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LXR及其靶基因COX-2和CETP在肥胖OSAHS幼鼠肝组织中的保护作用
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作者 赖明昱 叶新华 《西安交通大学学报(医学版)》 CAS CSCD 北大核心 2024年第6期895-901,共7页
目的阐明肝X受体(liver X receptor,LXR)及其靶基因环氧化酶-2(cyclooxygenase-2,COX-2)、胆固醇酯转移蛋白(cholesteryl ester transfer protein,CETP)的高表达是肥胖幼鼠阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea-hypopnea s... 目的阐明肝X受体(liver X receptor,LXR)及其靶基因环氧化酶-2(cyclooxygenase-2,COX-2)、胆固醇酯转移蛋白(cholesteryl ester transfer protein,CETP)的高表达是肥胖幼鼠阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)发病过程中的保护性因素,为肥胖儿童OSAHS的发病机制提供基础研究资料。方法24只3~4周龄雄性Wistar幼鼠分为正常对照组(control组)、单纯肥胖组(obesity组)、单纯OSAHS组(OSAHS组)、肥胖+OSAHS组(obesity+OSAHS组)。HE染色观察幼鼠肝组织病理变化;蛋白免疫印迹法(Western blotting)检测幼鼠肝组织中LXRα、COX-2、CETP的表达水平;运用免疫组化方法检测幼鼠肝组织中LXRα、COX-2、CETP的表达水平及分布情况。结果单纯肥胖组和肥胖+OSAHS组幼鼠体质量、总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)含量与正常对照组相比均明显增加(P<0.05),单纯OSAHS组和肥胖+OSAHS组幼鼠血氧饱和度与正常对照组相比均明显降低(P<0.05)。单纯肥胖组、单纯OSAHS组及肥胖+OSAHS组肝组织与正常对照组肝组织相比均有明显损伤,肥胖+OSAHS组肝组织损伤较单纯肥胖组、单纯OSAHS组肝组织损伤程度明显升高。单纯OSAHS组和单纯肥胖组幼鼠肝组织中LXRα、COX-2、CETP表达水平较正常对照组均明显升高(P<0.05)。肥胖+OSAHS组幼鼠肝组织中LXRα、COX-2、CETP表达水平较其余各组均明显升高(P<0.05)。结论LXR及其靶基因COX-2、CETP在肥胖OSAHS幼鼠肝脏中高表达,是发病过程中的可能保护性因素。 展开更多
关键词 x受体(lxr) 阻塞性睡眠呼吸暂停综合征(OSAHS) 肥胖 幼鼠 保护作用
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Liver X receptors and epididymal epithelium physiology
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作者 Fabrice Saez Eléore Chabory +4 位作者 Rémi Cadet Patrick Vernet Silvère Baron2 Jean-Marc A. Lobaccaro Joeol R. Drevet 《Asian Journal of Andrology》 SCIE CAS CSCD 2007年第4期574-582,共9页
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
关键词 EPIDIDYMIS liver x receptors nuclear receptors LIPIDS CHOLESTEROL gene expression
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Role of liver X receptors alpha agonist on expressions of LPS-induced inflammatory response associated factor IRAK-4 and NF-kappaB in Kupffer cells
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作者 Wang Ding Miao Chunmu Gong Jianping 《Journal of Medical Colleges of PLA(China)》 CAS 2008年第2期70-75,共6页
Objective: To explore the role of activated liver X receptor α (LXRα) on the expressions of interleukin-1 receptor associated kinase-4 (IRAK-4) and NF-kappaB (NF-κB) in the inflammatory response which induce... Objective: To explore the role of activated liver X receptor α (LXRα) on the expressions of interleukin-1 receptor associated kinase-4 (IRAK-4) and NF-kappaB (NF-κB) in the inflammatory response which induced by LPS in the Kupffer cells and to investigate the possible mechanisms of LXRα negative regulation of inflammatory response. Methods: The Kupffer cells were isolated from male Kunming mice by collagen perfusion in situ. And these cells were divided into 4 groups: normal control group, LPS treatment group, LXRct agonist T0901317 treatment group, LPS and T0901317 combined treatment group. The LPS treatment group were treated with a final concentration of 1 μg/ml LPS in RPMI 1640 and cultured for 6 h, the T0901317 treatment group were treated with a final concentration of 5 μg/ml in RPMI 1640 and cultured for 24 h, and the combined treatment group received pre-culture for 24 h with a final concentration of 1μg/ml T0901317 in RPMI 1640 and then cultured for 6 h with a final concentration of 5 μg/ml LPS in RPMI 1640. All groups were cultured for 30 h. The expression of LXRα, IRAK-4 and NF-κB at mRNA and protein levels were detected by real-time PCR and Western blotting, and the TNF-α and IL-1β levels were detected by ELISA. Results: The levels of LXRα mRNA and protein were highest in T0901317 group, and lowest in LPS group (P〈0.05). The level of IRAK4 and NF-κB mRNAs and proteins were evidently lower in the Combined-treated group than in LPS group (P〈0.05). And the level of TNF-α and IL-1 were observed highest in LPS group (P〈0.05), but no difference among the Control group, T0901317 group and Combined-treated group (P〉0.05). Conclusion: These date suggest that the LXR agonists can effectively up-regulate the expressions of LXRα mRNA and protein and inhibit the inflammatory response. This may be via down-regulating the expressions of IRAK4 and NF-κB at mRNA and protein levels. 展开更多
关键词 liver x receptors Kupffer cells Inflammation Interleukin-1 receptor associated kinase-4 NF-KAPPAB
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肝脏X受体(LXRα)对奶牛子宫内膜炎调节机制的研究
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作者 赵立香 李荣权 《黑龙江畜牧兽医》 北大核心 2023年第13期68-73,共6页
为了探索肝脏X受体(LXRα)对脂多糖(LPS)诱导的奶牛子宫内膜上皮细胞炎症反应的调节机制,研究采用小鼠体内试验及奶牛子宫内膜上皮细胞体外试验,用LXRα激动剂T0901317激活LXRα,子宫灌注0.2 mg/mL LPS 50μL,检测奶牛子宫内膜上皮细胞... 为了探索肝脏X受体(LXRα)对脂多糖(LPS)诱导的奶牛子宫内膜上皮细胞炎症反应的调节机制,研究采用小鼠体内试验及奶牛子宫内膜上皮细胞体外试验,用LXRα激动剂T0901317激活LXRα,子宫灌注0.2 mg/mL LPS 50μL,检测奶牛子宫内膜上皮细胞活性、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、亚硝酸盐、前列腺素E_(2)(PGE_(2))等炎性细胞因子的表达情况,对核因子κB(NF-κB)、糖原合成酶激酶3β(GSK3β)-重组与合成蛋白(Nrf2)信号通路的影响。结果表明:10,20,40μmol/L的T0901317对奶牛子宫内膜上皮细胞没有毒性作用,对TNF-α、IL-1β、亚硝酸盐、PGE_(2)的表达具有极显著的抑制作用(P<0.01),可降低磷酸化蛋白65(p-p65)、磷酸化蛋白ⅠκB(p-ⅠκB)的磷酰化水平,提高磷酸化葡萄糖合成激酶3β(p-GSK3β)、Nrf2及Nrf2调控的抗氧化因子血红素氧化酶-1(HO-1)的表达。说明LXRα可以通过调节GSK3β-Nrf2信号通路抑制LPS诱导的子宫内膜炎症。 展开更多
关键词 肝脏x受体(lxrα) 脂多糖 奶牛子宫内膜上皮细胞 lxrα激动剂T0901317 炎症反应 调节机制
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Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease 被引量:7
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作者 Jiao-Ya Xu Zhong-Ping Li +1 位作者 Li Zhang Guang Ji 《World Journal of Gastroenterology》 SCIE CAS 2014年第37期13493-13500,共8页
Non-alcoholic fatty liver disease(NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cir... Non-alcoholic fatty liver disease(NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor(FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD. 展开更多
关键词 Farnesoid x receptor Non-alcoholic fatty liver disease MECHANISM THERAPY Lipid metabolism
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法尼醇X受体在治疗胆汁淤积性肝病中的作用机制和药物研究进展
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作者 胡莉 杨伟峰 +3 位作者 刘婷 冯伟红 卢晨娜 李春 《中国药物警戒》 2024年第10期1184-1191,1199,共9页
目的综述法尼醇X受体(FXR)在治疗胆汁淤积性肝病中的作用机制及以FXR为靶点的药物研究进展。方法对FXR通过调控胆汁酸的生成、代谢、转运以及肠肝循环等方式改善胆汁淤积的机制进行阐述,对FXR具有的抗炎、抗氧化和抗肝纤维化等作用和机... 目的综述法尼醇X受体(FXR)在治疗胆汁淤积性肝病中的作用机制及以FXR为靶点的药物研究进展。方法对FXR通过调控胆汁酸的生成、代谢、转运以及肠肝循环等方式改善胆汁淤积的机制进行阐述,对FXR具有的抗炎、抗氧化和抗肝纤维化等作用和机制进行论述,对甾体和非甾体类FXR激动剂和FXR拮抗剂的治疗效果和临床试验进展进行综述。结果与结论胆汁淤积性肝病是以胆汁淤积为主要表现的一组临床常见疾病,其致病机制复杂,也一定程度上决定了用药的复杂性。核受体能调控胆汁酸体内平衡,是目前胆汁淤积治疗药物靶标的研究热点;FXR在保持胆汁酸平衡方面起着至关重要的作用,是一种生理性的胆汁酸核受体,被视为胆汁淤积和相关疾病的主要治疗靶点。随着对FXR研究的不断深入,发现其在胆汁酸稳态、抗炎、抗氧化、抗纤维化方面发挥核心调控作用,FXR激动剂和FXR拮抗剂不断被研发以治疗胆汁淤积性肝病。 展开更多
关键词 胆汁淤积性肝病 法尼醇x受体 法尼醇x受体激动剂 法尼醇x受体拮抗剂
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Pravastatin activates the expression of farnesoid X receptor and liver X receptor alpha in Hep3B cells 被引量:3
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作者 Hyun Woo Byun Eun Mi Hong +5 位作者 Soo Hee Park Dong Hee Koh Min Ho Choi Hyun Joo Jang Sea Hyub Kae Jin Lee 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS 2014年第1期65-73,共9页
BACKGROUND: Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among t... BACKGROUND: Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among the nuclear hormone receptors that regulate cholesterol-bile acid metabolism in the nuclei of hepatocytes. However, there is controversy over whether or how statins change the expression of peroxisome proliferator-activated receptor(PPAR)α, PPARγ, liver X receptor α(LXRα), farnesoid X receptor(FXR), ABCG5, ABCG8, and 7α-hydroxylase(CYP7A1) which are directly involved in the cholesterol saturation index in bile. METHODS: Human Hep3B cells were cultured on dishes. MTT assays were performed to determine the appropriate concentrations of reagents to be used. The protein expression of PPARα and PPARγ was measured by Western blotting analysis, and the mRNA expression of LXRα, FXR, ABCG5, ABCG8 and CYP7A1 was estimated by RT-PCR. RESULTS: In cultured Hep3B cells, pravastatin activated PPARα and PPARγ protein expression, induced stronger expression of PPARγ than that of PPARα, increased LXRα mRNA expression, activated ABCG5 and ABCG8 mRNA expression mediated by FXR as well as LXRα, enhanced FXR mRNA expression, and increased CYP7A1 mRNA expression mediated by the PPARγ and LXRα pathways, together or independently. CONCLUSION: Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRαand CYP7A1 in human hepatocytes. 展开更多
关键词 PRAVASTATIN PPARΓ liver x receptor α farnesoid x receptor gallstone disease
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Coronary heart disease:Significance of liver X receptor α genomics 被引量:3
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作者 Vivek Priy Dave Deepak Kaul 《World Journal of Cardiology》 CAS 2010年第6期140-149,共10页
Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease(CHD).In this regard ligand activated liver X receptor(LXR)-α has emerged as a... Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease(CHD).In this regard ligand activated liver X receptor(LXR)-α has emerged as a key molecular switch by its inherent ability to modulate an array of genes involved in these two fundamental cellular processes.In addition,LXR-α has also been found to play a role in hepatic lipogenesis and innate immunity.Although several lines of evidence in experimental model systems have established the atheroprotective nature of LXR-α,human subjects have been reported to possess a paradoxical situation in which increased blood cellular LXR-α gene expression is always accompanied by increased coronary occlusion.This apparent paradox was resolved recently by the finding that CHD patients possess a deregulated LXR-α transcriptome due to impaired ligand-receptor interaction.This blood cellular mutated LXR-α gene ex- pression correlated specifically with the extent of coro- nary occlusion and hence need is felt to devise new synthetic ligands that could restore the function of this mutated LXR-αprotein in order to modulate genes involved in reverse cholesterol transport and suppression of the inflammatory response leading to the effective treatment of CHD. 展开更多
关键词 CORONARY HEART disease liver x receptor LIPID METABOLISM Inflammation
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The LXRB-SREBP1 network regulates lipogenic homeostasis by controlling the synthesis of polyunsaturated fatty acids in goat mammary epithelial cells
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作者 Wenying Zhang Changhui Zhang +4 位作者 Jun Luo Huifen Xu Jianxin Liu Juan JLoor Hengbo Shi 《Journal of Animal Science and Biotechnology》 SCIE CAS CSCD 2023年第2期614-626,共13页
Background:In rodents,research has revealed a role of liver X receptors(LXR) in controlling lipid homeostasis and regulating the synthesis of polyunsaturated fatty acids(PUFA).Recent data suggest that LXRB is the pred... Background:In rodents,research has revealed a role of liver X receptors(LXR) in controlling lipid homeostasis and regulating the synthesis of polyunsaturated fatty acids(PUFA).Recent data suggest that LXRB is the predominant LXR subtype in ruminant mammary cells,but its role in lipid metabolism is unknown.It was hypothesized that LXRB plays a role in lipid homeostasis via altering the synthesis of PUFA in the ruminant mammary gland.We used overexpression and knockdown of LXRB in goat primary mammary epithelial cells(GMEC) to evaluate abundance of lipogenic enzymes,fatty acid profiles,content of lipid stores and activity of the stearoyl-Co A desaturase(SCD1) promoter.Results:Overexpression of LXRB markedly upregulated the protein abundance of LXRB while incubation with si RNA targeting LXRB markedly decreased abundance of LXRB protein.Overexpression of LXRB plus T0901317(T09,a ligand for LXR) dramatically upregulated SCD1 and elongation of very long chain fatty acid-like fatty acid elongases 5–7(ELOVL 5–7),which are related to PUFA synthesis.Compared with the control,cells overexpressing LXRB and stimulated with T09 had greater concentrations of C16:0,16:1,18:1n7,18:1n9 and C18:2 as well as desaturation and elongation indices of C16:0.Furthermore,LXRB-overexpressing cells incubated with T09 had greater levels of triacylglycerol and cholesterol.Knockdown of LXRB in cells incubated with T09 led to downregulation of genes encoding elongases and desaturases.Knockdown of LXRB attenuated the increase in triacylglycerol and cholesterol that was induced by T09.In cells treated with dimethylsulfoxide,knockdown of LXRB increased the concentration of C16:0 at the expense of C18:0,while a significant decrease in C18:2 was observed in cells incubated with both si LXRB and T09.The abundance of sterol regulatory element binding transcription factor 1 precursor(p SREBP1) and its mature fragment(n SREBP1) was upregulated by T09,but not LXRB overexpression.In the cells cultured with T09,knockdown of LXRB downregulated the abundance for p SREBP1 and n SREBP1.Luciferase reporter assays revealed that the activities of wild type SCD1 promoter or fragment with SREBP1 response element(SRE) mutation were decreased markedly when LXRB was knocked down.Activity of the SCD1 promoter that was induced by T09 was blocked when the SRE mutation was introduced.Conclusion:The current study provides evidence of a physiological link between the LXRB and SREBP1 in the ruminant mammary cell.An important role was revealed for the LXRB-SREBP1 network in the synthesis of PUFA via the regulation of genes encoding elongases and desaturases.Thus,targeting this network might elicit broad effects on lipid homeostasis in ruminant mammary gland. 展开更多
关键词 ELONGASE Lipid homeostasis liver x receptor Mammary gland Polyunsaturated fatty acids
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Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases 被引量:4
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作者 Sundhar Mohandas Balasubramaniyan Vairappan 《World Journal of Hepatology》 CAS 2017年第32期1210-1226,共17页
Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied t... Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor(PXR) is a ligandactivated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gutliver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. Pub Med was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases. 展开更多
关键词 Pregnane x receptor Bacterial translocation Chronic liver disease Intestinal permeability INFLAMMATION Tight junctions
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附子理中汤通过FXR-FGF15通路影响非酒精性脂肪肝胆汁酸代谢
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作者 杜念龙 杨家耀 +2 位作者 徐丹 张书 时昭红 《西部医学》 2024年第11期1576-1581,共6页
目的探讨附子理中汤对非酒精性脂肪性肝病(NAFLD)大鼠胆汁酸(TBA)代谢和肝脏损伤的影响及其机制。方法采用脂肪乳灌胃大鼠,连续4周,构建NAFLD动物模型。造模后用附子理中汤和阳性药物干预治疗,将大鼠分为对照组、模型组、附子理中汤组... 目的探讨附子理中汤对非酒精性脂肪性肝病(NAFLD)大鼠胆汁酸(TBA)代谢和肝脏损伤的影响及其机制。方法采用脂肪乳灌胃大鼠,连续4周,构建NAFLD动物模型。造模后用附子理中汤和阳性药物干预治疗,将大鼠分为对照组、模型组、附子理中汤组和阳性药物组。HE染色观察肝脏的病理变化,生化分析法检测高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、游离脂肪酸(NEFA)的含量,Western blot检测回肠组织中法尼酯X受体(FXR)、成纤维细胞生长因子15(FGF15)的蛋白表达和肝脏组织中FXR的蛋白表达,RT-PCR检测回肠组织中FXR、FGF15的mRNA表达和肝脏组织中FXR的mRNA表达,ELISA检测肝组织TBA水平。结果与对照组比较,模型组大鼠肝脏出现严重病理损伤,血清中HDL-C含量下降,LDL-C和NEFA含量增加(均P<0.01),大鼠肝脏组织中FXR蛋白、mRNA表达和回肠组织中FXR、FGF15的蛋白、mRNA表达上升(均P<0.01),肝组织中TBA水平下降(P<0.01)。与模型组比较,附子理中汤组和阳性药物组大鼠肝脏病理损伤缓解,HDL-C含量增加,LDL-C和NEFA含量下降(均P<0.05),大鼠肝组织中FXR蛋白、mRNA表达和回肠组织中FXR、FGF15蛋白、mRNA表达下降(P<0.05),肝组织中TBA水平增加(P<0.01)。结论附子理中汤治疗可通过激活回肠FXR-FGF15信号,增加肝脏TBA代谢,缓解NAFLD引起的肝损伤。 展开更多
关键词 附子理中汤 非酒精性脂肪肝 法内甾体受体x 成纤维细胞生长因子15 胆汁酸
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Bile acid receptors and nonalcoholic fatty liver disease 被引量:17
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作者 Liyun Yuan Kiran Bambha 《World Journal of Hepatology》 CAS 2015年第28期2811-2818,共8页
With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is ... With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH. 展开更多
关键词 BILE acids BILE acid receptors Nonalcoholicsteatohepatitis Farnesoid x receptor TransmembraneG protein-coupled receptor 5 NONALCOHOLIC fatty liverdisease Hepatic STEATOSIS
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Mechanism of FXR alleviating the liver fibrosis by regulating perilipin 5
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作者 HUANG Xiao‑xia ZHENG Zhi‑min +5 位作者 PANG Bi‑ying HUANG Na‑na LI Xin XIONG Wen‑ting KONG Bo LIU Ji‑sheng 《Journal of Hainan Medical University》 CAS 2023年第12期10-17,共8页
Objective:To investigate the regulatory mechanism in liver fibrosis progression by nuclear receptor of farnesoid X receptor(FXR)and the lipid droplet-associated protein of perilipin 5(PLIN5).Methods:FXR response eleme... Objective:To investigate the regulatory mechanism in liver fibrosis progression by nuclear receptor of farnesoid X receptor(FXR)and the lipid droplet-associated protein of perilipin 5(PLIN5).Methods:FXR response element(FXRE)upstream of PLIN5 gene was found by bioinformatics,and confirmed by a dual luciferase reporter gene system;a hepatic fibrosis model based on human hepatic stellate cell LX-2 was established by induction of transforming growth factor-β1(TGF-β1);mRNA and protein levels ofα-smooth muscle actin(α-SMA)and collagen栺were measured by qPCR and Western blot after transient overexpression of FXR or PLIN5;Oil red O staining was used to study the formation of lipid droplets.Results:The promoter region of the PLIN5 gene contained a known reverse repeats-1(IR-1);the gene expression of PLIN5 in LX-2 cells was up-regulated after FXR activation(P<0.01);overexpression of PLIN5 promoted the formation of lipid droplets and significantly reduced the TGF-β1 induced fibrosis gene expression(P<0.05);FXR activation showed no effects on the inhibition of LX-2 cells activation.Conclusion:Overexpression of PLIN5 promotes the formation of lipid droplets and inhibits activation of LX-2 cells.FXR might bind to the FXRE site upstream of PLIN5 gene and regulate its gene expression.In summary,FXR may prevent liver fibrosis progression partially by regulating lipid droplet-associated protein of PLIN5. 展开更多
关键词 Farnesoid x receptor PLIN5 Lipid droplet Hepatic stellate cell liver fibrosis
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肝X受体激动剂直接激活肝细胞NgBR的表达
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作者 贺晓雨 马佳玲 +1 位作者 闫亚丽 陈元利 《合肥工业大学学报(自然科学版)》 CAS 北大核心 2024年第6期784-789,817,共7页
Nogo-B受体(Nogo-B receptor,NgBR)参与脂肪肝和胰岛素敏感性的形成,但是并不清楚肝X受体(liver X receptor,LXR)激动剂是否能够调控NgBR的表达。文章使用人工合成的LXR激动剂(T0901317和GW3965)分析其对肝源细胞系中NgBR表达的影响,构... Nogo-B受体(Nogo-B receptor,NgBR)参与脂肪肝和胰岛素敏感性的形成,但是并不清楚肝X受体(liver X receptor,LXR)激动剂是否能够调控NgBR的表达。文章使用人工合成的LXR激动剂(T0901317和GW3965)分析其对肝源细胞系中NgBR表达的影响,构建正常或突变NgBR启动子,通过双荧光素酶报告基因系统检测LXR激动剂对启动子活性的影响;采用CRISPR-CAS9方法建立LXRα或LXRβ基因敲除的HepG2细胞系,通过Western Blot检测相关基因的表达变化;向ApoE-/-小鼠腹腔注射LXR激动剂T0901317,分析小鼠肝脏中NgBR的表达变化。结果发现,LXR激动剂能够通过激活LXR促进NgBR蛋白的表达,该诱导作用是以LXRE依赖的方式进行的,并且LXR的表达发挥着重要作用。在体内实验中,也证明了LXR激动剂T0901317上调NgBR蛋白表达。结果表明,NgBR是LXR的靶蛋白,LXR通过结合NgBR启动子LXRE序列促进其转录和翻译。 展开更多
关键词 x受体(lxr) Nogo-B受体(NgBR) lxr激动剂 肝脏
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Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance
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作者 Beibei Wu Yuqing Liu +4 位作者 Hongli Li Lemei Zhu Lingfeng Zeng Zhen Zhang Weijun Peng 《Neural Regeneration Research》 SCIE CAS 2025年第3期695-714,共20页
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar... Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease. 展开更多
关键词 ABCA1 Alzheimer's disease AMYLOID-BETA apolipoprotein E cholesterol metabolism liver liver x receptor low-density lipoprotein receptor-related protein 1 peripheral clearance tauroursodeoxycholic acid
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Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway
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作者 Lan Li Shengye Yang +5 位作者 Xinyu Liang Yameng Liu Hualing Xu Xiaozhen Guo Cen Xie Xiaojun Xu 《Food Science and Human Wellness》 SCIE CAS CSCD 2024年第5期2703-2717,共15页
Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active comp... Non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease worldwide.Bupleurum is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active components of Bupleurum.The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on“gut-liver axis”.Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice,improved insulin sensitivity,and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase(AST)and alanine aminotransferase(ALT).Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor(Fxr),small heterodimer partner(Shp),recombinant fibroblast growth factor 15(Fgf15)and apical sodium dependent bile acid transporter(Asbt)in the intestine,suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling.SSD can significantly reduce the gut microbiota associated with bile salt hydrolase(BSH)expression,such as Clostridium.Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids,thereby inhibiting the intestinal FXR.These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD. 展开更多
关键词 Saikosaponin D(SSD) Non-alcoholic fatty liver disease Bile acids Gut microbiota Farnesoid x receptor
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Team players in the pathogenesis of metabolic dysfunctionsassociated steatotic liver disease:The basis of development of pharmacotherapy
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作者 Shahid Habib 《World Journal of Gastrointestinal Pathophysiology》 2024年第4期1-29,共29页
Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leadin... Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed. 展开更多
关键词 Metabolic dysfunctions-associated steatotic liver disease Visceral adiposity Obesity Farnesoid x receptor Peroxisome proliferator-activated receptor Insulin ADIPONECTIN Glucagon-like peptide-1 GENETICS PNPLA3 TM6SF2 Diabetes DYSLIPIDEMIA Pathogenesis
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Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression
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作者 Yuan-Li Chen Ji-Hong Han Ya-Jun Duan 《中国动脉硬化杂志》 CAS CSCD 北大核心 2013年第9期I0074-I0074,共1页
关键词 LDL受体 巨噬细胞 白细胞介素 诱导 激活 氧化低密度脂蛋白 肝脏 动脉粥样硬化
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FXR激动剂在非酒精性脂肪性肝炎治疗中的研究进展
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作者 虞梦娟 吴雄健 《赣南医学院学报》 2024年第1期42-48,共7页
非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis,NASH),又称代谢性脂肪性肝炎,是病理变化与酒精性肝炎相似但无过量饮酒史的临床综合征,好发于中年特别是超重肥胖个体。非酒精性脂肪性肝炎与肥胖、胰岛素抵抗、2型糖尿病、高脂血症... 非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis,NASH),又称代谢性脂肪性肝炎,是病理变化与酒精性肝炎相似但无过量饮酒史的临床综合征,好发于中年特别是超重肥胖个体。非酒精性脂肪性肝炎与肥胖、胰岛素抵抗、2型糖尿病、高脂血症等代谢紊乱关系密切,主要特征为肝细胞大泡性脂肪变伴肝细胞损伤和炎症,严重者可发展为肝硬化,但至今NASH尚无得到批准的治疗方案。在寻找有效的治疗方法时,解决代谢失调、炎症和抗纤维化的新策略不断涌现。法尼类X受体(Farnesoid X receptor,FXR)除了是胆汁酸代谢和肠肝循环的关键调节剂外,还参与调节代谢稳态,使其成为NASH中有吸引力的治疗靶点。本文综述了FXR激动剂对NASH治疗的研究进展。 展开更多
关键词 非酒精性脂肪性肝炎 脂肪性肝病 代谢紊乱 法尼类x受体 FxR激动剂
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秦川牛LXRα基因第二外显子多态性及其与部分胴体、肉用性状关联性研究 被引量:12
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作者 黄磊 昝林森 +1 位作者 王洪宝 刘洪瑜 《畜牧兽医学报》 CAS CSCD 北大核心 2010年第5期531-535,共5页
旨在分析秦川牛肝X受体基因(LXRα)第二外显子的遗传变异与部分酮体、肉用性能指标的相关性。随机选择相同饲养条件下的497头18~20月龄秦川牛阉牛,采用PCR-SSCP技术进行了LXRα基因部分区段遗传变异检测,运用SPSS程序中的GLM模型分析... 旨在分析秦川牛肝X受体基因(LXRα)第二外显子的遗传变异与部分酮体、肉用性能指标的相关性。随机选择相同饲养条件下的497头18~20月龄秦川牛阉牛,采用PCR-SSCP技术进行了LXRα基因部分区段遗传变异检测,运用SPSS程序中的GLM模型分析所检测到的遗传变异与秦川牛部分肉用性能指标的关联性。结果,找到了LXRα基因DNA序列中的一个突变位点T1530C(NC_007313)。对该遗传变异结果进行分型并与114头秦川牛的肉用性状进行关联分析,结果表明,该位点的多态性与胴体长、大理石花纹评分和背膘厚之间存在显著相关(P<0.05);BB和AB基因型个体胴体长显著高于AA基因型个体(P<0.05),BB基因型个体大理石等级和背膘厚显著高于AA基因型个体(P<0.05),与AB基因型个体差异不显著(P>0.05)。试验结果表明该SNP位点的BB基因型为优势基因型,与胴体长、背膘厚、大理石花纹等肉用性状有相关性,提示LXRα基因能够作为分子标记辅助选择的候选基因。 展开更多
关键词 秦川牛 x受体基因(lxrα) PCR-SSCP 肉用性状
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