Mechanism of FXR alleviating the liver fibrosis by regulating perilipin 5

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.

X射线血管造影在肝癌介入TACE术后复发、疗效及肝脏肿瘤灌注减少的评估价值

目的:探讨X射线血管造影在肝癌介入经导管动脉化疗栓塞术(TACE)术后复发、疗效及肝脏肿瘤灌注减少的评估价值。方法:选取2015年1月至2020年12月于蚌埠市第三人民医院接受治疗的59例肝癌患者,所有患者术前1周、术后4周均行常规X射线血管造影检查,将获得的影像序列导入装有彩色编码数字减影血管造影(ccDSA)成像技术软件的工作站进行分析,在TACE前后的ccDSA图像上手动定义感兴趣区域(ROI),获得时间强度曲线并从中导出达峰时间(TTP)、受试者工作特征(ROC)曲线下面积(AUC)及最大斜率(MS)等定量灌注参数。通过其计算AUC,分析灌注参数对肝癌TACE术后复发、疗效及肝脏肿瘤灌注减少的评估效能。结果:纳入研究的59例患者根据术后复发定义,术后复发39例,未复发20例,术后复发患者灌注TTP(7.38±1.22)s明显低于未复发患者(9.03±1.01)s,差异有统计学意义(t=5.198,P<0.05),AUC、MS明显低于术后未复发患者,差异有统计学意义(t=10.741、31.499,P<0.05),术后复发和未复发患者术前TTP、AUC及MS比较,差异无统计学意义(P>0.05)。根据疗效判定标准,有效35例,无效24例,有效患者术后TTP(9.09±1.08)s明显高于无效患者(7.84±2.07)s,差异有统计学意义(t=3.029,P<0.05),AUC、MS明显高于无效患者,差异有统计学意义(t=3.852、54.366,P<0.05),有效患者和无效患者术前TTP、AUC及MS比较,差异均无统计学意义(P>0.05),有效患者和无效患者术后TTP、AUC及MS均高于术前,两组比较差异有统计学意义(t=3.029、3.852、54.366,P<0.05)。根据主观血管造影栓塞端点(SACE)分级标准,Ⅲ级33例,Ⅳ级26例,Ⅲ级和Ⅳ级患者术前TTP、AUC及MS比较,差异无统计学意义(P>0.05),Ⅳ级患者术后TTP、AUC及MS均明显低于Ⅲ级患者,两组比较差异有统计学意义(t=7.697、3.498、58.968,P<0.05)。TTP、AUC及MS评估肝癌介入TACE术后复发的灵敏度为66.70%、89.70%和59.00%,特异度为55.00%、55.00%和55.00%,TTP、AUC及MS评估肝癌介入TACE术后复发的AUC分别为0.629(95%CI:0.478~0.779)、0.827(95%CI:0.723~0.931)和0.512(95%CI:0.356~0.667);TTP、AUC及MS评估肝癌介入TACE术后疗效的灵敏度为64.10%、79.50%、61.50%,特异度为55.00%、65.00%和55.00%,TTP、AUC及MS评估肝癌介入TACE术后疗效的AUC分别为0.609(95%CI:0.462~0.756)、0.808(95%CI:0.698~0.918)和0.580(95%CI:0.413~0.747);TTP、AUC及MS评估肝癌介入TACE术后肝脏肿瘤灌注减少的灵敏度为69.20%、82.10%和53.80%,特异度为70.00%、75.00%和55.00%,TTP、AUC及MS评估肝癌介入TACE术后肝脏肿瘤灌注减少的AUC分别为0.745(95%CI:0.613~0.877)、0.842(95%CI:0.724~0.960)和0.507(95%CI:0.360~0.654)。结论:X射线血管造影检查后的数据通过ccDSA的定量分析获得的TTP、AUC及MS灌注参数,对肝癌介入TACE术后复发、疗效及肝脏肿瘤灌注减少的评估均具有一定应用价值。

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

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.

Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway

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.

肝X受体激动剂直接激活肝细胞NgBR的表达

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。

Team players in the pathogenesis of metabolic dysfunctionsassociated steatotic liver disease:The basis of development of pharmacotherapy

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.

癌-睾丸抗原SPANXB在肝癌中的表达及其影响肝癌进展的机制研究

目的·分析癌-睾丸抗原(cancer-testis antigen,CTA)家族成员SPANXB(sperm protein associated with the nucleus on the X chromosome B)在肝癌中的表达及其与肝癌患者预后之间的相关性,并探究SPANXB对肝癌细胞增殖的影响及其潜在机制。方法·利用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中的肝癌样本数据,分析SPANXB在肝癌组织中的表达及其与患者生存期的相关性。构建稳定敲低SPANXB与稳定过表达SPANXB的肝癌细胞系,利用活细胞成像实验、EdU细胞增殖实验和平板克隆形成实验评估SPANXB对肝癌细胞增殖的影响。通过RNA测序(RNA-sequence,RNA-seq)探究SPANXB调控肝癌细胞增殖的相关通路,并利用细胞周期实验验证SPANXB对肝癌细胞周期的影响。采用免疫沉淀-质谱联用技术(immunoprecipitation-mass spectrometry,IP-MS)探索与SPANXB相互作用的蛋白,并使用免疫共沉淀(co-immunoprecipitation,Co-IP)进行验证。结果·SPANXB mRNA在肝癌组织中的表达高于正常组织(P=0.003),且与肝癌患者的生存期呈负相关。稳定敲低SPANXB可降低肝癌细胞的增殖能力、克隆形成能力,而稳定过表达SPANXB则可促进这些过程。RNA-seq的结果显示,SPANXB的敲低可下调DNA复制与G1/S细胞周期转换相关通路,细胞周期实验的结果显示SPANXB的敲低可导致肝癌细胞周期发生改变。IP-MS和Co-IP结果显示,SPAXNB与有丝分裂停滞缺陷2样蛋白1(mitotic arrest deficient 2-like protein 1,MAD2L1)、WD重复域蛋白5(WD repeat domain 5,WDR5)等细胞周期相关蛋白存在相互作用。结论·SPANXB的高表达与肝癌的预后呈负相关,其可能通过与MAD2L1、WDR5相互作用调控细胞周期并增强肝癌细胞的增殖活性。

TO901317经LXRα/NF-κB抑制MCF-7乳腺癌细胞迁移

目的探究肝X受体(LXR)激动剂TO901317对MCF-7人乳腺癌细胞迁移能力的作用及机制。方法体外培养MCF-7细胞。先运用不同浓度的TO901317处理MCF-7细胞24 h,然后通过LXRαsiRNA转染或核因子κB(NF-κB)抑制剂PDTC处理细胞,划痕愈合实验检测MCF-7细胞迁移能力的改变,同时运用蛋白免疫印迹法检测LXRα、NF-κB p65与IκBα的表达。结果随着TO901317处理浓度的增加,MCF-7细胞的迁移能力明显得到抑制,差异具有统计学意义(P<0.05);同时LXRα与IκBα的表达逐渐增强,而NF-κB p65的表达则显著降低。LXRαsiRNA可显著延缓TO901317的上述作用,PDTC处理则进一步增强TO901317对乳腺癌细胞迁移的抑制作用。结论TO901317可激活LXRα,下调NF-κB p65、上调IκBα的表达,抑制乳腺癌细胞迁移。

FXR激动剂在非酒精性脂肪性肝炎治疗中的研究进展

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。

肝X受体α(LXRα)及三磷酸腺苷结合盒转运体A1(ABCA1)参与子痫前期发病的机理研究

目的探讨在子痫前期发病中LXRα和ABCA1的变化及二者与脂质代谢异常的关系。方法选取2019年10月至2023年6月在福建医科大学附属泉州第一医院妇产科分娩的子痫前期孕妇112例(子痫前期组),根据妊娠34周前是否诊断为子痫前期,将其分为早发组和晚发组;同期住院生产的70名正常孕产妇为正常对照组(正常组),采用生化方法测得血清中血脂水平(TG、TC、LDL及HDL);采用ELISA法检测2组患者血清中的LXRα与ABCA1蛋白表达水平;采用免疫组化及半定量PCR(RT-PCR)检测正常组及子痫前期组胎盘组织中LXRα与ABCA1的表达。分析LXRα和ABCA1表达与血脂异常的关系。结果子痫前期组TG、TC、LDL高于正常组,HDL低于正常组,差异均具有统计学意义(均P<0.05)。RT-PCR及免疫组化显示子痫前期组胎盘和血清的LXRα、ABCA1表达低于正常组(P<0.05)。胎盘上LXRαmRNA水平与LXRα蛋白表达水平呈正相关,差异具有统计学意义(P<0.05);两组患者血清ABCA1的表达水平与其胎盘上ABCA1蛋白浓度呈正相关,与血液循环中LDL的浓度水平呈负相关,与血液循环中HDL的浓度水平呈正相关,差异均有统计学意义(均P<0.05)。结论子痫前期妇女的血脂水平及血清中LXRα、ABCA1表达异常,且与病情严重程度相关;LXRα及ABCA1参与了子痫前期的血脂代谢异常的发生,可以作为临床上评判相关病程进展的依据。

慢病毒-HBx表达载体的构建及其在人正常肝细胞系Chang liver的稳定表达

目的:构建乙型肝炎病毒X基因(hepatitis B virus x,HBx)慢病毒表达载体,建立稳定表达HBx蛋白的人正常肝细胞系Chang liverHBx.方法:应用聚合酶链式反应(polymerase chain reaction,PCR)方法从质粒中扩增HBx基因,并克隆到慢病毒p EB-3xflag-GP-Puro载体上,经PCR、酶切和测序鉴定正确后经慢病毒包装感染人肝细胞Chang liver,再用嘌呤霉素筛选出稳定表达HBx蛋白的细胞株,最后用免疫荧光和Western blot技术检测HBx蛋白的表达.结果:酶切鉴定和基因测序证实HBx基因成功克隆到慢病毒表达载体上,重组慢病毒经包装纯化后获得滴度为1×108 TU/m L,用包装好的重组慢病毒感染人肝细胞Chang liver,经嘌呤霉素筛选获得单克隆细胞株Chang liver-HBx,利用免疫荧光和Western blot技术检测发现细胞株Chang liver-HBx可稳定表达HBx蛋白.结论:成功构建了HBx的重组慢病毒表达载体,获得了稳定表达HBx的Chang liver细胞系Chang liver-HBx,为进一步研究HBx诱导正常肝细胞恶性转化提供细胞模型.

法尼醇X受体激动剂对非酒精性脂肪性肝炎治疗作用研究进展

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

Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease

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.

Reduction in Bile Acid Pool Causes Delayed Liver Regeneration Accompanied by Down-regulated Expression of FXR and C-Jun mRNA in Rats

The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile acid size,and then a partial hepatectomy(PH)was performed.Rats fed on the normal diet served as the controls.Measurements were made on the rate of liver regeneration,the labeling indices of PCNA,the plasma total bile acids(TBA),and the mRNA expression of cholesterol 7alpha-hydroxylase(CYP7A1),...

Pravastatin activates the expression of farnesoid X receptor and liver X receptor alpha in Hep3B cells

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.

Coronary heart disease:Significance of liver X receptor α genomics

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.

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

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.

In-line X-ray phase-contrast imaging of murine liver microvasculature ex vivo

Imaging blood vessels is of importance for determining the vascular distribution of organs and tumors.Phase-contrast X-ray imaging can reveal the vessels in much more detail than conventional X-ray absorption method.Visualizing murine liver microvasculature ex vivo with phase-contrast X-ray imaging was performed at Shanghai Synchrotron Radiation Facility.Barium sulfate and physiological saline were used as contrast agents for the blood vessels.Blood vessels of <Φ20μm could be detected by replacing resident blood with physiological saline or barium sulfate.An entire branch of the portal vein (from the main axial portal vein to the ninth generation of branching) could be captured in a single phase-contrast image.It is demonstrated that selective angiography based on phase contrast X-ray imaging,with a physiological material of low Z elements (such as saline) being the contrast agent,is a viable imaging strategy.Further efforts will be focused on using the technique to image tumor angiogenesis.

Gut-liver axis signaling in portal hypertension

Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.

沙棘熊果酸对酒精性肝损伤大鼠肝FXR信号通路的影响

目的:初步探讨沙棘熊果酸对酒精性肝损伤大鼠肝法尼醇X受体(Farnesoid X receptor,FXR)信号通路关键蛋白表达的影响。方法:6周龄SPF级SD大鼠随机分为4组,每组9只,分别为正常对照组、酒精模型组、熊果酸对照组和熊果酸+酒精组,干预时间为8周。采用苏木精-伊红(H&E)染色法观察大鼠肝组织病理学变化;测定大鼠血清中谷丙转氨酶(Alanine aminotransferase,ALT)、谷草转氨酶(Aspartateaminotransferase,AST)活力和血清总胆汁酸(Total bile acid,TBA)、肝脏甘油三酯(Triglyceride,TG)、总胆固醇(Total cholesterol,TC)含量;酶联免疫吸附(Enzyme linked immunosorbent assay,ELISA)法检测血清细胞因子肿瘤坏死因子α(Tumor necrosis factor-α,TNF-α)、白细胞介素1β(Interleukin 1β,IL-1β)、白细胞介素10(Interleukin 10,IL-10)含量;免疫印迹法(Western blotting)测定大鼠肝FXR信号通路相关蛋白表达情况。结果:与正常对照组相比,酒精模型组大鼠肝脏存在大小不一的脂肪空泡和大量炎性细胞浸润;血清ALT、AST活力,TNF-ɑ、IL-1β水平,TBA含量和肝脏TG、TC含量均显著升高(P<0.05)、IL-10水平显著下降(P<0.05)。经熊果酸干预后,肝脏脂肪变性得到明显改善,炎性细胞浸润减少;血清ALT、AST活力,TNF-α、IL-1β水平,TBA含量和肝脏TG含量均有不同程度的显著下降(P<0.05),IL-10水平显著提高(P<0.05)。Western blotting结果显示,与正常对照组相比,模型组大鼠肝脏FXR蛋白表达显著降低(P<0.05),CYP7A1和SREBP-1c蛋白表达均显著升高(P<0.05);而经熊果酸干预后,FXR蛋白表达明显提高,CYP7A1及SREBP-1c蛋白表达明显下调,且差异均具有统计学意义(P<0.05)。结论:沙棘熊果酸能够明显改善酒精诱导的肝脏损伤,其作用机制可能与上调肝FXR、抑制CYP7A1和SREBP-1c的蛋白表达,从而维胆汁酸稳态、调节脂质代谢有关。