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。     

胆汁酸受体在非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)作为一种慢性肝病,在全球的发病率逐年递增。胰岛素抵抗和脂质代谢紊乱,以及随后的炎症反应和纤维化的激活,在其发生发展过程中发挥重要作用。但是对其认识仍很欠缺,且临床尚缺乏有效的药物。科研人员正极力探索NAFLD的相关病因及治疗的新的突破口。胆汁酸是在肝中合成的众多代谢产物之一。除帮助脂肪消化吸收外,胆汁酸还作为信号分子激活胆汁酸受体,一种重要的转录调节因子而发挥效应,对维持机体正常生理代谢至关重要。越来越多的证据表明,胆汁酸受体的功能与NAFLD的发生发展关系密切,研究其相关的作用与功能可为治疗NAFLD提供新见解和药物治疗靶点。本文就胆汁酸受体包括核受体,诸如法尼醇X受体 (farnesoid X receptor, FXR)、孕烷X受体 (pregnane X receptor ,PXR)等,和细胞表面受体,诸如跨膜G蛋白偶联胆汁酸受体5(transmembrane G protein-coupled receptor 5, TGR5)、鞘氨醇-1-磷酸受体2(phingosine-1-phosphate receptor 2, S1PR2)和毒蕈碱胆碱受体3 (M3 muscarinic receptor, M3R)通过调节胆汁酸稳态、脂质和糖代谢、能量代谢、肝的炎症和纤维化等参与NAFLD发病机制的研究进展进行总结,并进一步阐述了胆汁酸受体激动剂对NAFLD的治疗现状,以期更全面地了解NAFLD的发病机制以及为治疗找到更有效的途径。     

乳酸菌胆盐水解酶和共轭脂肪酸产生及对宿主脂代谢影响的研究进展

乳酸菌是一类影响宿主脂代谢的人体肠道益生菌。乳酸菌对脂代谢的影响作用与其产生胆盐水解酶(bile salt hydrolase,EC3.5.1.24,BSH)及共轭转化多不饱和脂肪酸(polyunsaturated fatty acids,PUFAs)关系密切。菌株差异、菌群分布和饮食差异是影响BSH及共轭脂肪酸产生的重要因素。本文重点阐述了两类物质对宿主脂代谢的影响机制,以期为后续研究提供借鉴。BSH能够降解肝脏分泌的胆汁酸(bile acids,BAs),降低脂类物质的吸收。BAs的降解产物胆汁酸脱氧胆酸(deoxycholic acid,DCA)和石胆酸(lithocholic acid,LCA)能够通过机体信号通路法尼类X受体(farnesoid X receptor,FXR)、小异二聚体伴侣(small heterodimer partner,SHP)及肝脏X受体(liver X receptor,LXR)等信号通路进行调控,促进胆固醇转运及向BAs转化。此外,BSH还能够通过下调固醇调节元件结合蛋白1c (sterol regulatory element binding protein 1c,SREBP-1c)、上调5ʹ-腺苷单磷酸激活蛋白激酶α(5ʹ-AMP activated protein kinase,AMPKα)和过氧化物酶体增殖物激活受体α (peroxisome proliferator-activated receptor α,PPARα)抑制脂质合成,促进脂质的分解。PUFAs可被乳酸菌转化产生共轭脂肪酸,如共轭亚油酸(conjugated linoleic acid,CLA)和共轭亚麻酸(conjugated linolenic acid,CLNA),CLA/CLNA能够促进机体产生瘦素(leptin,LP),抑制食欲、促进能量消耗;CLA/CLNA还可以通过激活PPARα进行调控,促进人体脂质的氧化分解。乳酸菌通过以上多种途径共同作用调节宿主的脂代谢,对深入理解乳酸菌调控脂代谢机制及临床应用有着重要意义。     

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。     

胆汁酸的合成调控及其在生理与病理中的功能机制

胆汁酸是一类胆固醇的代谢物,在机体胆固醇与能量代谢平衡和小肠营养物质吸收等方面起着重要作用。肝脏是合成胆汁酸的主要场所。饥饿条件下,胆汁酸从肝脏分泌进入胆管并被储存到胆囊;进食后胆囊收缩,贮存的胆汁酸被排出进入小肠。在小肠中,95%的胆汁酸会被小肠重新吸收,通过肝门静脉返回肝脏,这一过程被称为胆汁酸的肝肠循环。胆汁酸一方面作为乳化剂促进小肠中脂类等物质的吸收及转运,同时也作为重要的信号分子与多种受体结合,包括核受体法呢醇X受体(farnesoidXreceptor,FXR)、维生素D受体(vitaminD receptor,VDR)、孕烷X受体(pregnaneXreceptor,PXR)以及细胞膜表面受体G蛋白偶联受体(cellmembrane surface receptor-G protein coupled receptor, TGR5)等,在调节体内胆汁酸的代谢平衡、糖脂代谢与能量代谢平衡等方面发挥重要作用。肝细胞生长因子(hepatocyte growth factor, HGF)、白介素1-(interleukin-1, IL-1)及肿瘤坏死因子(tumor necrosis factor, TNF-)等协同作用构成了胆汁酸合成的精密调控网络。本文主要综述了胆汁酸的合成调控及其功能方面的最新研究进展,旨在为胆汁酸代谢相关研究提供参考。     

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。     

单纯性肥胖的基因调控机制

单纯性肥胖的产生主要是由于能量摄入超过能量消耗,引起脂肪在细胞内的积累,导致脂肪细胞数目增多、体积增大.能量的摄取与消耗涉及到体内多个代谢调控环节,其中胰岛素样生长因子 -1(insulin-like growth factor-1, IGF-1)信号通路、哺乳类动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)信号通路以及Sirt1信号通路起着关键性作用,它们又可通过影响g过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor g,PPARg)来调控脂肪细胞的分化与形成.     

孕烷X受体在内源物质代谢中的功能

核受体(nuclear receptor, NR)超家族成员孕烷X受体(pregnane X receptor, PXR)是一个配体激活型转录因子,高表达于肝脏和肠组织,在其它某些组织器官中也存在表达。PXR与维甲酸X受体(retinoid X receptor, RXR)形成异源二聚体,在招募大量共活化因子后,与特异性DNA响应元件结合发挥转录调控功能。PXR是一个公认的外源物质感受器,因此,PXR最初被认为是一种调节药物代谢酶和转运体的NR。但目前已知PXR也是同等重要的内源物质受体。最近的研究显示PXR激活可以调节体内葡萄糖代谢、脂质代谢、类固醇内分泌稳态、胆酸和胆红素去毒化、骨矿物质平衡和免疫炎症反应等,本文就这几个方面对PXR作一个综述。     

小胶质细胞极化与抑郁症关系的研究进展

小胶质细胞控制着中枢神经系统主要的免疫功能,在各种精神疾病中发挥重要作用. 某些信号通路的激活引发的神经炎症与抑郁症的发生有着密切的关系. 小胶质细胞是神经炎症的主要介导者,不同的刺激促进小胶质细胞极化,不同极化类型的小胶质细胞能分泌多种炎性细胞因子,在神经炎症调节中具有重要的作用. 临床研究和体内外实验研究表明,抑郁症与小胶质细胞极化介导的神经炎症有关. 小胶质细胞极化参与抑郁症发生发展的可能机制包括NF-κB信号通路激活、呼吸爆发、补体受体3信号通路、NLRP3炎症激活、cannibalism受体1、Notch-1信号通路和过氧化物酶体增殖物激活受体γ的激活. 本文就小胶质细胞极化与抑郁关系的研究进展作一综述.     

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。     

Essential roles of bile acids and their nuclear receptors,FXR and PXR,in the cholestatic liver disease

Bile acids (BAs) are steroid acids found predominantly in the bile of mammals and other vertebrates. Though BAs have been known as digestive juice, recent studies have revealed that BAs act as signaling molecules to control metabolism and inflammation. Today, BAs are considered as potential therapeutic molecules for treatment of complex metabolic liver disease. However, the detergent properties of BAs lead to hepatic injury and intrahepatic cholestasis when BAs are accumulated in the liver with impaired bile flow into gall bladder. Cholestasis is a pathological condition of hepatic retention of cytotoxic bile acids. To date, hydrophilic ursodeoxycholic acid has been currently used to treat cholestasis, but the efficacy of UDCA for cholestasis is still limited. Given that BAs are endogenous ligands of several nuclear receptors, including Farnesoid X receptor and Pregnane X receptor, novel synthetic ligands for those nuclear receptors are promising for the treatment of cholestatic liver diseases.     

Amelioration of hyperglycaemia and hyperlipidaemia by adjusting the interplay between gut microbiota and bile acid metabolism: Radix Scutellariae as a case

BackgroundOur previous clinical research showed that the interaction between gut microbiota and bile acids (BAs) in patients with type 2 diabetes mellitus (T2DM) changed significantly. We hypothesized that T2DM could be improved by adjusting this interaction mediated by farnesoid X receptor (FXR). T2DM belongs to the category of “xiaoke” in traditional Chinese medicine. Radix scutellariae has the effects of clearing away heat and eliminating dampness, curing jaundice and quenching thirst and is widely used alone or in combination with other medicines for the treatment of T2DM in China and throughout Asia. Additionally, the interaction between Radix scutellariae and gut microbiota may influence its efficacy in the treatment of T2DM.PurposeThis study chose Radix scutellariae to validate that T2DM could improve by adjusting the interaction between gut microbiota and bile acid metabolism.Study design and methodsRadix scutellariae water extract (WESB) was administered to a T2DM rat model established by a high-fat diet combined with streptozotocin. The body weight and blood glucose and insulin levels were measured. The levels of serum lipids, creatinine, uric acid, albumin and total bile acid were also detected. Changes in the pathology and histology of the pancreas, liver and kidney were observed by haematoxylin-eosin staining. The 16S rRNAs of gut microbiota were sequenced, and the faecal and serum BAs were determined by liquid chromatography tandem mass spectrometry. The expression levels of BA metabolism-associated proteins in the liver and intestine were evaluated by immunoblot analysis.ResultsThe results showed that WESB improved hyperglycaemia, hyperlipaemia, and liver and kidney damage in T2DM rats. In addition, the abundances of key gut microbiota and the concentrations of certain secondary BAs in faeces and serum were restored. Moreover, there was a significant correlation between the restored gut microbiota and BAs, which might be related to the activation of liver cholesterol 7α-hydroxylase (CYP7A1) and the inhibition of FXR expression in the intestine rather than the liver.ConclusionsThis study provided new ideas for the prevention or treatment of clinical diabetes and its complications by adjusting the interaction between gut microbiota and bile acid metabolism.     

Modulation of bile acid profile by gut microbiota in chronic hepatitis B

Chronic hepatitis B (CHB) is a global epidemic disease that may progress to fibrosis, cirrhosis and hepatocellular carcinoma. The role of the liver‐bile acid‐microbiota axis in CHB remains unclear. The aims of this study are to elucidate the alteration of the gut microbiota and its functions in bile acid homeostasis in CHB patients with different degrees of fibrosis. In the present study, we evaluated serum and faecal bile acid profiles in healthy controls and CHB patients with biopsy‐proven diagnosis: patients had stage 0‐1 fibrosis were classified as mild CHB and patients had stage 2‐4 fibrosis were classified as moderate/advanced CHB. The levels of serum total bile acids (BAs) and primary BAs were increased in CHB patients with moderate/advanced fibrosis, whereas faecal total and secondary BAs levels were significantly lower. Analyses of gut microbiota exhibited a trend of decreased abundance in bacteria genera responsible for BA metabolism in CHB patients with moderate/advanced fibrosis. CHB is associated with altered bile acid pool which is linked with the dysregulated gut microbiota. The higher level of FGF‐19 may act in a negative feedback loop for maintaining the bile acid homeostasis.     

Metabolic alterations of the gut–liver axis induced by cholic acid contribute to hepatic steatosis in rats

12α-Hydroxylated (12αOH) bile acids (BAs) selectively increase with high-fat diet intake. Dietary supplementation with cholic acid (CA) in rats is a possible strategy to reveal the causal link between 12αOH BAs and hepatic steatosis. The present study aimed to investigate the metabolic mechanism underlying the effect of 12αOH BAs on hepatic steatosis. Male WKAH rats were fed either a control (Ct) or CA-supplemented diet (0.5 g/kg). After the 12-week intervention, the CA diet elevated the 12αOH BA levels in the gut–liver axis. CA-fed rats showed greater hepatic lipid accumulation than in the Ct group, regardless of the dietary energy balance. Untargeted metabolomics suggested marked differences in the fecal metabolome of rats subjected to the CA diet compared with that of Ct, characterized by the depletion of fatty acids and enrichment of amino acids and amines. Moreover, the liver metabolome differed in the CA group, characterized by an alteration in redox-related pathways. The CA diet elevated nicotinamide adenine dinucleotide consumption owing to the activation of poly(ADP-ribose) polymerase 1, resulting in impaired peroxisome proliferator-activated receptor α signaling in the liver. The CA diet increased sedoheptulose 7-phosphate, and enhanced glucose-6-phosphate dehydrogenase activity, suggesting promotion of the pentose phosphate pathway that generates reducing equivalents. Integrated analysis of the gut–liver metabolomic data revealed the role of deoxycholic acid and its liver counterpart in mediating these metabolic alterations. These observations suggest that alterations in metabolites induced by 12αOH BAs in the gut–liver axis contribute to the enhancement of liver lipid accumulation.     

Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein–coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.     

Endocrine functions of bile acids

Bile acids (BAs), a group of structurally diverse molecules that are primarily synthesized in the liver from cholesterol, are the chief components of bile. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has recently emerged that BAs are also signaling molecules, with systemic endocrine functions. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor TGR5, and activate nuclear hormone receptors such as farnesoid X receptor alpha. Through activation of these diverse signaling pathways, BAs can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, BA-controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type II diabetes, hyperlipidemia, and atherosclerosis.     

Bile acids: From digestion to cancers

Bile acids (BAs) are cholesterol metabolites that have been extensively studied these last decades. BAs have been classified in two groups. Primary BAs are synthesized in liver, when secondary BAs are produced by intestinal bacteria. Recently, next to their ancestral roles in digestion and fat solubilization, BAs have been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor FXRα or of the G-protein-coupled receptor TGR5. These two receptors have selective affinity to different types of BAs and show different expression patterns, leading to different described roles of BAs. It has been suggested for long that BAs could be molecules linked to tumor processes. Indeed, as many other molecules, regarding analyzed tissues, BAs could have either protective or pro-carcinogen activities. However, the molecular mechanisms responsible for these effects have not been characterized yet. It involves either chemical properties or their capacities to activate their specific receptors FXRα or TGR5. This review highlights and discusses the potential links between BAs and cancer diseases and the perspectives of using BAs as potential therapeutic targets in several pathologies.     

Bile acids and their receptors in regulation of gut health and diseases

It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.     

机体胆汁酸肠-肝轴的研究进展

机体肠道与肝脏间的交互作用形成肠-肝轴,后者的紊乱是肝脏疾病发生的重要原因,而良好的肠道稳态和肝脏的保护对维持机体内环境的稳定起着重要作用。胆汁酸(胆盐)作为肠-肝轴循环中的重要组成成分,不仅参与了机体营养物质的消化代谢,还作为一种信号分子和代谢调节因子,能够激活核受体和G蛋白偶联受体(GPCR)信号通路参与调节肝脏脂质、葡萄糖和能量平衡,维持机体代谢平衡。本文将结合近年来有关胆汁酸的研究进展,从胆汁酸的来源、在肠-肝轴中的循环以及胆汁酸在机体中的作用等方面进行综述,以加深对肠-肝轴重要性的理解。