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G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment 被引量:3
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作者 Ming Yang Chun-Ye Zhang 《World Journal of Gastroenterology》 SCIE CAS 2021年第8期677-691,共15页
Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumula... Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD. 展开更多
关键词 Nonalcoholic fatty liver disease g protein-coupled receptors METABOLISM bile acids Short-chain fatty acids gut microbiota
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G蛋白偶联胆汁酸受体1调控机体炎症信号通路的研究进展
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作者 何孟娟 黎力之 +5 位作者 幸清凤 关玮琨 廖晓鹏 张海波 郭冬生 樊庆灿 《中国畜牧杂志》 CAS CSCD 北大核心 2023年第7期59-63,69,共6页
G蛋白偶联胆汁酸受体1(GPBAR1)与胆汁酸(BAs)及其衍生物结合后,激活下游通路传导,调控动物的多种代谢过程。GPBAR1通过核转录因子κB(NF-κB)、信号转导和转录激活因子3(STAT3)、NOD样受体蛋白3(NLRP3)炎症小体信号转导通路,调节动物体... G蛋白偶联胆汁酸受体1(GPBAR1)与胆汁酸(BAs)及其衍生物结合后,激活下游通路传导,调控动物的多种代谢过程。GPBAR1通过核转录因子κB(NF-κB)、信号转导和转录激活因子3(STAT3)、NOD样受体蛋白3(NLRP3)炎症小体信号转导通路,调节动物体炎症反应。因此,本文重点阐述GPBAR1对动物炎症通路的调控进展,为BAs及其衍生物成为治疗炎症性疾病的潜在药物提供参考。 展开更多
关键词 g蛋白偶联胆汁酸受体1 炎症 核转录因子ΚB 信号转导和转录激活因子3 NOD样受体蛋白3 胆汁酸
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Role of bile acids in liver diseases mediated by the gut microbiome 被引量:8
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作者 Jun-Wei Shao Tian-Tian Ge +5 位作者 Sen-Zhong Chen Gang Wang Qin Yang Chun-Hong Huang Li-Chen Xu Zhi Chen 《World Journal of Gastroenterology》 SCIE CAS 2021年第22期3010-3021,共12页
The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and... The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites.The interaction between the gut microbiome and bile acids is bidirectional.The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes.Similarly,bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system.The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases,especially liver diseases.As essential mediators of the gut-liver crosstalk,bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1.Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases.We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle. 展开更多
关键词 bile acids gut microbiome Liver diseases Farnesoid X-activated receptor g protein-coupled bile acid receptor 1 Immune response
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Takeda G蛋白偶联受体5在血管平滑肌细胞增殖和迁移中的作用
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作者 杨曦 张黎 +3 位作者 杨耀 王嘉 孙雄山 王强 《中国药理学通报》 CAS CSCD 北大核心 2024年第8期1447-1454,共8页
目的探讨Takeda G蛋白偶联受体5(Takeda G protein-coupled receptor 5,TGR5)在小鼠血管平滑肌细胞(vascular smooth muscle cells,VSMCs)增殖和迁移中的作用及机制。方法用血小板衍生生长因子(platelet-derived growth factor,PDGF-BB... 目的探讨Takeda G蛋白偶联受体5(Takeda G protein-coupled receptor 5,TGR5)在小鼠血管平滑肌细胞(vascular smooth muscle cells,VSMCs)增殖和迁移中的作用及机制。方法用血小板衍生生长因子(platelet-derived growth factor,PDGF-BB)诱导VSMCs增殖、迁移,以INT-777特异性激活TGR5,CCK-8试剂盒及增殖细胞核抗原(Ki-67)免疫荧光染色用于检测细胞增殖能力,划痕试验用于检测细胞迁移能力。Western blot检测TGR5蛋白水平变化。为探究TGR5在血管内膜增生中的作用,将40只雄性野生型C57BL/6J小鼠随机分为假手术组、内膜损伤组、假手术+UDCA(熊去氧胆酸,TGR5激动剂)组及内膜损伤+UDCA组,每组10只。造模完成后按组分别予以口服普通维持饲料及含0.5%UDCA的普通维持饲料,持续21 d后分别取材,HE染色观察颈动脉内膜增生程度,Ki-67免疫荧光染色观察颈动脉内膜血管平滑肌增殖变化。结果特异性激活TGR5明显降低VSMCs增殖活力及Ki-67阳性细胞率,同时使VSMCs划痕愈合速度减慢。特异性激活TGR5使细胞内UCP2表达增加、活性氧(reactive oxygen species,ROS)水平降低。过氧化氢恢复细胞内ROS水平后,TGR5抑制VSMCs增殖迁移的作用被削弱。激活TGR5能减轻颈动脉损伤后内膜增生。结论TGR5可能通过UCP2改善细胞内氧化应激,从而抑制小鼠VSMCs的增殖和迁移。 展开更多
关键词 细胞增殖 细胞迁移 血管平滑肌 再狭窄 g蛋白偶联胆汁酸受体1 INT-777
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丙型肝炎不同基因型G蛋白偶联胆汁酸受体1含量变化及原因研究
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作者 龚卫锋 张养民 《陕西医学杂志》 CAS 2019年第9期1126-1129,共4页
目的:分析陕西省内医院就诊患者中基因分布情况以及对不同基因型进行病情严重程度分析,比较丙肝不同基因型GPBAR1受体含量变化及原因。方法:对就诊的679例丙肝阳性患者中的362例丙肝分型阳性患者进行基因含量、肝功能指标和病情严重程... 目的:分析陕西省内医院就诊患者中基因分布情况以及对不同基因型进行病情严重程度分析,比较丙肝不同基因型GPBAR1受体含量变化及原因。方法:对就诊的679例丙肝阳性患者中的362例丙肝分型阳性患者进行基因含量、肝功能指标和病情严重程度分析,采用ELISA方法检测不同基因型患者血清中的GPBAR1含量。结果:14例Ia型和159例Ib型初期症状较轻,37例甚至到肝硬化失代偿期才被发现;144例Ⅱa型初期症状较重。胆汁酸受体I含量1a﹑1b和2a型结果明显高于3a、3b型和6a型(P<0.05﹚。丙肝患者治疗前后丙肝基因含量比较有统计学差异(P<0.05﹚。丙肝不同亚型病情严重程度比较有统计学差异(P<0.05﹚。362例不同基因型结果比较有统计学差异(P<0.05)。结论:陕西省内丙肝患者以Ⅰb型和Ⅱa型为主,分型结果与患者病情严重程度以及病情进程发展有较大关系。患者接受治疗后遏制了丙肝基因的复制,胆汁酸受体I含量在判断基因型严重程度和个体严重程度上有重要意义。不同基因型患者,因病毒不同分型对肝脏损害程度不同,所以可反映炎性指标的GPBAR1受体含量结果也有明显区别。 展开更多
关键词 丙型肝炎 g蛋白偶联胆汁酸受体1 原因 基因分型
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Dysregulated bile acid homeostasis:unveiling its role in metabolic diseases 被引量:1
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作者 Yanyan Wang Huangru Xu +2 位作者 Xiqiao Zhou Weidong Chen Huiping Zhou 《Medical Review》 2024年第4期262-283,共22页
Maintaining bile acid homeostasis is essential for metabolic health.Bile acid homeostasis encompasses a complex interplay between biosynthesis,conjugation,secretion,and reabsorption.Beyond their vital role in digestio... Maintaining bile acid homeostasis is essential for metabolic health.Bile acid homeostasis encompasses a complex interplay between biosynthesis,conjugation,secretion,and reabsorption.Beyond their vital role in digestion and absorption of lipid-soluble nutrients,bile acids are pivotal in systemic metabolic regulation.Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases,including obesity,type 2 diabetes melli-tus(T2DM),and metabolic dysfunction-associated steatotic liver disease(MASLD).Bile acids are essential signaling molecules that regulate many critical biological processes,including lipid metabolism,energy expenditure,insulin sensitivity,and glucose metabolism.Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms,hormonal dysregu-lation,interactions with the gut microbiota,and changes in the expression and function of bile acid transporters and receptors.This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity,T2DM,and MASLD.We aim to underscore the significance of bile acids as potential diag-nostic markers and therapeutic agents in the context of metabolic diseases,providing insights into their application in translational medicine. 展开更多
关键词 bile acids metabolic diseases OBESITY takeda g protein-coupled receptor 5 type 2 diabetes mellitus metabolic dysfunction-associated steatotic liver disease
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激活TGR5通过抑制CaN/NAFT3减轻ET-1诱导的心肌细胞肥大 被引量:3
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作者 陈德秀 李家富 冯健 《第三军医大学学报》 CAS CSCD 北大核心 2019年第10期939-946,共8页
目的观察G蛋白偶联胆汁酸受体1(G protein-coupled bile acid receptor 1,TGR5)受体激活后对内皮素-1(endothelin-1,ET-1)诱导心肌细胞肥大的作用及其机制的探讨。方法原代培养乳鼠心肌细胞,分为空白对照组和ET-1组,ET-1组的浓度分别为1... 目的观察G蛋白偶联胆汁酸受体1(G protein-coupled bile acid receptor 1,TGR5)受体激活后对内皮素-1(endothelin-1,ET-1)诱导心肌细胞肥大的作用及其机制的探讨。方法原代培养乳鼠心肌细胞,分为空白对照组和ET-1组,ET-1组的浓度分别为10^(-6)、10^(-7)、10^(-8) mmol/L,分别培养12、24、36、48 h,分别检测各组心肌细胞表面积和总蛋白浓度,建立心肌肥大细胞模型。将心肌细胞分为对照组、ET-1组、ET-1+INT-777(TGR5受体激动剂)组、ET-1+INT-777+TGR5 siRNA(干扰TGR5表达)组、ET-1+INT-777+TGR5 siRNA-NC(空病毒)组。采用图像分析系统测定心肌细胞表面积,BCA法测定细胞总蛋白量,RT-PCR检测TGR5、钙调神经磷酸酶(calcineurin,CaN)的mRNA,Western blot方法检测心房尿钠因子(atrial natriuretic factor,ANF)、β-肌球蛋白重链(β-myosin heavy chain,β-MHC)、TGR5、CaN、活化T细胞核因子3(activated T cell nuclear factor 3,NFAT3)的蛋白表达变化。结果 48 h内,ET-1诱导心肌细胞肥大在10^(-8) mmol/L~10^(-6) mmol/L浓度范围内成明显浓度依赖性和时间依赖性(P<0.05),其中ET-1 10^(-6) mmol/L培养48 h心肌细胞表面积为(3 624.7±71.60)um^2,总蛋白量(51.810±1.47)μg,显著高于对照组表面积(1 560.8±3 188.94)um^2和总蛋白(37.827±0.47)μg(P<0.05)。与对照组相比,ET-1组心肌细胞表面积、总蛋白、ANF及β-MHC表达增加(P<0.05),CaN及NFAT3的表达增加(P<0.05)。与ET-1组心肌细胞表面积(4 167.59±271.11)um^2、总蛋白(57.765±0.553)μg、ANF/GAPDH(0.587±0.012)、β-MHC/GAPDH(0.422±0.016)、CaN/GAPDH(0.529±0.006)及NFAT3/Histone3(0.811±0.014)相比,给予TGR5受体激动剂组心肌细胞表面积(2 421.69±123.61)um^2、总蛋白(42.714±0.542)μg、ANF/GAPDH(0.229±0.011)、β-MHC/GAPDH(0.230±0.018)、CaN/GAPDH(0.247±0.008)及NFAT3/Histone3(0.407±0.008)的表达表达增加受到抑制(P<0.05)。予以siTGR5转染细胞后,部分消除了上述的抑制作用(P<0.05)。结论激活TGR5可改善ET-1诱导心肌细胞肥大,其机制可能部分与抑制CaN/NFAT3信号通路有关。 展开更多
关键词 g蛋白偶联胆汁酸受体1 内皮素-1 心肌细胞肥大 钙调神经磷酸酶 活化T细胞核因子3
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激活TGR5受体减轻ET-1致乳小鼠心肌细胞氧化应激损伤的作用及机制 被引量:2
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作者 陈德秀 李家富 +1 位作者 冯健 范欣荣 《重庆医科大学学报》 CAS CSCD 北大核心 2020年第4期442-447,共6页
目的:观察G蛋白偶联胆汁酸受体-1(G protein-coupled bile acid receptor 1,TGR5)激活后对内皮素-1(endothelin-1,ET-1)所致的乳鼠心肌细胞氧化应激损伤的作用,并探讨其可能的机制。方法:原代培养心肌细胞,ET-1浓度分别为10-8、10-7、10... 目的:观察G蛋白偶联胆汁酸受体-1(G protein-coupled bile acid receptor 1,TGR5)激活后对内皮素-1(endothelin-1,ET-1)所致的乳鼠心肌细胞氧化应激损伤的作用,并探讨其可能的机制。方法:原代培养心肌细胞,ET-1浓度分别为10-8、10-7、10-6mmol/L,分别作用12、24、36、48 h,建立心肌细胞氧化应激损伤模型。建立氧化应激损伤模型后,分别给予INT-777(TGR5激动剂)、TGR5 siRNA(病毒干扰TGR5表达)及TGR5空病毒处理48 h。采用CCK-8法观察心肌细胞的存活率,生化试剂盒法检测丙二醛(malonaldehyde,MDA)、超氧化物歧化酶(superoxide dismutase,SOD)、乳酸脱氢酶(lactic dehydrogenase,LDH)含量,Western blot检测细胞核中核因子相关因子-2(nuclear factor erythroid 2-related factor-2,Nrf2)蛋白的表达,Real-time PCR检测Nrf2下游抗氧化基因血红素加氧酶(heme oxygenase,HO-1)mRNA、醌氧化还原酶(quinone oxidoreductase,NQO-1)mRNA、硫氧化蛋白还原酶-1(thioredoxin reductase-1,Txnrd-1)mRNA的表达水平。结果:浓度为10-8、10-7、10-6 mmol/L的ET-1均可诱导SOD活力下降(P=0.000),MDA生成增加(P=0.000);且随着ET-1浓度增加和培养时间延长,心肌细胞氧化应激损伤程度越严重。ET-1(10-6 mmol/L)组MDA及LDH明显增加(均P=0.000),SOD活性明显下降(P=0.000),Nrf2、HO-1 mRNA、Txnrd-1mRNA表达增加(均P=0.000)。予以30μmol/L INT-777可有效改善ET-1诱导的氧化应激损伤,与ET-1组相比,心肌细胞存活率明显增加(P=0.000),MDA及LDH减少(均P=0.000),SOD活性增加(P=0.000),Nrf2、HO-1 mRNA、NQO-1 mRNA、Txnrd-1mRNA表达明显增加(均P=0.000);而病毒干扰TGR5组可部分阻断TGR5激动剂对心肌细胞损伤的改善作用,Nrf2、HO-1mRNA、NQO-1 mRNA、Txnrd-1 mRNA表达下降(均P=0.000)。结论:激活TGR5可能通过激活Nrf2其下游抗氧化基因HO-1、NQO-1及Txnrd-1减轻ET-1对心肌细胞的损伤作用。 展开更多
关键词 g蛋白偶联胆汁酸受体-1 内皮素-1 氧化应激 核因子相关因子-2 血红素加氧酶 醌氧化还原酶 硫氧化蛋白还原酶-1
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Nrf2/HO-1、cAMP/PKA在TGR5减轻高糖、高脂诱导H9C2心肌细胞损伤中的作用机制 被引量:3
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作者 李熠 冯健 《中西医结合心脑血管病杂志》 2021年第21期3667-3673,共7页
目的探讨核因子E2相关因子2(Nrf2)/血红素加氧酶-1(HO-1)、环磷酸腺苷(cAMP)/蛋白激酶A(PKA)在G蛋白偶联胆汁酸受体1(TGR5)减轻高糖、高脂诱导H9C2心肌细胞损伤中的作用机制。方法将大鼠H9C2心肌细胞进行传代培养后分为对照组、高糖+高... 目的探讨核因子E2相关因子2(Nrf2)/血红素加氧酶-1(HO-1)、环磷酸腺苷(cAMP)/蛋白激酶A(PKA)在G蛋白偶联胆汁酸受体1(TGR5)减轻高糖、高脂诱导H9C2心肌细胞损伤中的作用机制。方法将大鼠H9C2心肌细胞进行传代培养后分为对照组、高糖+高脂组、高糖+高脂+齐墩果酸组、干扰组(高糖+高脂+齐墩果酸+TGR5 shRNA)、Nrf2/HO-1组[高糖+高脂+齐墩果酸+Nrf2 siRNA病毒与HO-1抑制剂锌原卟啉(ZnPP)预处理]、cAMP/PKA组[高糖+高脂+齐墩果酸+SQ22536(cAMP抑制剂)预处理],荧光显微镜观察心肌细胞4′,6-二脒基-2-苯基吲哚(DAPI)染色结果,采用四甲基偶氮唑盐(MTT)比色法测定各组心肌细胞活性,采用活性氧荧光探针检测心肌细胞内活性氧(ROS)水平,应用图像分析法、BCA法分别测定各组心肌细胞表面积、蛋白含量,采用蛋白免疫印迹法(Western Blot)检测各组Nrf2、HO-1、PKA水平,以比色法测定肌酸激酶(CK)、乳酸脱氢酶(LDH)水平,高效液相色谱法(HPLC)测定cAMP水平。结果荧光显微镜显示,高糖+高脂组心肌细胞染色强度较对照组增加,而高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组大部分心肌细胞恢复正常,仅少许细胞被染成强蓝色,干扰组染色强度较高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组增加。与对照组比较,高糖+高脂组心肌细胞活性率下降,ROS水平及心肌细胞表面积、心肌细胞蛋白含量增加,而高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组心肌细胞活性率高于高糖+高脂组,ROS水平及心肌细胞表面积、心肌细胞蛋白含量低于高糖+高脂组,差异均有统计学意义(P<0.01);与高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组比较,干扰组心肌细胞活性率下降,ROS水平及心肌细胞表面积、心肌细胞蛋白含量增加,差异均有统计学意义(P<0.01);高糖+高脂组Nrf2、HO-1、PKA、LDH、cAMP水平高于对照组,高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组Nrf2、HO-1、PKA、LDH、cAMP水平均低于高糖+高脂组,干扰组Nrf2、HO-1、PKA、LDH、cAMP水平均高于高糖+高脂+齐墩果酸组、Nrf2/HO-1组、cAMP/PKA组,差异均有统计学意义(P<0.01)。结论激活TGR5受体可能对高糖、高脂诱导H9C2心肌细胞损伤有保护作用,其信号转导机制可能与抑制Nrf2/HO-1、cAMP/PKA信号通路有关。 展开更多
关键词 心肌细胞损伤 核因子E2相关因子2 血红素加氧酶-1 环磷酸腺苷 蛋白激酶A g-蛋白偶联胆汁酸受体1 高糖 高脂 实验研究
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G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes 被引量:1
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作者 Xiaoli Wei Fan Yin +13 位作者 Miaomiao Wu Qianqian Xie Xueqin Zhao Cheng Zhu Ruiqian Xie Chongqing Chen Menghua Liu Xueying Wang Ruixue Ren Guijie Kang Chenwen Zhu Jingjing Cong Hua Wang Xuefu Wang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第3期1128-1144,共17页
Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Fat accumulation“sensitizes”the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35... Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Fat accumulation“sensitizes”the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35(GPR35)is involved in metabolic stresses,but its role in NAFLD is unknown.We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis.Specifically,we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose(HFCF)diet-induced steatohepatitis,whereas loss of GPR35 had the opposite effect.Administration of the GPR35 agonist kynurenic acid(Kyna)suppressed HFCF diet-induced steatohepatitis in mice.Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4(STARD4)through the ERK1/2 signaling pathway,ultimately resulting in hepatic cholesterol esterification and bile acid synthesis(BAS).The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1(CYP7A1)and CYP8B1,promoting the conversion of cholesterol to bile acid.The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice.STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice.Our findings indicate that the GPR35–STARD4 axis is a promising therapeutic target for NAFLD. 展开更多
关键词 g protein-coupled receptor 35 Kynurenic acid STEATOHEPATITIS CHOLESTEROL bile acid STARD4 ACAT2 CYP7A1
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Microbial transformations of bile acids and their receptors in the regulation of metabolic dysfunction-associated steatotic liver disease 被引量:1
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作者 Yuhua Gao Jun Lin +2 位作者 Chuan Ye Siqi Guo Changtao Jiang 《Liver Research》 CSCD 2023年第3期165-176,共12页
Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produce... Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produces primary BAs,the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions.Mechanistically,BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors.Disruption of BA transport and homeostasis leads to the progression of liver diseases,including metabolic dysfunction-associated steatotic liver disease(MASLD)and hepatocellular carcinoma(HCC).Here,we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases. 展开更多
关键词 bile acids(BAs) gut microbiota Metabolic dysfunction-associated steatotic liver disease(MASLD) Metabolic dysfunction-associated steatohepatitis(MASH) Hepatocellular carcinoma(HCC) Farnesoid X receptor(FXR) g protein-coupled bile acid receptor 1(TgR5)
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Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease 被引量:2
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作者 Michele Biagioli Stefano Fiorucci 《Liver Research》 CSCD 2021年第3期119-141,共23页
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors... Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors.The two best characterized receptors of this family are the nuclear receptor,farnesoid X re-ceptor(FXR)and the G protein-coupled receptor,G protein-coupled bile acid receptor 1(GPBAR1).FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism,energy balance,autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders.Clinical trials in non-alcoholic fatty liver disease(NAFLD),however,have shown that selective FXR agonists cause side effects while their efficacy is partial.Because FXR and GPBAR1 exert additive effects,dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials.Here,we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease. 展开更多
关键词 bile acid Farnesoid X receptor(FXR) g protein-coupled bile acid receptor 1(gpbar1) IMMUNITY Lipid metabolism Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH)
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Bile acid receptors and signaling crosstalk in the liver, gut and brain 被引量:4
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作者 Jessica M.Ferrell John Y.L.Chiang 《Liver Research》 CSCD 2021年第3期105-118,共14页
Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasi... Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasis.Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome,while gut microbes influence the composition of the circulating bile acid pool.Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself.This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis,as well as their function as mediators of cellular signaling in the liver-gut-brain axis. 展开更多
关键词 bile acid metabolism Farnesoid X receptor(FXR) gut-brain axis MICROBIOME Neurodegenerative disease Takeda g protein-coupled receptor(TgR5)
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Bile acid receptors and gastrointestinal functions 被引量:18
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作者 Alexander L.Ticho Pooja Malhotra +2 位作者 Pradeep K.Dudeja Ravinder K.Gill Waddah A.Alrefai 《Liver Research》 2019年第1期31-39,共9页
Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea an... Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract. 展开更多
关键词 bile acids Nuclear receptors Farnesoid X receptor(FXR) Takeda g protein-coupled receptor 5(TgR5) gastrointestinal function
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Regulation of bile acid receptor activity 被引量:9
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作者 Yu-Jui Yvonne Wan Lili Sheng 《Liver Research》 2018年第4期180-185,共6页
Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Take... Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases. 展开更多
关键词 bile acid receptor Farnesoid X receptor(FXR) g protein-coupled bile acid receptor Takeda g protein receptor 5(TgR5) Sphingosine-1-phosphate receptor 2 (S1PR2) ACETYLATION Methylation gLYCOSYLATION
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胆汁酸调控S1PR2通路在动物炎症中的作用研究进展
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作者 李保锋 黎力之 +6 位作者 幸清凤 谢芳 廖晓鹏 关玮琨 文龙 张海波 郭冬生 《中国畜牧杂志》 CAS 北大核心 2022年第4期42-46,共5页
胆汁酸(BAs)作为1-磷酸鞘氨醇受体2(S1PR2)上游激活物之一,可直接调控S1PR2活性,也可通过BAs相关信号通路法尼醇X受体(FXR)和G蛋白胆汁酸偶联受体5(TGR5)介导S1PR2途径。S1PR2通过平衡核因子KappaB(NF-κB)与c-Jun氨基末端激酶(JNK)信... 胆汁酸(BAs)作为1-磷酸鞘氨醇受体2(S1PR2)上游激活物之一,可直接调控S1PR2活性,也可通过BAs相关信号通路法尼醇X受体(FXR)和G蛋白胆汁酸偶联受体5(TGR5)介导S1PR2途径。S1PR2通过平衡核因子KappaB(NF-κB)与c-Jun氨基末端激酶(JNK)信号转导通路,调节动物体炎症。本文就BAs代谢及对S1PR2途径的影响和S1PR2途径介导动物免疫反应进行综述,为调控动物免疫反应、调节机体炎症提供参考。 展开更多
关键词 胆汁酸 1-磷酸鞘氨醇受体2 法尼酯X受体 g蛋白胆汁酸偶联受体5 炎症
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TGR5与心血管疾病 被引量:2
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作者 陈德秀(综述) 李家富(审校) 《西南医科大学学报》 2019年第5期489-492,共4页
心血管疾病是严重危害人类健康的疾病之一,病因复杂,目前心血管疾病的预防和治疗充满挑战。G蛋白结合胆汁酸受体1(Gprotein-coupledbileacidreceptor1,TGR5)是一种由胆汁调控的细胞表面G蛋白偶联受体,具有调节能量平衡、改善胰岛素抵抗... 心血管疾病是严重危害人类健康的疾病之一,病因复杂,目前心血管疾病的预防和治疗充满挑战。G蛋白结合胆汁酸受体1(Gprotein-coupledbileacidreceptor1,TGR5)是一种由胆汁调控的细胞表面G蛋白偶联受体,具有调节能量平衡、改善胰岛素抵抗、抗动脉粥样硬化、抗炎、抑制癌细胞生长等作用。在心血管系统的作用包括预防及减轻糖尿病心肌病、抗动脉粥样硬化、改善心功能等,有望成为心血管疾病预防及治疗的药物靶点。 展开更多
关键词 g蛋白偶联胆汁酸受体1 心血管疾病 糖尿病心肌病 动脉粥样硬化
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G蛋白偶联胆汁酸受体1通过抑制内质网应激减轻内皮素-1介导的乳鼠心肌细胞凋亡
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作者 陈德秀 雷贤英 李家富 《西南医科大学学报》 2024年第6期528-534,共7页
目的观察G蛋白偶联胆汁酸受体1(G protein-coupled bile acid receptor 1,TGR5)被激活后对内皮素-1(endothelin-1,ET-1)介导的心肌细胞凋亡的作用,并探讨其机制。方法首先分对照组和ET-1组,ET-1浓度分别为10-6、10-7、10-8 mmol/L,分别... 目的观察G蛋白偶联胆汁酸受体1(G protein-coupled bile acid receptor 1,TGR5)被激活后对内皮素-1(endothelin-1,ET-1)介导的心肌细胞凋亡的作用,并探讨其机制。方法首先分对照组和ET-1组,ET-1浓度分别为10-6、10-7、10-8 mmol/L,分别培养12、24、36、48 h,流式细胞术检测各组各时段凋亡率。选择凋亡率较高的ET-1浓度及时间,进行后续实验。后续实验分为对照组、ET-1组、TGR5激动组、TGR5表达抑制组、TGR5空病毒组,流式细胞术检测各组心肌细胞凋亡率,CCK-8测心肌细胞存活率,RT-PCR检测TGR5mRNA,Western blot检测TGR5、C/EBP同源蛋白(C/EBP homologous protein,CHOP)、c-Jun氨基末端激酶(c-Jun-N-terminal protein kinase,JNK)、磷酸化JNK(phosphorylated JNK,p-JNK)及门冬氨酸特异性半胱氨酸蛋白酶(casepase-12)表达。结果ET-1在10^(-8)~10^(-6) mmol/L的浓度范围呈浓度依赖性,48 h内呈时间依赖性介导心肌细胞凋亡(P<0.05)。后续实验发现激活TGR5后,相较于ET-1组,心肌细胞凋亡率下降,心肌细胞存活率提高,且CHOP、p-JNK、Caspase12蛋白表达受到抑制(P<0.05)。而抑制TGR5表达后可阻断TGR5对心肌细胞凋亡的抑制作用,降低心肌细胞存活率,CHOP、p-JNK、Caspase12蛋白表达增加(P<0.05)。结论ET-1可介导心肌细胞凋亡,其机制可能与内质网应激(endoplasmic reticulum stress,ERS)过度激活有关,而TGR5可能通过抑制ERS,拮抗ET-1对心肌细胞介导的凋亡作用。 展开更多
关键词 g蛋白偶联胆汁酸受体1 心肌细胞凋亡 内皮素-1 内质网应激
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加味葛根芩连汤对2型糖尿病db/db小鼠胰腺组织TGR5/cAMP/GLP-1信号通路的影响 被引量:9
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作者 柳荣 杨霞 +3 位作者 高艳奎 王佳慧 梁永林 朱向东 《中国实验方剂学杂志》 CAS CSCD 北大核心 2023年第4期25-32,共8页
目的:探讨加味葛根芩连汤对肥胖型2型糖尿病(T2DM)模型小鼠血糖血脂及胰腺组织中G蛋白偶联胆汁酸受体5(TGR5)相关途径的影响。方法:将10只7周龄无特定病原体(SPF)级雄性m/m小鼠及50只7周龄SPF级雄性db/db小鼠在SPF级实验室适应性喂养1周... 目的:探讨加味葛根芩连汤对肥胖型2型糖尿病(T2DM)模型小鼠血糖血脂及胰腺组织中G蛋白偶联胆汁酸受体5(TGR5)相关途径的影响。方法:将10只7周龄无特定病原体(SPF)级雄性m/m小鼠及50只7周龄SPF级雄性db/db小鼠在SPF级实验室适应性喂养1周。m/m小鼠作为空白组。成模后随机分为5组,每组10只,分别作为模型组、二甲双胍组(0.2 g·kg^(-1))、加味葛根芩连汤高、中、低剂量组(31.9、19.1、6.4 g·kg^(-1)),灌胃体积均为10 mL·kg^(-1),模型组和空白组灌服等体积蒸馏水,1次/d,连续12周。定期检测小鼠空腹血糖(FBG)。药物干预12周后,检测血清中糖化血清蛋白(GSP)、血清葡萄糖(GLU)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)水平;采用苏木素-伊红(HE)染色观察各组小鼠胰腺组织病理改变,蛋白免疫印迹法(Western blot)检测胰腺组织TGR5、蛋白激酶A(PKA)、磷酸化(p)-PKA、环磷腺苷效应元件结合蛋白(CREB)、p-CREB、前蛋白转化酶1/3(PC1/3)、胰高糖素样肽-1(GLP-1)蛋白的表达水平,酶联免疫吸附测定法(ELISA)检测胰腺组织环磷腺苷(cAMP)的含量。结果:与空白组比较,模型组小鼠胰腺组织出现病理学改变;小鼠FBG、GSP、GLU、TC、TG、LDL-C水平显著增高(P<0.01),HDL-C水平明显降低(P<0.05);胰腺组织中TGR5、p-PKA(Thr197)/PKA、p-CREB(Ser133)/CREB、PC1/3、GLP-1蛋白表达水平显著降低(P<0.01);胰腺组织中cAMP的含量显著降低(P<0.01)。与模型组比较,治疗组胰腺组织病变程度减轻;加味葛根芩连汤高剂量组及二甲双胍组均能够明显降低db/db小鼠FBG、GSP、GLU、TC、TG、LDL-C水平(P<0.05,P<0.01),显著增高db/db小鼠HDL-C水平(P<0.01);除加味葛根芩连汤中剂量组GLP-1蛋白外,加味葛根芩连汤高、中剂量组及二甲双胍组TGR5、p-PKA(Thr197)/PKA、p-CREB(Ser133)/CREB、PC1/3、GLP-1蛋白表达水平均有不同程度的增加(P<0.05,P<0.01);加味葛根芩连汤高、中剂量组及二甲双胍组胰腺组织中cAMP的含量明显增高(P<0.05,P<0.01)。结论:加味葛根芩连汤能够改善T2DM模型db/db小鼠的葡萄糖稳态,其机制可能与调控TGR5/cAMP/GLP-1信号通路相关蛋白表达有关。 展开更多
关键词 2型糖尿病 加味葛根芩连汤 胆汁酸 g蛋白偶联胆汁酸受体5(TgR5)/环磷腺苷(cAMP)/胰高糖素样肽-1(gLP-1)信号通路
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Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis 被引量:7
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作者 John Y.L.Chiang Jessica M.Ferrell 《Liver Research》 2020年第2期47-63,共17页
Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene... Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades.Discovery of bile acid-activated receptors and their roles in the regulation of lipid,glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases,liver cirrhosis,diabetes,obesity and hepatocellular carcinoma.This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years. 展开更多
关键词 Cholesterol 7 alpha-hydroxylase(CYP7A1) bile acid metabolism Farnesoid X receptor(FXR) Takeda g protein-coupled receptor 5(TgR5) bile acid receptors Liver metabolism
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