Aim： To investigate the roles of liver X receptors （LXR） in the lipid composition and gene expression regulation in the murine caput epididymidis. LXR are nuclear receptors for oxysterols, molecules derived from ch...Aim： To investigate the roles of liver X receptors （LXR） in the lipid composition and gene expression regulation in the murine caput epididymidis. LXR are nuclear receptors for oxysterols, molecules derived from cholesterol metabolism that are present in mammals as two isoforms： LXRα, which is more specifically expressed in lipid-metabolising tissues, such as liver, adipose and steroidogenic tissues, and macrophages, whereas LXRβ is ubiquitous. Their importance in reproductive physiology has been sustained by the fact that male mice in which the function of both LXR has been disrupted have fertility disturbances starting at the age of 5 months, leading to complete sterility by the age of 9 months. These defects are associated with epididymal epithelial degeneration in caput segments one and two, and with a sperm midpiece fragility, leading to the presence of isolated sperm heads and flagella when luminal contents are recovered from the cauda epididymidis. Methods： The lipid composition of the caput epididymidis of wild-type and LXR-deficient mice was assessed using oil red O staining on tissue cryosections and lipid extraction followed by high performance liquid chromatography or gas chromatography. Gene expression was checked by quantitative real time polymerase chain reaction. Results： Using LXR-deficient mice, we showed an alteration of the lipid composition of the caput epididymidis as well as a significantly decreased expression of the genes encoding SREBPlc, SCD1 and SCD2, involved in fatty acid metabolism. Conclusion： Altogether, these results show that LXR are important regulators of epididymal function, and play a critical role in the lipid maturation processes occurring during sperm epididymal maturation. （Asian J Androl 2007 July; 9： 574-582）展开更多
肝X受体(liver X receptor,LXR)是人体内一种重要的核受体,为配体依赖性蛋白。LXR作为体内激素和营养信号的整合者,主要通过调控脂质和糖类等途径调节机体新陈代谢,参与Ⅱ型糖尿病、肥胖、心血管疾病、高脂血症等多种常见代谢疾病的发...肝X受体(liver X receptor,LXR)是人体内一种重要的核受体,为配体依赖性蛋白。LXR作为体内激素和营养信号的整合者,主要通过调控脂质和糖类等途径调节机体新陈代谢,参与Ⅱ型糖尿病、肥胖、心血管疾病、高脂血症等多种常见代谢疾病的发生发展。有研究证明,多个LXR基因多态性位点与代谢类疾病发生发展密切相关。研究LXR参与代谢性疾病的病理机制、探究LXR基因多态性与代谢性疾病的相关性,有利于从基因层面检测和评估代谢类疾病的发生风险,从而实现早期发现和预防该疾病的发生,提高代谢性疾病患者的生存质量,延长生存期。本文拟就近五年LXR参与代谢途径和其基因多态性与代谢性疾病的相关性做一综述。展开更多
目的探讨肝X受体(liver X receptor,LXR)激动剂T0901317对高脂饲养ApoE基因敲除(apolipoprotein E gene knockout,ApoE-/-)小鼠在动脉粥样硬化病变形成的早期动脉壁内C-反应蛋白(CRP)和CD40配体(CD40L)表达及平滑肌细胞含量的影响。方法...目的探讨肝X受体(liver X receptor,LXR)激动剂T0901317对高脂饲养ApoE基因敲除(apolipoprotein E gene knockout,ApoE-/-)小鼠在动脉粥样硬化病变形成的早期动脉壁内C-反应蛋白(CRP)和CD40配体(CD40L)表达及平滑肌细胞含量的影响。方法8周龄雄性ApoE-/-小鼠12只,按随机数字表法分入LXR激动剂T0901317组和二甲基亚砜(DMSO)溶剂对照组,每组6只。均给予高脂饲养8周,在高脂饲养的后4周,分别给予LXR激动剂T090131720mg·kg-1·d-1或相当剂量的DMSO腹腔注射。麻醉处死小鼠后,取小鼠主动脉,以石蜡包埋,行主动脉根部连续切片,采用免疫组化法检测主动脉壁内CRP、CD40L和平滑肌细胞α-actin的表达,以Image Pro Plus 6.0软件进行图像分析。结果LXR激动剂组动脉壁CRP表达水平较对照组明显减少(P<0.05),LXR激动剂组动脉壁CD40L表达水平较对照组明显减少(P<0.05),动脉粥样硬化斑块内平滑肌细胞α-actin表达水平与对照组比较没有统计学差异(P>0.05)。结论LXR激动剂可能通过抑制ApoE-/-小鼠动脉壁中CRP和CD40L的表达,减轻血管壁的炎症反应,从而发挥抗动脉粥样硬化形成的作用。展开更多
目的探讨沉默肝X受体α(liver X receptorα,LXRα)基因对HepG2.2.15细胞脂质代谢相关基因表达的影响。方法设立空白对照组(不转染任何质粒)、阴性对照组(转染阴性HK质粒)和shLXRα转染组(转染shLXRα质粒)。构建针对LXRα基因的shLXR...目的探讨沉默肝X受体α(liver X receptorα,LXRα)基因对HepG2.2.15细胞脂质代谢相关基因表达的影响。方法设立空白对照组(不转染任何质粒)、阴性对照组(转染阴性HK质粒)和shLXRα转染组(转染shLXRα质粒)。构建针对LXRα基因的shLXRα质粒并转染HepG2.2.15细胞,用荧光显微镜及蛋白质印迹法检测转染质粒24～96h绿色荧光蛋白和LXRα蛋白的表达以确定质粒的最佳干扰时间,根据结果给予激动剂T0901317刺激细胞,用三酰甘油(TG)含量检测肝细胞脂肪变性程度,RT-PCR检测固醇调节元件结合蛋白1c(sterol regulatory element binding protein-1c,SREBP-1c)mRNA的表达,蛋白质印迹法检测乙肝病毒X(hepatitis B virus X,HBx)蛋白及脂肪酸合成酶(fatty acid synthase,FAS)蛋白的表达。结果成功构建shLXRα质粒并转染HepG2.2.15细胞。与空白对照组和阴性对照组比较,shLXRα转染组LXRα蛋白表达下降,于转染后48～72h表达最低,差异有统计学意义(P<0.01);随着激动剂T0901317处理时间延长,各组HBx和FAS蛋白表达、TG含量、SREBP-1cmRNA水平均逐渐增加,同一时间点HBx蛋白在各组差异无统计学意义(P>0.05),而FAS蛋白、TG含量、SREBP-1cmRNA水平,在shLXRα转染组中的表达较空白对照组和阴性对照组低,差异有统计学意义(P<0.01)。结论 HBx对脂代谢的调控可能部分通过LXRα/SREBP-1c/FAS途径实现。展开更多
目的:探讨江苏地区冠心病患者肝X受体(liver X receptor,LXR)基因-6A(rs11039155)多态性位点与冠心病遗传易感性的关系。方法:选取江苏地区冠心病患者165例,健康体检者191例作为对照。采用单荧光标记探针技术检测LXR-6A基因型。同时测...目的:探讨江苏地区冠心病患者肝X受体(liver X receptor,LXR)基因-6A(rs11039155)多态性位点与冠心病遗传易感性的关系。方法:选取江苏地区冠心病患者165例,健康体检者191例作为对照。采用单荧光标记探针技术检测LXR-6A基因型。同时测定两组样本三酰甘油、总胆固醇、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖等生化指标。结果:LXR-6A(rs11039155)仅检出一种基因型,与探针完全匹配,出现一个融解峰,Tm值55.21℃。随机抽取22例样本进行测序,提示基因型为GG纯合子。结论:江苏地区汉族人群不存在LXR-6A(rs11039155)单核苷酸多态性位点。展开更多
The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role o...The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.展开更多
The philosophy of heart and brain are very ancient in our literature where the things good for the heart are not suggested good for the brain and vice-versa.Modern medicine is characterized by a high degree of special...The philosophy of heart and brain are very ancient in our literature where the things good for the heart are not suggested good for the brain and vice-versa.Modern medicine is characterized by a high degree of specialization and the heart-brain connection that could be targeted to treat these complex cardiovascular/brain disorders.The idea that adverse diet/genome interactions can cause disease is not new.In the recent era the science of nutritional genomics have increased our understanding of diet-health-gene interactions and have provided a number of benefits for individuals,groups and societies.Since dietary chemicals are regularly ingested and participate indirectly and directly in regulating gene expression,it follows that a subset of genes regulated by diet must be involved in disease initiation,progression,and severity.In this regards Liver X Receptor(LXR)-a,a key transcription factors,associated with the several chronic pathological situation including coronary heart disease and neurodegenerative diseases have recently been found to be regulated by the dietary components.The crucial findings at molecular biology unit,Post Graduate Institute of Medical Education and Research(PGIMER),Chandigarh,INDIA have not only forced us to explore nutritional genomics as a holistic systems approach to understand the relationship between diet and health,but also to look into the disease preventing and health promoting foods that match our lifestyles,cultures and genetics.After all,we are what we eat.展开更多
文摘Aim： To investigate the roles of liver X receptors （LXR） in the lipid composition and gene expression regulation in the murine caput epididymidis. LXR are nuclear receptors for oxysterols, molecules derived from cholesterol metabolism that are present in mammals as two isoforms： LXRα, which is more specifically expressed in lipid-metabolising tissues, such as liver, adipose and steroidogenic tissues, and macrophages, whereas LXRβ is ubiquitous. Their importance in reproductive physiology has been sustained by the fact that male mice in which the function of both LXR has been disrupted have fertility disturbances starting at the age of 5 months, leading to complete sterility by the age of 9 months. These defects are associated with epididymal epithelial degeneration in caput segments one and two, and with a sperm midpiece fragility, leading to the presence of isolated sperm heads and flagella when luminal contents are recovered from the cauda epididymidis. Methods： The lipid composition of the caput epididymidis of wild-type and LXR-deficient mice was assessed using oil red O staining on tissue cryosections and lipid extraction followed by high performance liquid chromatography or gas chromatography. Gene expression was checked by quantitative real time polymerase chain reaction. Results： Using LXR-deficient mice, we showed an alteration of the lipid composition of the caput epididymidis as well as a significantly decreased expression of the genes encoding SREBPlc, SCD1 and SCD2, involved in fatty acid metabolism. Conclusion： Altogether, these results show that LXR are important regulators of epididymal function, and play a critical role in the lipid maturation processes occurring during sperm epididymal maturation. （Asian J Androl 2007 July; 9： 574-582）
文摘肝X受体(liver X receptor,LXR)是人体内一种重要的核受体,为配体依赖性蛋白。LXR作为体内激素和营养信号的整合者,主要通过调控脂质和糖类等途径调节机体新陈代谢,参与Ⅱ型糖尿病、肥胖、心血管疾病、高脂血症等多种常见代谢疾病的发生发展。有研究证明,多个LXR基因多态性位点与代谢类疾病发生发展密切相关。研究LXR参与代谢性疾病的病理机制、探究LXR基因多态性与代谢性疾病的相关性,有利于从基因层面检测和评估代谢类疾病的发生风险,从而实现早期发现和预防该疾病的发生,提高代谢性疾病患者的生存质量,延长生存期。本文拟就近五年LXR参与代谢途径和其基因多态性与代谢性疾病的相关性做一综述。
文摘目的探讨肝X受体(liver X receptor,LXR)激动剂T0901317对高脂饲养ApoE基因敲除(apolipoprotein E gene knockout,ApoE-/-)小鼠在动脉粥样硬化病变形成的早期动脉壁内C-反应蛋白(CRP)和CD40配体(CD40L)表达及平滑肌细胞含量的影响。方法8周龄雄性ApoE-/-小鼠12只,按随机数字表法分入LXR激动剂T0901317组和二甲基亚砜(DMSO)溶剂对照组,每组6只。均给予高脂饲养8周,在高脂饲养的后4周,分别给予LXR激动剂T090131720mg·kg-1·d-1或相当剂量的DMSO腹腔注射。麻醉处死小鼠后,取小鼠主动脉,以石蜡包埋,行主动脉根部连续切片,采用免疫组化法检测主动脉壁内CRP、CD40L和平滑肌细胞α-actin的表达,以Image Pro Plus 6.0软件进行图像分析。结果LXR激动剂组动脉壁CRP表达水平较对照组明显减少(P<0.05),LXR激动剂组动脉壁CD40L表达水平较对照组明显减少(P<0.05),动脉粥样硬化斑块内平滑肌细胞α-actin表达水平与对照组比较没有统计学差异(P>0.05)。结论LXR激动剂可能通过抑制ApoE-/-小鼠动脉壁中CRP和CD40L的表达,减轻血管壁的炎症反应,从而发挥抗动脉粥样硬化形成的作用。
文摘目的探讨沉默肝X受体α(liver X receptorα,LXRα)基因对HepG2.2.15细胞脂质代谢相关基因表达的影响。方法设立空白对照组(不转染任何质粒)、阴性对照组(转染阴性HK质粒)和shLXRα转染组(转染shLXRα质粒)。构建针对LXRα基因的shLXRα质粒并转染HepG2.2.15细胞,用荧光显微镜及蛋白质印迹法检测转染质粒24～96h绿色荧光蛋白和LXRα蛋白的表达以确定质粒的最佳干扰时间,根据结果给予激动剂T0901317刺激细胞,用三酰甘油(TG)含量检测肝细胞脂肪变性程度,RT-PCR检测固醇调节元件结合蛋白1c(sterol regulatory element binding protein-1c,SREBP-1c)mRNA的表达,蛋白质印迹法检测乙肝病毒X(hepatitis B virus X,HBx)蛋白及脂肪酸合成酶(fatty acid synthase,FAS)蛋白的表达。结果成功构建shLXRα质粒并转染HepG2.2.15细胞。与空白对照组和阴性对照组比较,shLXRα转染组LXRα蛋白表达下降,于转染后48～72h表达最低,差异有统计学意义(P<0.01);随着激动剂T0901317处理时间延长,各组HBx和FAS蛋白表达、TG含量、SREBP-1cmRNA水平均逐渐增加,同一时间点HBx蛋白在各组差异无统计学意义(P>0.05),而FAS蛋白、TG含量、SREBP-1cmRNA水平,在shLXRα转染组中的表达较空白对照组和阴性对照组低,差异有统计学意义(P<0.01)。结论 HBx对脂代谢的调控可能部分通过LXRα/SREBP-1c/FAS途径实现。
文摘目的:探讨江苏地区冠心病患者肝X受体(liver X receptor,LXR)基因-6A(rs11039155)多态性位点与冠心病遗传易感性的关系。方法:选取江苏地区冠心病患者165例,健康体检者191例作为对照。采用单荧光标记探针技术检测LXR-6A基因型。同时测定两组样本三酰甘油、总胆固醇、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖等生化指标。结果:LXR-6A(rs11039155)仅检出一种基因型,与探针完全匹配,出现一个融解峰,Tm值55.21℃。随机抽取22例样本进行测序,提示基因型为GG纯合子。结论:江苏地区汉族人群不存在LXR-6A(rs11039155)单核苷酸多态性位点。
基金supported in the part by the U.S. National Institutes of Health National Institute for Environmental Health Sciences [Grant R01ES-019487 to Xiao-bo Zhong]U.S. National Institutes of Health National Institute of General Medical Sciences [Grants R01GM-087376 and R01GM118367 to Xiao-bo Zhong]
文摘The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.
文摘目的探讨肝核受体(LXRs)激动剂T0901317对正常SD大鼠骨骼肌细胞中脂肪酸较运酶(FAT/CD36)基因mRNA表达的影响。方法将原代培养的5只SD大鼠骨骼肌细胞分为T0901317 1μmol/L作用组、0.5μmol/L作用组和未作用(阴性对照)组,采用SYBR Green I实时荧光定量聚合酶链反应(PCR)法检测各组SD大鼠骨骼肌细胞FAT/CD36基因mRNA表达水平,并进行比较分析。结果1μmol/L、0.5μmol/L作用组与阴性对照组比较,差异无显著性意义(P=0.116)。结论LXRs激动剂T0901317对SD大鼠骨骼肌细胞中FAT/CD36基因mRNA的表达水平没有明显作用,提示T0901317在促进SD大鼠骨骼肌细胞内脂肪酸的堆积作用尚无确切的证据。
文摘The philosophy of heart and brain are very ancient in our literature where the things good for the heart are not suggested good for the brain and vice-versa.Modern medicine is characterized by a high degree of specialization and the heart-brain connection that could be targeted to treat these complex cardiovascular/brain disorders.The idea that adverse diet/genome interactions can cause disease is not new.In the recent era the science of nutritional genomics have increased our understanding of diet-health-gene interactions and have provided a number of benefits for individuals,groups and societies.Since dietary chemicals are regularly ingested and participate indirectly and directly in regulating gene expression,it follows that a subset of genes regulated by diet must be involved in disease initiation,progression,and severity.In this regards Liver X Receptor(LXR)-a,a key transcription factors,associated with the several chronic pathological situation including coronary heart disease and neurodegenerative diseases have recently been found to be regulated by the dietary components.The crucial findings at molecular biology unit,Post Graduate Institute of Medical Education and Research(PGIMER),Chandigarh,INDIA have not only forced us to explore nutritional genomics as a holistic systems approach to understand the relationship between diet and health,but also to look into the disease preventing and health promoting foods that match our lifestyles,cultures and genetics.After all,we are what we eat.
