoxemia. Significant positive correlations were obtained between BMI and LBP (r=0.610, P=0.001), total cholesterol and LBP (r=0.385, P=0.007), TG and LBP (r=0.356, P=0.014) in patients with metabolic endotoxemia. Conclusions: Metabolic endotoxemia arising from increased circulating level of bacterial derive particles consequent to perturbation in the gut microbial community and the elevated ;serum level of LBP may precede the development of obesity, characterized by dyslipidemia, dysregulation of gut energy harvest, and metabolic energy imbalance.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.
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.
文摘Objectives: To determine the anthropometric indices, lipopolysaccharide-binding proteins (LBP), and lipid profile in patients with metabolic endotoxemia. Methods: The study comprised of 47 patients with metabolic endotoxemia (the metabolic endotoxemia group) and 43 controls (the control group). Patients in the metabolic endotoxemia group were categorized further into three subgroups including the normal weight group (n=8), the overweight group (n=12) and the obese group (n=27). Height, weight, waist, and hip circumference were measured, and waist-hip ratio (WHR) and body mass index (BMI) were calculated. LBP was determined by ELISA and total cholesterol, triglycerides, high density lipoprotein by the respective enzymatic colorimetric methods. In addition, low density lipoprotein and very low density lipoprotein were determined by Friedewald's formula. Results: The mean waist circumference (WC), hip circumference (HC), BMI, total cholesterol, low density lipoprotein, and LBP of the metabolic endotoxemia group were significantly higher (P<0.05) than those of the control group. WHR, TG, high density lipoprotein and very low density lipoprotein of the metabolic endotoxemia group were not significantly different (P>0.05) from those of the control group. The mean WC, HC, WHR, and BMI of the obese group with metabolic endotoxemia were significantly higher (P<0.05) than those of the overweight group and the normal weight group with metabolic endotoxemia. Significant positive correlations were obtained between BMI and LBP (r=0.610, P=0.001), total cholesterol and LBP (r=0.385, P=0.007), TG and LBP (r=0.356, P=0.014) in patients with metabolic endotoxemia. Conclusions: Metabolic endotoxemia arising from increased circulating level of bacterial derive particles consequent to perturbation in the gut microbial community and the elevated ;serum level of LBP may precede the development of obesity, characterized by dyslipidemia, dysregulation of gut energy harvest, and metabolic energy imbalance.
