法尼醇X受体在高甘油三酯血症大鼠肾脏的表达和定位

目的 通过观察法尼醇X受体在高甘油三酯血症大鼠肾脏的表达和定位,探讨脂质肾毒性的作用机制.方法 将32只大鼠分为正常对照组(N组)及高果糖组(F组),每组16只.8w及16 w时分批处死,检测各组大鼠的肾功能、空腹血糖、血脂及24h尿微量白蛋白;检测大鼠肾皮质甘油三酯含量;油红0染色观察肾脏脂质;采用免疫组化分析法尼醇X受体表达和定位,并观察肾脏病理变化.结果 与对照组比较,高果糖组血中甘油三酯和极低密度脂蛋白水平明显升高,肾组织中甘油三酯水平明显增高,肾脏病理改变加重,肾组织法尼醇X受体表达明显下调,且随时间延长而加重(P＜0.05).结论 法尼醇X受体在高甘油三酯血症大鼠肾组织中表达下调,从而使肾脏脂质合成增加,进而导致肾脏损伤.     

富含甘油三酯脂蛋白受体及其在脂蛋白代谢中的作用

正常人血浆中富含甘油三酯脂蛋白为极低密度脂蛋白和乳糜微粒及它们的载脂蛋白残粒。已有几种该脂蛋白受体的报道，它们中的多数属于低密度脂蛋白受体家族。低密度脂蛋白受体或载脂蛋白Ｂ／Ｅ受体，主要负责载脂蛋白Ｂ１００介导低密度脂蛋白的代谢，同时低密度脂蛋白自身能够通过载脂蛋白Ｅ识别残粒。但是，在肝脏中，低密度脂蛋白受体相关蛋白才是真正的乳糜微粒残粒受体，它主要通过载脂蛋白Ｅ及脂酶结合乳糜微粒残粒而发挥脂蛋白受体作用。极低密度脂蛋白受体在肌肉和脂肪组织中含量最多，可能是由极低密度脂蛋白和中密度脂蛋白携带的内源性甘油三酯从肝脏转运到脂肪酸代谢部位所必需的。三种受体在脂蛋白代谢中均有各自的作用并且可能优先识别其特异配体，但在必要时，它们亦可部分发挥受体家族中其它成员的作用。     

胆酸对大鼠肝部分切除术后肝细胞脂质代谢及法尼醇X受体表达的影响

目的探讨胆酸对肝细胞脂质代谢、法尼醇X受体(FXR)及肝再生的影响。方法建立部分肝切除大鼠模型,随机分成3组:G1组(正常喂养),G2组(给予0.2%胆酸喂养),G3组(正常饮食中加入50%葡萄糖),每组10只,喂养后7 d切除大鼠70%肝组织,于术后72 h取出肝组织及血液标本,检测相关指标。RT-PCR和Western印迹检测SHP、CYP7A1、BSEP的表达;试剂盒检测肝细胞中甘油三酯、胆固醇的水平。结果与G1相比,G2组小异二聚体伴侣(SHP)、胆盐输出泵(BSEP)表达显著升高(P0.05),胆固醇7α-羟化醇(CYP7A1)表达显著降低(P0.05);G3组SHP、BSEP表达略增高(P0.05),CYP7A1显著升高(P0.05)。G2组甘油三酯(TG)水平显著降低,胆固醇(TC)含量显著升高,而G3组TG略升高,TC含量降低(均P0.05)。结论胆酸可促进肝细胞再生,FXR在调控肝细胞代谢中发挥重要作用。     

法尼醇X受体缺失能改善自身血糖稳态

最近研究结果显示,法尼醇x受体（FXR）广泛参与胆汁酸及糖脂代谢。肥胖状态下FXR表达异常增高。然而,目前尚无关于FXR与肥胖并发症相关性的报道。本研究拟在肥胖小鼠模型中探讨FXR缺失是否与胰岛素抵抗及脂代谢异常相关。     

法尼醇X受体激动剂对非酒精性脂肪性肝炎治疗作用研究进展

代谢相关脂肪性肝病(metabolic dysfunction-associated fatty liver disease,MAFLD)的全球患病率为20%～40%,伴随着沉重的疾病负担和晚期疾病相关的高病死率,目前尚无批准治疗MAFLD的标准药物。法尼醇X受体(farnesoid X receptor,FXR)具有调控糖脂代谢和改善胰岛素抵抗的作用,其中奥贝胆酸作为FXR激动剂,已被多项研究证实可改善MAFLD患者的肝组织学特征。本文主要阐述FXR激动剂的作用机制和研究现状以供临床参考。     

法尼醇X受体激动剂在非酒精性脂肪性肝炎治疗中的应用

非酒精性脂肪性肝炎(NASH)作为患病率较高的一种肝病,严重危害人类健康。近年来,法尼醇X受体相关药物在调节胆汁酸、糖脂代谢以及抑制炎症方面发挥了重要作用。总结了不同种类的法尼醇X受体激动剂在NASH治疗中的应用,为NASH的防治提供一定的依据。     

法尼醇X受体激动剂对雌激素诱导的肝内胆汁淤积症孕鼠胆汁酸代谢的影响及其分子机制

目的 研究法尼醇X受体(FXR)激动剂鹅去氧胆酸(CDCA)对雌激素诱导的肝内胆汁淤积孕鼠胆汁酸代谢的影响及其分子机制.方法 用苯甲酸雌二醇诱导孕鼠发生肝内胆汁淤积,建立妊娠期肝内胆汁淤积症(ICP)模型,将FXR激动剂CDCA作用于ICP模型组,比色法检测孕鼠血总胆汁酸,RT-PCR和免疫组织化学法检测孕鼠肝组织FXR及其靶基因胆盐转运泵(BSEP)的mRNA及蛋白质表达.结果 与模型组相比,CDCA治疗组孕鼠血清胆汁酸水平明显降低[(17.2±4.1)μmol/L比(29.3±6.4)μmol/L,P＜0.017],肝组织FXR mRNA(0.76±0.09比0.53±0.06,P＜0.05)及蛋白质表达(2.35±0.06比1.83±0.05,P＜0.017)明显升高,BSEP mRNA(0.99±0.21比0.76±0.07,P＜0.017)及蛋白质表达(1.88±0.03比1.46±0.06,P＜0.017)也明显升高.结论 FXR在调节胆汁酸代谢过程中起重要作用,其激动剂CDCA通过上调BSEP的表达促进胆汁酸转运降低血胆汁酸水平,可能为ICP的治疗提供新的思路和药物靶点.     

富含甘油三酯脂蛋白代谢及其在动脉粥样硬化中的作用

甘油三酯(TG)主要存在于富含甘油三酯脂蛋白(TRLs)中,TRLs代谢失调与动脉粥样硬化发生发展密切相关。脂蛋白脂酶(LPL)是一种由实质细胞分泌的糖蛋白,可将TRLs中的TG分解为游离脂肪酸。许多因子通过调控LPL表达与活性影响TRLs代谢及动脉粥样硬化进程。因此,阐明TRLs代谢及调控机制对于心血管疾病防治具有重要意义。     

肠道法尼醇X受体在非酒精性脂肪性肝病中的作用机制及相关靶向药物

近年来非酒精性脂肪性肝病(NAFLD)发病率日益剧增,若患者不良生活方式无法及时调整,且临床尚缺乏有效的药物,使得NAFLD的治疗差强人意。法尼醇X受体(FXR)作为胆汁酸的主要受体,通过参与糖、脂代谢来影响NAFLD,而肠道FXR(iFXR)具有局限作用于肠道的优势,可避免全身释放所带来的副作用,在NAFLD的治疗上具有潜在的价值,但也存在一定的争议。综述了近年来iFXR在NAFLD的研究进展。     

法尼酯衍生物X受体与肝纤维化

法尼酯衍生物X受体(FXR)是一种在肝肠系统等组织器官表达的胆汁酸受体,属于激素核受体超家族的一员,在胆汁酸代谢及胆固醇代谢中发挥重要作用.当FXR配体与FXR羧基末端配体结合区(LBD)直接结合后,核受体空间构象发生改变并与视黄醛衍生物受体(RXR)形成异源二聚体,最后与靶基因特定FXR DNA反应元件结合从而调节靶基因的转录.初级胆汁酸鹅脱氧胆酸是FXR最有效的配体,次级胆汁酸石胆酸和脱氧胆酸也可以激活FXR.目前还有合成FXR配体(如6-ECDCA、GW4064等),其与FXR结合力比天然配体强数倍.FXR的主要靶基因包括胆盐输出泵(BSEP)、小异源二聚体伴侣受体(SHP)等,FXR通过和这些基因启动子上的FXR反应元件(FXRE)结合从而调控这些基因的表达.但如胆固醇7α羟化酶(CYP7α1)等主要FXR调控基因的启动子序列中没有典型FXR结合反应序列,FXR则是间接通过诱导转录抑制因子SHP表达,然后SHP与CYP7α1启动子肝受体同源物1(LRH-1)形成抑制性复合物,从而阻断CYP7α1和其它LRH-1靶基因转录.由于FXR在胆汁酸及胆固醇代谢中的重要作用,这将使其和肝脏相关疾病关系日益受到关注[1,2].     

Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression

BACKGROUND & AIMS: Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression. METHODS: The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells. RESULTS: In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the I(4) footprint between nucleotides -739 and -704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4alpha from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4alpha-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR. CONCLUSIONS: We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists.     

The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism

Bile acids are the end products of cholesterol metabolism. They are synthesized in the liver and secreted via bile into the intestine, where they aid in the absorption of fat-soluble vitamins and dietary fat. Subsequently, bile acids return to the liver to complete their enterohepatic circulation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and has emerged as a key player in the control of multiple metabolic pathways. On its activation by bile acids, FXR regulates bile acid synthesis, conjugation, and transport, as well as various aspects of lipid and glucose metabolism. This review summarizes recent advances in deciphering the role of FXR in the context of hepatic lipid and glucose homeostasis and discusses the potential of FXR as a pharmacological target for therapeutic applications.     

Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response

The farnesoid X receptor (FXR) is a nuclear receptor that plays key roles in hepatoprotection by maintaining the homeostasis of liver metabolism. FXR null mice display strong hepatic inflammation and develop spontaneous liver tumors. In this report, we demonstrate that FXR is a negative modulator of nuclear factor kappaB (NF-kappaB)-mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to NF-kappaB activation in both HepG2 cells and primary hepatocytes cultured in vitro. In vivo, compared with wild-type controls, FXR(-/-) mice displayed elevated messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interferon-inducible protein 10, and interferon-gamma in response to lipopolysaccharide (LPS). Examination of FXR(-/-) livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage or inflammation in wild-type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX-2, interferon-inducible protein 10 and interferon-gamma mRNA levels induced by LPS administration. FXR activation had no negative effects on NF-kappaB-activated antiapoptotic genes, suggesting that FXR selectively inhibits the NF-kappaB-mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF-kappaB activation suppressed FXR-mediated gene expression both in vitro and in vivo, indicating a negative crosstalk between the FXR and NF-kappaB signaling pathways. Our findings reveal that FXR is a negative mediator of hepatic inflammation, which may contribute to the critical roles of FXR in hepatoprotection and suppression of hepatocarcinogenesis.     

类法尼醇X受体在巨噬细胞中下调单核细胞趋化蛋白1的表达

目的研究小鼠巨噬细胞株ANA-1中类法尼醇X受体的表达情况,并进一步研究类法尼醇X受体天然配体鹅脱氧胆酸在ANA-1中对单核细胞趋化蛋白1表达的影响,以探讨类法尼醇X受体在动脉粥样硬化发生发展中的作用。方法应用逆转录聚合酶链反应检测类法尼醇X受体在ANA-1细胞中的表达,及鹅脱氧胆酸处理后单核细胞趋化蛋白1的转录水平,Westernblot检测类法尼醇X受体的表达及其激活后对自身蛋白表达的调节,以及单核细胞趋化蛋白1蛋白的表达水平。结果类法尼醇X受体在ANA-1中表达,并依赖鹅脱氧胆酸浓度自我上调,鹅脱氧胆酸能显著下调单核细胞趋化蛋白1的表达水平(P<0.05)。结论类法尼醇X受体在小鼠巨噬细胞株ANA-1中组成型表达并呈配体浓度依赖性自我上调,类法尼醇X受体激活后可通过直接或间接方式下调单核细胞趋化蛋白1的表达。