核受体FXR与非酒精性脂肪肝

核受体FXR也称为胆汁酸受体,调控体内胆汁酸的合成及重吸收。研究表明,FXR还与肝脏脂质代谢和糖代谢密切相关,FXR激活后可通过抑制肝脏甘油三酯合成、加速胆固醇逆向转运、抑制糖异生等多种途径缓解肝脏脂质蓄积。另外,FXR激活后还可减轻肝脏炎症和纤维化。因此,FXR可能是潜在的非酒精性脂肪肝的治疗靶点。本文将综述激活的FXR对肝脏糖脂代谢等多种通路的调控作用。     

核受体FXR代谢调控作用及肿瘤细胞增殖机制研究进展

类法尼酯衍生物X受体(farnesoid X receptor,FXR)是配体激活的转录因子,为核受体超家族的主要成员。FXR在胆汁酸代谢、胆固醇代谢、脂代谢以及糖代谢中发挥重要作用。近期研究显示,FXR在代谢性疾病,如高糖血症和高脂血症,以及肠道炎症性疾病、肝再生,甚至肿瘤细胞的增殖和凋亡中发挥重要的调控作用。然而现阶段对于FXR的代谢调控作用在肿瘤发生、发展中的意义尚不明了,甚至存在争议。本文综述了FXR对代谢的调控作用,以及FXR对肿瘤细胞增殖的不同作用和相关机制研究的新进展。     

法尼酯X受体在脂质代谢过程中的调控作用

法尼酯X受体(Farnesoid X Receptor,FXR)属于配体依赖的核转录因子,可被内源性配体胆汁酸激活,通过调节胆汁酸、胆固醇、脂蛋白及脂肪酸代谢维持血浆中脂质的稳态,从而达到调节脂质代谢的目的。最近研究发现FXR在脉管系统中也有表达活性,开辟了FXR调节脂质代谢的新途径。随着新配体及靶基因的发现,研究FXR的作用机制以及寻找对脂质代谢具有调控作用的FXR的配体,对于脂代谢异常和动脉粥样硬化的防治具有重要意义。本文综述了该领域的最新进展。     

核受体FXR:一种新型代谢调节因子

法尼酯衍生物X受体(farnesoid X receptor,FXR)是一种胆汁酸受体,属于核受体超家族成员。FXR通过调控一系列基因的表达,在胆汁酸、脂质和糖代谢中发挥重要作用,进而有望成为治疗一系列代谢性疾病的药物靶点。本文将就FXR的相关研究进展作一综述。     

类法尼醇X受体对脂代谢的调控作用

类法尼醇X受体（famesoid X receptor,FXR）属于于配体激活的核转录因子,是核受体超家族中的一员。受配体激活后．FXR在胆汁酸、脂质代谢中具有重要调控作用。随着FXR特异性配体及拮抗剂的发现,其在代谢及相关疾病中的调控作用日趋明显。最近发现,FXR在心血管系统中有表达活性,开辟了FXR调控网络的新领域。     

胆汁酸对代谢性疾病的调控

胆汁酸作为一种信号分子通过激活肝、肠道和外周组织中的胆汁酸受体影响体内葡萄糖和脂质的代谢平衡,对于调节肥胖、2型糖尿病和非酒精性脂肪肝等代谢性疾病具有非常重要的意义。胆汁酸与相应核受体,如法尼醇X受体(farnesoid X receptor, FXR)和Takeda G蛋白偶联受体5 (Takeda G protein-coupled receptor 5,TGR5)的相互作用影响了这些代谢性疾病。FXR主要通过影响胆汁酸的合成及转运对非酒精性脂肪肝发挥作用,TGR5则是间接增加褐色脂肪组织中的生热作用,改善肥胖和2型糖尿病。这些调控机制的研究是非常必要的。本文综述了胆汁酸代谢及其对代谢性疾病调控的分子机制的研究进展,以期为科研工作者提供一定的参考。     

FXR与糖尿病相关性研究进展

国际糖尿病联盟(IDF)最新数据表明目前中国糖尿病患者在剧增。糖尿病是以胰岛素分泌相对或和绝对不足导致的慢性高血糖为特征的代谢性疾病,法尼醇X受体(farnesoid X receptor,FXR,NR1H4)是能被胆汁酸激活的转录因子,FXR能对胆汁酸的代谢进行调节,胆汁酸代谢与糖尿病相关,胆汁酸代谢在β细胞的功能是通过FXR介导的,本文回顾国内外有关法尼醇X受体通过抑制肝糖原异生、增加肝糖原储存、影响胰岛素信号、增加胰岛素的分泌和增强胰岛素的敏感性等机制发挥调节血糖平衡作用的研究,意在探索FXR与糖尿病的相关性,为糖尿病的发病机制提供新的理论依据。     

核受体FXR在肝星状细胞及肝纤维化中的作用

法尼醇X受体(farnesoid X receptor,FXR)是核受体超家族的重要成员,以作为胆汁酸受体被大家所熟知.除了调节胆汁酸的合成和转运,FXR在调控葡萄糖代谢、甘油三酯代谢、炎症、凝血等方面也发挥重要作用.肝纤维化是慢性肝脏疾病发展成肝硬化的共同途径,终末期肝纤维化将导致肝硬化、肝衰竭,甚至危及生命.肝星状...     

Nature Medicine:激活小肠FXR,向肥胖说不

<正>近日,著名国际期刊Nature Medicine发表了美国科学家的一项最新研究成果,他们发现特异性激活肠道FXR会促进肠道FGF15表达改变胆汁酸组成成分,同时能够通过增加产热以及白色脂肪棕色化,改善肥胖小鼠的体重及代谢恶化表型。研究人员指出,目前利用胆汁酸感应因子FXR的全身性表达靶向胆固醇代谢,甘油三酯合成,肝脏脂肪变性和胆汁淤积治疗相关疾病正成为新兴疗法。相比于全身性治疗方法,在进食情况下选择性释放胆汁酸能够激活肠道FXR。通过模拟这种组织特异性效应,利用特异性FXR激动     

核受体FXR调控SHP的机制及FXR-SHP轴在肝脏中作用的研究进展

法尼醇X受体(Farnesoid X Receptor,FXR)属于代谢性核受体,是需配体激活的转录因子,在肝脏胆汁酸、脂质代谢过程,肝脏炎症和肿瘤的发展过程中起着重要的调节作用。小异二聚体伴侣受体(Small Heterodimer Partner,SHP)是核受体超家族中的一个特殊成员,在特异的组织中作为转录调节的共抑制因子,抑制其他多种转录因子的活性,在众多代谢通路中起到了负性调节作用。近年来研究发现,核受体FXR通过对SHP的调控来实现其在肝脏的多种功能。本文着重对FXR调节SHP的机制及FXR-SHP轴在肝脏中作用进行综述。     

5beta-Cholane activators of the farnesol X receptor

The farnesoid X receptor (FXR) is activated by bile acids, natural agonists for this nuclear receptor. FXR-target genes play important roles in cholesterol and lipid metabolism. We have found that a series of 5beta-cholanic acid derivatives, even though without a hydroxyl group or any other substituent on the steroidal rings, can activate FXR more potently than hydroxylated bile acids in a reporter gene assay. The most potent compound among these derivatives, N-methyl-5beta-glycocholanic acid (NMGCA), induces the formation of receptor/coactivator complex in a gel-shift assay and also increases the expression of FXR target genes in human hepatoma HepG2 cells. Furthermore, in rats, NMGCA causes hypolipidemic effects as well as induction of the FXR target genes in liver. Our results suggest that NMGCA and its derivatives are important FXR activators in the study of the physiological functions of FXR and are potentially useful as pharmaceutical agents for treatment of cholesterol and lipid-related diseases.     

Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis

Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.     

Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA

Recent studies have indicated that bile acids regulate the expression of several genes involved in bile acid and lipid metabolism as ligands for the farnesoid X receptor (FXR). We report here that bile acids are directly able to govern cholesterol metabolism by a novel mechanism. We show that chenodeoxycholic acid (CDCA) enhances low density lipoprotein (LDL) receptor gene expression in human cultured cell lines (HeLa, Hep G2, and Caco-2). The proteolytic activation of sterol regulatory element-binding protein-2 (SREBP-2), a major regulator for LDL receptor gene expression, is not affected by CDCA. Both deoxycholic acid and lithocholic acid as well as CDCA, but not ursodeoxycholic acid, increase the mRNA level for the LDL receptor, even when Hep G2 cells are cultured with 25-hydroxycholesterol, a potent suppressor of gene expression for the LDL receptor. Although it seems possible that FXR might be involved in genetic regulation, both reporter assays with a reporter gene containing the LDL receptor promoter as well as Northern blot analysis reveal that FXR is not involved in the process. On the other hand, inhibition of mitogen-activated protein (MAP) kinase activities, which are found to be induced by CDCA, abolishes the CDCA-mediated up-regulation of LDL receptor gene expression. We further demonstrate that CDCA stabilizes LDL receptor mRNA and that the MAP kinase inhibitors accelerate its turnover. Taken together, these results indicate that bile acids increase LDL uptake and the intracellular cholesterol levels through the activation of MAP kinase cascades in conjunction with a down-regulation of bile acid biosynthesis by FXR. This work opens up a new avenue for developing pharmaceutical interventions that lower plasma LDL by stabilizing LDL receptor mRNA.     

BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis.

During the last three years there have been a plethora of publications on the liver X-activated receptors (LXRalpha, NR1H3, and LXRbeta, NR1H2), the farnesoid X-activated receptor (FXR, NR1H4), and the pregnane X receptor (PXR, NR1I2) and the role these nuclear receptors play in controlling cholesterol, bile acid, lipoprotein and drug metabolism. The current interest in these nuclear receptors is high, in part, because they appear to be promising therapeutic targets for new drugs that have the potential to control lipid homeostasis.In this review we emphasize i) the role of LXR in controlling many aspects of cholesterol and fatty acid metabolism, ii) the expanded role of FXR in regulating genes that control not only bile acid metabolism but also lipoprotein metabolism, and iii) the regulation of bile acid transport/metabolism in response to bile acid-activated PXR.     

孤儿受体与胆固醇及胆汁酸的代谢调节

30多年前,已经发现体内胆固醇及胆汁酸在转录水平受反馈激活或反馈抑制的调节,其机理不清楚。最近,随着孤儿受体LXR基因的克隆及其功能的研究,逐步认识到包括LXR在内的几种孤儿受体作为体内胆固醇及胆汁酸的感受器,在转录水平调节体内胆固醇及胆汁酸的代谢平衡。这4类孤儿受体在胆固醇及其代谢产物与自身代谢平衡之间建立了直接的联系。综述了4类孤儿受体的研究进展,特别是它们和胆固醇及胆汁酸代谢平衡的关系。     

Complementary roles of farnesoid X receptor,pregnane X receptor,and constitutive androstane receptor in protection against bile acid toxicity

The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-Fxrtm1Gonz (FXR-null) and B6;129-Pxrtm1Glaxo-Wellcome (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxrtm1Gonz Pxrtm1Glaxo-Wellcome (FXR-PXR double null or FPXR-null) mice fed a 1% cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase alpha), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.     

Identification of a novel function of hepatic long-chain acyl-CoA synthetase-1 (ACSL1) in bile acid synthesis and its regulation by bile acid-activated farnesoid X receptor

Long-chain acyl-CoA synthetase 1 (ACSL1) plays a pivotal role in fatty acid β‑oxidation in heart, adipose tissue and skeletal muscle. However, key functions of ACSL1 in the liver remain largely unknown. We investigated acute effects of hepatic ACSL1 deficiency on lipid metabolism in adult mice under hyperlipidemic and normolipidemic conditions. We knocked down hepatic ACSL1 expression using adenovirus expressing a ACSL1 shRNA (Ad-shAcsl1) in mice fed a high-fat diet or a normal chow diet. Hepatic ACSL1 depletion generated a hypercholesterolemic phenotype in mice fed both diets with marked elevations of total cholesterol, LDL-cholesterol and free cholesterol in circulation and accumulations of cholesterol in the liver. Furthermore, SREBP2 pathway in ACSL1 depleted livers was severely repressed with a 50% reduction of LDL receptor protein levels. In contrast to the dysregulated cholesterol metabolism, serum triglycerides, free fatty acid and phospholipid levels were unaffected. Mechanistic investigations of genome-wide gene expression profiling and pathway analysis revealed that ACSL1 depletion repressed expressions of several key enzymes for bile acid biosynthesis, consequently leading to reduced liver bile acid levels and altered bile acid compositions. These results are the first demonstration of a requisite role of ACSL1 in bile acid biosynthetic pathway in liver tissue. Furthermore, we discovered that Acsl1 is a novel molecular target of the bile acid-activated farnesoid X receptor (FXR). Activation of FXR by agonist obeticholic acid repressed the expression of ACSL1 protein and mRNA in the liver of FXR wild-type mice but not in FXR knockout mice.