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Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.  相似文献   
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Background and study aimsTo identify the roles and interaction of farnesoid X receptor (FXR) and peroxisome proliferator activated receptors (PPARs) in Non-alcoholic fatty liver disease (NAFLD) pathogenesis.Material and Methods16 C57/BL male FXR knockout (KO) mice and sex- and age-matched C57/BL wild type mice were received either standard rodent chow or high-fat and sucrose diet (Blank control, NAFLD, FXR KO and FXR KO NAFLD) for 8 weeks. After that, all mice were sacrificed. Liver tissues and blood samples were collected for laboratory and RT-PCR examination.ResultsNAFLD, FXR KO and FXR KO NAFLD mouse models were successful established. Compared with blank control, FXR and PPAR-α mRNA expression decreased significantly (P < 0.05), PPAR-β expression increased slightly (P > 0.05), PPAR-γ expression increased significantly in NAFLD (P < 0.05). Slight increased PPAR-α mRNA expression (P > 0.05) and markedly decreased PPAR-β and PPAR-γ expression (P < 0.05) were found in FXR KO. Compared with FXR KO group, there was a slight increase in PPAR-αand PPAR-βmRNA expression (P > 0.05) and significant increase in PPAR-γ expression (P < 0.05) in FXR KO NAFLD group. Comparison with NAFLD, PPAR-α mRNA expression increased slightly (P > 0.05), PPAR-β and PPAR-γ expression decreased significantly (P < 0.05) in FXR KO NAFLD.ConclusionFXR and PPARs interaction may play important roles in NAFLD pathogenesis.  相似文献   
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Introduction: Bacterial infections are a serious complication of cirrhosis, as they can lead to decompensation, multiple organ failure, and/or death. Preventing infections is therefore very relevant. Because gut bacterial translocation is their main pathogenic mechanism, prevention of infections is mostly based on the use of orally administered poorly absorbed antibiotics such as norfloxacin (selective intestinal decontamination). However, antibiotic prophylaxis leads to antibiotic resistance, limiting therapy and increasing morbidity and mortality. Prevention of bacterial infections in cirrhosis should therefore move away from antibiotics.

Areas Covered: This review focuses on various potentially novel methods to prevent infections in cirrhosis focusing on non-antibiotic strategies. The use of probiotics, nonselective intestinal decontamination with rifaximin, prokinetics and beta-blockers or fecal microbiota transplant as means of targeting altered gut microbiota, bile acids and FXR agonists are all potential alternatives to selective intestinal decontamination. Prokinetics and beta-blockers can improve intestinal motility, while bile acids and FXR agonists help by improving the intestinal barrier. Finally, granulocyte colony stimulating factor (G-CSF) and statins are emerging therapeutic strategies that may improve immune dysfunction in cirrhosis.

Expert Opinion: Evidence for these strategies has been restricted to animal studies and proof-of concept studies but we expect this to change in coming years.  相似文献   
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韩宗萍  卓飞霞  李芳  夏瑾瑜  黄明星 《新医学》2021,52(10):759-763
目的 探索何首乌对肝细胞脂质沉积的影响及其机制。方法 利用永生化肝细胞系LO2,采用1 mmol/L游离脂肪酸(FFA)处理,建立脂肪肝沉积细胞模型。同时加入不同浓度的何首乌提取物处理(0、2.5、5、10 μg/mL),采用油红O染色以观察何首乌对LO2细胞脂肪沉积的作用;采用实时荧光定量PCR进行实验组LO2细胞内法尼酯X受体(FXR)基因及其下游通路胆盐输出泵(BSEP)、小分子异源二聚体伴侣(SHP)、胆固醇7α-羟化酶1(CYP7A1)关键基因的检测;并采用蛋白免疫印迹法检测FXR及其下游通路关键蛋白的表达水平。结果 何首乌处理后的LO2细胞中,油红O的染色量会随着药物浓度增加而增加;FXR的mRNA表达下降,而FXR蛋白诱导促进的下游基因BSEP、SHP的表达相应下降,而其下游抑制基因CYP7A1的表达则上升(P均<0.05)。何首乌处理的LO2肝细胞中,FXR的蛋白水平明显降低,蛋白激酶C (PKC)蛋白磷酸化水平明显降低,而PKC总蛋白表达水平无明显改变,SHP的蛋白水平也明显下降。结论 何首乌可通过抑制FXR-PKC/SHP信号转导通路,从而促进LO2肝细胞内的脂质沉积。为何首乌导致胆汁淤积所引起的肝损伤的治疗提供新的理论依据。  相似文献   
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Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.Amplification of the chromosomal region 3q26-29 is the most frequent genomic alteration in primary squamous cell lung cancers (1) and occurs in many other cancers (2). The best studied oncogenes of this amplicon include phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (3, 4), TP63 (5), sex-determining region Y box 2 (SOX2) (6), epithelial cell transforming 2 (ECT2) (7), and protein kinase C, iota (PRKCI) (8). In an effort to identify oncogenic drivers in lung cancer associated the 3q26-29 amplicon, we previously integrated genomic and gene expression analysis of multiple lung SCC datasets and identified Fragile X-related 1 (FXR1) as a potential new candidate driver gene (9). FXR1 belongs to a small family of RNA-binding proteins that includes Fragile X mental retardation 1 (FMR1) and Fragile X-related 2 (FXR2) (10). Inactivation of FMR1 expression is the cause of the Fragile X syndrome in humans, whereas alterations of FXR1 are yet to be associated with the pathogenesis of human disease. RNA-binding proteins (RBPs) are essential in RNA metabolism, from synthesis to degradation. RBPs coordinate elaborate networks of RNA–protein and protein–protein interactions that link RNA metabolism to signal transduction pathways (11). Aberrant function of RBPs contributes to the progression of many human diseases including cancer. Nevertheless, few RBPs have been identified as oncogenes or tumor suppressors and clinical implications of these cancer related RBPs is largely unknown. FXR1 is highly expressed in vertebrate muscle cells and FXR1 knockout mice die early during embryogenesis, suggesting an essential role for FXR1 in development (12). In this study, we examined whether RNA binding protein FXR1 is a regulator of tumor progression in nonsmall cell lung cancer (NSCLC) and a driver of the 3q amplicon. We tested this hypothesis across a large number of clinical specimens, in gain- and loss-of-function and mechanistic studies in vitro and in vivo. We investigated the translational relevance of our findings in NSCLC tissue microarrays and in datasets of multiple human cancers available in the public domain.  相似文献   
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Introduction: Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease.

Areas covered: Following a summary of FXR’s physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date.

Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.  相似文献   

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目的建立基于报告基因法的高通量筛选细胞模型,用来发现PXR、FXR和LXRα受体激动剂。方法利用Real-time定量PCR方法比较HEK293、Hep G2和LS174T细胞中内源性核受体PXR、FXR和LXRα的表达量,将p SG5-h PXR和p GL3-XREM-CYP3A4、p EGFP-N3-h FXR和EcRETK-Luc、p CMX-FLAG-h LXRα和p GL3-XREM-CYP3A4等质粒分别共转染到工具细胞中,优化共转染比例,并考察阳性药与萤光素酶报告基因表达强度的量效关系、模型特异性和稳定性。结果 1根据Real-time定量PCR结果,模型选用低表达PXR、FXR和LXRα的HEK293细胞作为工具细胞;2根据不同共转染比例对报告基因活性的结果,PXR、FXR和LXRα报告基因药物筛选模型的报告基因和过表达质粒比例,最终分别选择1∶1、2∶1和2∶1;3模型中,报告基因活性均与相应阳性药物(PXR/Rif、FXR/CDCA和LXRα/T0901317)呈剂量依赖性增长;4仅PXR激动剂Rif、FXR激动剂CDCA和LXRα激动剂T0901317可分别明显增加相应筛选模型的报告基因活性,分别重复5次试验后,计算得Z'值分别为0.58、0.66和0.63。结论该研究建立的PXR、FXR和LXRα激动剂高通量筛选模型,具有良好的特异性和稳定性,适用于对PXR、FXR和LXRα受体激动剂的筛选,进而开发以核受体作为药物靶点的药物。  相似文献   
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