Liver Research最新文献_第7页

Direct-acting antivirals sofosbuvir and daclatasvir attenuate CCl4-induced liver fibrosis in mice 直接作用抗病毒药物索非布韦和daclatasvir可减轻ccl4诱导的小鼠肝纤维化

Q2 Medicine

Liver Research

Pub Date : 2023-02-01 DOI: 10.1016/j.livres.2023.02.001

Mayadah M. Abdelsalam, N. El-Mahdy, Sabry Abou-Saif

引用次数: 0

A novel nomogram based on routine clinical indicators for screening for Wilson’s disease 一种新的基于常规临床指标的肝豆状核变性筛查图

Q2 Medicine

Liver Research

Pub Date : 2023-02-01 DOI: 10.1016/j.livres.2023.02.003

Jiahui Pang, Shuru Chen, W. Gan, Guo-fang Tang, Y. Jie, Zhanyi Li, Y. Chong, Youming Chen, Jiao Gong, Xinhua Li, Yongyu Mei

引用次数: 0

MUTYH is a potential prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma MUTYH是一种潜在的预后生物标志物，与肝细胞癌的免疫浸润相关

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.12.002

Fan Yang , Qinghai Lian , Beibei Ni , Xiusheng Qiu , Yizhan He , Xiaoguang Zou , Fangping He , Wenjie Chen

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The development of biomarkers for early detection and monitoring of HCC has not shown significant progress. Meanwhile, the second adenomatous polyposis-related gene, MUTYH, which encodes a DNA glycosylase, has been observed in its contribution to oxidative DNA damage repair. Abnormal expression of MUTYH can reduce cell survival rate. Therefore, this study investigated the usefulness of MUTYH in diagnosing and prognosis HCC.

Materials and methods

Using The Cancer Genome Atlas (TCGA) data, we analyzed the prognostic value of MUTYH in HCC. We used logistic regression, Wilcoxon signed-rank test, and Kruskal–Wallis test to examine MUTYH expression concerning clinical-pathologic characteristics. Univariate and multivariate Cox regression methods and Kaplan-Meier analysis were applied to determine the related prognostic factors of HCC. The enrichment analysis (GSEA) was used to determine the critical pathways associated with MUTYH. The single-sample gene set enrichment analysis (ssGSEA) was conducted to examine the correlation between MUTYH expression and cancer immune infiltration.

Results

The higher expression of MUTYH in HCC patients was associated with a poorer overall survival rate and a shorter disease-specific survival rate. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that all differentially expressed genes (DEGs) between the high and low expression levels of MUTYH significantly enriched in the trace ligand-receptor interaction, cell cycle, oocyte meiosis, gap junction, and DNA replication. Group analysis revealed the signals of their open access. The neuron system, M phase, DNA repair, Rho GTPase effector, and cell cycle checkpoints were significantly enriched. ssGSEA showed a positive correlation between MUTYH expression and the infiltration levels of Th2 cells, NK cells, and T helper cells. Moreover, a negative correlation was found between MUTYH expression and the infiltration levels of dendritic cells (DCs) and cytotoxic cells.

Conclusions

MUTYH expression levels were positively correlated with immune checkpoint gene expression levels in HCC tissues. The expression level of MUTYH was related to the prognosis of HCC and the immune infiltration of HCC.

背景:肝细胞癌(HCC)是世界范围内癌症相关死亡的主要原因。用于HCC早期检测和监测的生物标志物的开发尚未取得重大进展。与此同时，第二个腺瘤性息肉病相关基因MUTYH编码DNA糖基化酶，已被观察到其对DNA氧化损伤修复的贡献。MUTYH的异常表达可降低细胞存活率。因此，本研究探讨MUTYH在HCC诊断和预后中的作用。材料与方法利用肿瘤基因组图谱(TCGA)数据，分析MUTYH在HCC中的预后价值。我们采用逻辑回归、Wilcoxon符号秩检验和Kruskal-Wallis检验来检验MUTYH表达与临床病理特征的关系。采用单因素和多因素Cox回归方法及Kaplan-Meier分析确定HCC的相关预后因素。富集分析(GSEA)用于确定与MUTYH相关的关键途径。采用单样本基因集富集分析(ssGSEA)检测MUTYH表达与肿瘤免疫浸润的相关性。结果HCC患者中MUTYH的高表达与较差的总生存率和较短的疾病特异性生存率相关。京都基因与基因组百科全书(KEGG)分析显示，MUTYH高表达水平和低表达水平之间的所有差异表达基因(DEGs)在微量配体-受体相互作用、细胞周期、卵母细胞减数分裂、间隙连接和DNA复制中均显著富集。群体分析揭示了他们开放获取的信号。神经元系统、M期、DNA修复、Rho GTPase效应和细胞周期检查点显著富集。ssGSEA显示MUTYH的表达与Th2细胞、NK细胞和T辅助细胞的浸润水平呈正相关。此外，MUTYH的表达与树突状细胞(dc)和细胞毒性细胞的浸润水平呈负相关。结论肝癌组织中smutyh表达水平与免疫检查点基因表达水平呈正相关。MUTYH的表达水平与肝癌的预后及肝癌的免疫浸润有关。

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引用次数: 1

Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis 武田G蛋白偶联受体5基因敲除小鼠血清素代谢的改变对饮食诱导的肝纤维化的保护作用

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.11.009

Jessica M. Ferrell , Matthew Dilts , Zachary Stahl , Shannon Boehme , Sabita Pokhrel , Xinwen Wang , John Y.L. Chiang

Background and aims

Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis, which is a major public health concern. Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor (Fxr) and the membrane receptor Takeda G protein-coupled receptor 5 (Tgr5). Tgr5 is highly expressed in the gut and skeletal muscle, and in cholangiocytes and Kupffer cells of the liver. Tgr5 is implicated in the mediation of liver and gut inflammation, as well as the maintenance of energy homeostasis. Here, we used a high fat, high fructose, and high sucrose (HFS) diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.

Materials and methods

Female C57BL/6J control wild type (WT) and Tgr5 knockout (Tgr5^−/−) mice were fed HFS (high fat (40% kcal), high fructose, and 20% sucrose water) diet for 20 weeks. Metabolic phenotypes were characterized through examination of bile acid synthesis pathways, lipid and cholesterol metabolism pathways, and fibrosis and inflammation pathways.

Results

Tgr5^−/− mice were more glucose intolerant when fed HFS diet, despite gaining the same amount of weight as WT mice. Tgr5^−/− mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice, and gene expression of lipogenic genes was significantly upregulated. Hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) gene expression was consistently elevated in Tgr5^−/− mice, while oxysterol 7alpha-hydroxylase (Cyp7b1), sterol 27-hydroxylase (Cyp27a1), Fxr, and small heterodimer partner (Shp) were downregulated by HFS diet. Surprisingly, hepatic inflammation and fibrosis were also significantly reduced in Tgr5^−/− mice fed HFS diet, which may be due to altered serotonin signaling in the liver.

Conclusions

Tgr5^−/− mice may be protected from high fat, high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.

背景和目的饮食引起的肥胖和代谢综合征可引发脂肪肝疾病发展为非酒精性脂肪性肝炎和纤维化，这是一个主要的公共卫生问题。胆汁酸通过激活核法内甾体X受体(Fxr)和膜受体Takeda G蛋白偶联受体5 (Tgr5)来调节肝脏和肠道的代谢稳态和炎症。Tgr5在肠道和骨骼肌、肝胆管细胞和库普弗细胞中高度表达。Tgr5参与肝脏和肠道炎症的调解，以及能量稳态的维持。在这里，我们采用高脂肪、高果糖和高蔗糖(HFS)饮食来确定在脂肪肝向非酒精性脂肪性肝炎和纤维化进展过程中，胆汁酸信号通过Tgr5调节代谢的机制。材料和方法雌性C57BL/6J对照野生型(WT)和Tgr5敲除型(Tgr5−/−)小鼠饲喂高脂(40% kcal)、高果糖和20%蔗糖水)饲料20周。通过检查胆汁酸合成途径、脂质和胆固醇代谢途径以及纤维化和炎症途径来表征代谢表型。结果stgr5−/−小鼠在获得与WT小鼠相同的体重的情况下，在饲喂HFS时表现出更多的葡萄糖不耐受。与WT小鼠相比，高脂饮食组的Tgr5−/−小鼠肝脏胆固醇和甘油三酯积累显著增加，脂质基因表达显著上调。肝脏胆固醇7 α -羟化酶(Cyp7a1)基因表达在Tgr5−/−小鼠中持续升高，而羟化酶(Cyp7b1)、甾醇27-羟化酶(Cyp27a1)、Fxr和小异源二聚体伴侣(Shp)基因表达在HFS饮食中下调。令人惊讶的是，喂食HFS的Tgr5 - / -小鼠的肝脏炎症和纤维化也显著减少，这可能是由于肝脏中血清素信号的改变。结论stgr5−/−小鼠可能由于血清素代谢的改变而免受高脂、高糖诱导的肝脏炎症和损伤。

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引用次数: 1

Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR 酒精相关性肝病中的肝脂肪组织串扰：mTOR的作用。

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.11.006

Yssa Rodriguez, Jack Dunfield, Tyson Roderique, Hong-Min Ni

Background

Alcohol-associated liver disease (ALD) is a major chronic liver disease around the world without successful treatment. Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality, which is often associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy. Increasing evidence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase that regulates lipid metabolism, cell proliferation and autophagy. However, the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear.

Methods

We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR (Rptor) knockout (Rptor^LKO and Rptor^AKO) as well as Mtor knockout (Mtor^LKO and Mtor^AKO) mice, by crossing Rptor^flox and Mtor^flox mice with albumin Cre or adiponectin Cre mice, respectively. In addition, we generated liver and adipocyte double deletion of Rptor or Mtor (Mtor^LAKO and Rptor^LAKO) mice. The knockout mice with their matched wild-type littermates (Rptor^WT and Mtor^WT) were subjected to acute gavage of 7 g/kg ethanol.

Results

Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities, increased hepatic levels of triglyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage. Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor. Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNFα as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice, which were further increased in adipocyte-specific Mtor or Rptor knockout mice. Conversely, levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage. Moreover, adipocyte-specific Mtor or Rptor knockout mice al

背景：酒精相关性肝病（ALD）是世界上一种主要的慢性肝病，目前尚未得到成功的治疗。急性酒精性肝炎是最严重的ALD之一，死亡率很高，通常与酗酒有关。饮酒失调脂质代谢，增加脂肪组织脂解，并诱导肝脏脂肪变性和脂肪组织萎缩。越来越多的证据表明肝脏和脂肪组织的相互作用在ALD的发病机制中。雷帕霉素的机制靶点（mTOR）是一种磷脂酰肌醇3-激酶（PI3K）样丝氨酸/苏氨酸蛋白激酶，调节脂质代谢、细胞增殖和自噬。然而，mTOR在酗酒诱导的器官损伤中调节脂肪肝串扰的作用尚不清楚。方法：我们通过将Rptor-flox和mTOR-flox小鼠分别与白蛋白-Cre或脂联素-Cre小鼠杂交，产生mTOR（Rptor）敲除（Rptor LKO和Rptor AKO）和mTOR敲除（mTOR LKO和mTOR AKO）小鼠的肝特异性和脂肪细胞特异性调节相关蛋白。此外，我们产生了Rptor或Mtor（Mtor LAKO和Rptor LAKO）小鼠的肝脏和脂肪细胞双重缺失。对敲除小鼠及其匹配的野生型同窝仔（Rptor WT和Mtor WT）进行7g/kg乙醇的急性灌胃。结果：Rptor或Mtor脂肪细胞缺失的小鼠出现肝肿大和脂肪组织萎缩。灌胃酒精增加了小鼠肝脏的肝损伤、肝脂肪变性和炎症，表现为灌胃酒精后小鼠肝脏中血清丙氨酸氨基转移酶活性升高、甘油三酯水平升高和CD68阳性巨噬细胞的肝脏数量增加。脂肪细胞Rptor或Mtor的缺失进一步加重了肝损伤。血清脂肪因子阵列分析显示，野生型小鼠急性灌胃酒精后，促炎细胞因子IL-6和TNFα以及趋化因子MCP-1的水平增加，而脂肪细胞特异性Mtor或Rptor敲除小鼠的促炎细胞细胞因子水平进一步增加。相反，在脂肪细胞特异性Mtor或Rptor敲除小鼠中，抗炎细胞因子IL-10的水平降低。灌胃酒精后，野生型小鼠的循环成纤维细胞生长因子21（FGF21）水平升高，而循环脂联素和胎球蛋白A水平降低。有趣的是，脂肪细胞特异性Mtor或Rptor敲除小鼠已经降低了FGF21的基础水平，而FGF21通过灌胃酒精而增加。此外，脂肪细胞特异性Mtor或Rptor敲除小鼠已经增加了脂联素的基础水平，降低了胎球蛋白A，而酒精灌胃并没有进一步改变这一水平。结论：脂肪细胞而非肝细胞对Mtor通路的消融可导致急性酒精性肝损伤并增加炎症。我们的研究结果证明了脂肪细胞mTOR在ALD中调节脂肪肝串扰的关键作用。

{"title":"Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR","authors":"Yssa Rodriguez, Jack Dunfield, Tyson Roderique, Hong-Min Ni","doi":"10.1016/j.livres.2022.11.006","DOIUrl":"10.1016/j.livres.2022.11.006","url":null,"abstract":"<div><h3>Background</h3><p>Alcohol-associated liver disease (ALD) is a major chronic liver disease around the world without successful treatment. Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality, which is often associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy. Increasing evidence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase that regulates lipid metabolism, cell proliferation and autophagy. However, the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear.</p></div><div><h3>Methods</h3><p>We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR (<em>Rptor</em>) knockout (<em>Rptor</em><sup>LKO</sup> and <em>Rptor</em><sup>AKO</sup>) as well as <em>Mtor</em> knockout (<em>Mtor</em><sup>LKO</sup> and <em>Mtor</em><sup>AKO</sup>) mice, by crossing <em>Rptor</em><sup>flox</sup> and <em>Mtor</em><sup>flox</sup> mice with albumin Cre or adiponectin Cre mice, respectively. In addition, we generated liver and adipocyte double deletion of <em>Rptor</em> or <em>Mtor</em> (<em>Mtor</em><sup><em>L</em>AKO</sup> and <em>Rptor</em><sup><em>L</em>AKO</sup>) mice. The knockout mice with their matched wild-type littermates (<em>Rptor</em><sup>WT</sup> and <em>Mtor</em><sup>WT</sup>) were subjected to acute gavage of 7 g/kg ethanol.</p></div><div><h3>Results</h3><p>Mice with adipocyte deletion of <em>Rptor</em> or <em>Mtor</em> developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities, increased hepatic levels of triglyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage. Liver injury was further exacerbated by deletion of adipocyte <em>Rptor</em> or <em>Mtor</em>. Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNFα as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice, which were further increased in adipocyte-specific <em>Mtor</em> or <em>Rptor</em> knockout mice. Conversely, levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific <em>Mtor</em> or <em>Rptor</em> knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific <em>Mtor</em> or <em>Rptor</em> knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage. Moreover, adipocyte-specific <em>Mtor</em> or <em>Rptor</em> knockout mice al","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"6 4","pages":"Pages 227-237"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/ed/nihms-1869594.PMC10134744.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9399334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Prediction of effective percutaneous transhepatic biliary drainage in patients with hepatocellular carcinoma: A multi-central retrospective study 预测肝细胞癌患者经皮经肝胆道引流的有效性:一项多中心回顾性研究

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.11.008

Haofan Wang , Yitao Mao , Chunning Zhang , Xiaojun Hu , Bin Chen , Luwen Mu , Shuyi Wang , Yifen Lin , Zhanwang Xiang , Mingsheng Huang

Background and aim

Percutaneous transhepatic biliary drainage (PTBD) does not always lead to a reduction in serum total bilirubin (TBil) level in patients with hepatocellular carcinoma and obstructive jaundice. We aimed to develop a model for pre-PTBD prediction of post-procedural TBil decrease in these patients.

Materials and methods

Retrospective database searches were conducted at four teaching hospitals (reference period: January 2010 to December 2018), and baseline characteristics of eligible patients were extracted. Any decrease in TBil after PTBD and the lowest level of TBil post-PTBD <5 mg/dL, 3 mg/dL, and 2 mg/dL were each taken as the standard of effectiveness for computation of its own predictive nomogram. For data dimension decrease and feature selection, the least absolute shrinkage and selection operator (LASSO) regression model was used. A multivariable logistic regression analysis was used to develop nomograms. Each nomogram's performance was internally evaluated for its calibration, discriminative ability, and clinical usefulness.

Results

Included in the study were 138 patients. The model for end-stage liver disease (MELD) score, platelet count, and portal vein thrombosis (PVT) were predictors in the nomogram for any decrease in TBil; international normalized ratio (INR), MELD score, platelet count, and PVT were predictors for a decrease to <5 mg/dL; MELD score, cholinesterase level (CHE), platelet count, and PVT were predictors for a decrease to <3 mg/dL; and MELD score, CHE, platelet count, and pre-albumin level were predictors for a decrease to <2 mg/dL. The clinical value of the nomograms was proven by decision curve analysis.

Conclusions

These models may help inform clinical decision making for performing PTBD procedures.

背景和目的经皮经肝胆道引流(PTBD)并不总是导致肝细胞癌和梗阻性黄疸患者血清总胆红素(TBil)水平的降低。我们的目的是建立一个预测这些患者手术后TBil下降的ptbd前模型。材料与方法回顾性检索四所教学医院的数据库(参考期:2010年1月至2018年12月)，提取符合条件的患者的基线特征。PTBD后TBil的任何下降和PTBD后TBil的最低水平(5mg /dL, 3mg /dL和2mg /dL)均被作为计算其自身预测nomogram的有效性标准。对于数据降维和特征选择，采用最小绝对收缩和选择算子(LASSO)回归模型。采用多变量逻辑回归分析来形成模态图。每个图的表现是内部评估其校准，判别能力和临床用途。结果本研究纳入138例患者。终末期肝病(MELD)评分模型、血小板计数和门静脉血栓形成(PVT)是图中TBil下降的预测因子;国际标准化比值(INR)、MELD评分、血小板计数和PVT是降至5 mg/dL的预测因子;MELD评分、胆碱酯酶水平(CHE)、血小板计数和PVT是降至3 mg/dL的预测因子;MELD评分、CHE、血小板计数和前白蛋白水平是降至2 mg/dL的预测因子。决策曲线分析证实了图的临床价值。结论这些模型可以帮助临床决策实施PTBD手术。

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引用次数: 1

Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis 胆汁酸转运蛋白钠抑制剂与奥贝胆酸联合治疗实验性非酒精性脂肪性肝炎的疗效

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.11.002

David J. Matye , Xuan Qin , Mohammad Nazmul Hasan , Lijie Gu , Yung Dai Clayton , Feng Li , Tiangang Li

Background and aims

Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restricted apical sodium-bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) with adeno-associated virus (AAV)-mediated liver fibroblast growth factor 15 (FGF15) overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat, cholesterol, and fructose (HFCFr) diet-induced NASH mouse model. The beneficial effects of the combined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption. The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid (OCA), which induces endogenous FGF15 and inhibits hepatic bile acid synthesis, can achieve similar anti-NASH effect as the GSK + AAV-FGF15 co-treatment in HFCFr-diet-fed mice.

Materials and methods

Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis. The effect of GSK, OCA, and GSK + OCA treatments on NASH development was compared and contrasted among all groups.

Results

Findings from this study showed that the GSK + OCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period. Neither single treatment nor the GSK + OCA co-treatment reduce hepatic steatosis, but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude. The GSK + OCA co-treatment caused a higher degree of total bile acid pool reduction (∼55%) than either GSK or OCA treatment alone. However, such bile acid pool reduction was insufficient to cause increased fecal lipid loss. The GSK + OCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression. GSK did not reduce gallbladder OCA amount in the GSK + OCA group compared to the OCA group, suggesting that ASBT inhibition does not reduce hepatic OCA distribution.

Conclusions

Unlike the GSK + AAV-FGF15 co-treatment, the GSK + OCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice. The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSK + AAV-FGF15 co-treatment.

背景和目的几种以胆汁酸为基础的单一疗法已被开发用于治疗非酒精性脂肪性肝炎(NASH)，但临床试验结果表明，它们不能令人满意地改善许多患者的NASH和肝纤维化。最近，我们已经证明，在高脂肪、胆固醇和果糖(HFCFr)饮食诱导的NASH小鼠模型中，将肠限制型根尖钠-胆汁酸转运体(ASBT)抑制剂GSK2330672 (GSK)与腺相关病毒(AAV)介导的肝成纤维细胞生长因子15 (FGF15)过表达联合治疗，可显著提高治疗NASH和肝纤维化的疗效。联合治疗的有益效果可归因于胆汁酸池的明显减少，减少了肝脏胆汁酸负担和肠道脂质吸收。本研究的目的是进一步研究GSK与口服生物可利用的奥比胆酸(OCA)联合治疗是否能在hffr -饮食喂养小鼠中达到与GSK + AAV-FGF15联合治疗相似的抗nash效果。材料与方法采用HFCFr饲粮诱导C57BL/6J小鼠NASH和肝纤维化。比较各组间GSK、OCA和GSK + OCA治疗对NASH发展的影响。结果:本研究结果显示，GSK + OCA联合治疗在12周的治疗期间没有引起持续的肥胖减少。无论是单一治疗还是GSK + OCA联合治疗都不能减少肝脂肪变性，但这三种治疗都能减少肝炎症细胞因子和纤维化的程度相似。与单独使用GSK或OCA治疗相比，GSK + OCA联合治疗使总胆汁酸池减少的程度更高(约55%)。然而，这种胆汁酸池的减少不足以引起粪便脂质损失的增加。GSK + OCA共处理阻止了GSK介导的肝胆固醇7 α -羟化酶的诱导，但未能诱导回肠FGF15的表达。与OCA组相比，GSK + OCA组没有减少胆囊OCA的量，提示ASBT抑制没有减少肝脏OCA的分布。结论与GSK + AAV-FGF15联合治疗一样，GSK + OCA联合治疗对小鼠NASH和肝纤维化的疗效并没有提高。缺乏协同效应可能部分归因于总胆汁酸池的适度减少和缺乏高水平的FGF15暴露，如GSK + AAV-FGF15联合治疗中所见。

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引用次数: 1

Prevalence, diagnosis, treatment, and associated factors of hepatitis C in the United States from 1999 to 2018: A population-based cross-sectional study 1999年至2018年美国丙型肝炎的患病率、诊断、治疗和相关因素:一项基于人群的横断面研究

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.12.003

Congnan Zhang , Jiahui Lu , Yajing Zhang , Pengyuan He , Jinyu Xia , Mingxing Huang

Background and aim

Hepatitis C virus (HCV) infection is one of the major global health challenges, leading to a significant increase in rates of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate preventive behavioral interventions. Herein, we sought to determine prevalence, diagnosis, treatment, and risk factors for HCV infection in the general United States (US) population.

Methods

This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey (NHANES). The prevalence of HCV-RNA-positive (HCV-RNA+) was weighted using patient serum sample data collected from 1999 to 2018. A propensity score matching model was used due to the imbalance in the number of HCV-RNA+ and HCV-RNA-negative (HCV-RNA−) patients. Matched variables included gender, age, educational level, marital status, language, household size, alcohol consumption, smoking, number of family members and family income to poverty ratio.

Results

The weighted prevalence of HCV-RNA+ was 1.11% (95% confidence interval (CI): 1.02–1.20), 1.58% (95% CI: 1.42–1.74) for men and 0.67% (95% CI: 0.57–0.77) for women aged 20 years or older in the US from 1999 to 2018. The weighted prevalence of HCV-RNA+ increased from 0.87% (95% CI: 0.62–1.12) in 2013–2014, 0.95% (95% CI: 0.68–1.22) in 2015–2016 to 1.00% (95% CI: 0.72–1.28) in 2017–2018, respectively. In propensity-matched analysis, patients with HCV-RNA+ were more likely to be non-Hispanic black, and have had drug use and blood transfusions. Meanwhile, the weighted diagnostic and treatment rates were 56.27% (95% CI: 50.90–61.64) and 35.40% (95% CI: 27.64–43.16) from 1999 to 2018, respectively.

Conclusions

Active HCV infection rate increased between 2013 and 2018, varied by demographic and risk variables. In the direct-acting antiviral era, affordable treatment and universal screening have the potential to improve overall national health.

背景和目的丙型肝炎病毒(HCV)感染是全球主要的健康挑战之一，导致肝纤维化、肝硬化和肝细胞癌的发病率显著增加。对流行趋势和相关因素进行全面的全国调查可以促进预防性行为干预。在此，我们试图确定美国普通人群中HCV感染的患病率、诊断、治疗和危险因素。方法对美国国家健康与营养检查调查(NHANES)的公开数据进行二次分析。使用1999年至2018年收集的患者血清样本数据对HCV-RNA阳性(HCV-RNA+)的流行率进行加权。由于HCV-RNA+和HCV-RNA阴性(HCV-RNA−)患者数量不平衡，使用倾向评分匹配模型。匹配的变量包括性别、年龄、教育程度、婚姻状况、语言、家庭规模、饮酒、吸烟、家庭成员人数和家庭收入与贫困比。结果1999年至2018年，美国20岁及以上女性的HCV-RNA+加权患病率为1.11%(95%可信区间(CI): 1.02-1.20)，男性为1.58% (95% CI: 1.42-1.74)，女性为0.67% (95% CI: 0.57-0.77)。HCV-RNA+的加权患病率分别从2013-2014年的0.87% (95% CI: 0.62-1.12)、2015-2016年的0.95% (95% CI: 0.68-1.22)增加到2017-2018年的1.00% (95% CI: 0.72-1.28)。在倾向匹配分析中，HCV-RNA+患者更有可能是非西班牙裔黑人，并且有过吸毒和输血。1999 - 2018年的加权诊断率和治疗率分别为56.27% (95% CI: 50.90 ~ 61.64)和35.40% (95% CI: 27.64 ~ 43.16)。结论2013 - 2018年活动性HCV感染率呈上升趋势，随人口统计学和风险变量的变化而变化。在直接作用抗病毒时代，负担得起的治疗和普遍筛查有可能改善整体国民健康。

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引用次数: 1

Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) 甘草中孕烷X受体激活剂的化学基础☆

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.11.007

Anqi Cheng , Saifei Lei , Junjie Zhu , Jie Lu , Mary F. Paine , Wen Xie , Xiaochao Ma

Background and aims

The herbal supplement Gancao, also known as licorice, belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect. Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor (PXR)-mediated induction of hepatic cytochrome P450 3A4 (CYP3A4). The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.

Methods

DPX2 cells were used for cell-based PXR reporter assays. The phytochemicals in Gancao extract were identified using a metabolomics approach. The effects of PXR activators identified from in vitro studies were further investigated in PXR- and CYP3A4-humanized mouse models.

Results

Gancao was verified to be a PXR-activating herb. Two major phytochemicals in Gancao, glycyrrhizin (GZ) and glycyrrhetinic acid (GA), did not activate PXR in the cell-based reporter assays. However, glabridin was shown to activate PXR in a dose-dependent manner. In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator. Although GA did not active PXR in vitro, it induced CYP3A4 expression in a PXR-dependent manner in the PXR- and CYP3A4-humanized mice.

Conclusions

GZ is not a PXR activator. GA could not activate PXR in cell-based reporter assays but it could activate PXR in vivo. Glabridin is a weak PXR activator. This work provides novel insights into the underlying mechanisms of Gancao-related herb-drug interactions via PXR.

背景与目的甘草是甘草属的一种草药补充剂，因其保护肝脏的作用而在世界范围内得到广泛应用。最近的研究引起了人们对肝草通过妊娠X受体(PXR)介导的肝细胞色素P450 3A4 (CYP3A4)的潜在草药相互作用的关注。目前的工作旨在确定甘草中激活PXR和诱导CYP3A4的植物化学物质。方法采用sdpx2细胞进行PXR报告细胞检测。采用代谢组学方法对甘草提取物中的植物化学物质进行了鉴定。在PXR和cyp3a4人源化小鼠模型中进一步研究了从体外研究中鉴定出的PXR激活剂的作用。结果甘草为促pxr活性的中药。甘草中的两种主要植物化学物质甘草酸(glycyrrhizin, GZ)和甘草酸(glycyrrhetinic acid, GA)在基于细胞的报告基因检测中没有激活PXR。然而，光定被证明以剂量依赖的方式激活PXR。体内研究证实GZ不是PXR激活剂，光甘草定是弱PXR激活剂。虽然GA在体外没有激活PXR，但它在PXR和CYP3A4人源化小鼠中以PXR依赖的方式诱导CYP3A4表达。结论sgz不是PXR激活剂。在基于细胞的报告基因试验中，GA不能激活PXR，但在体内可以激活PXR。光定是弱PXR活化剂。本研究通过PXR为肝草相关中草药相互作用的潜在机制提供了新的见解。

{"title":"Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice)","authors":"Anqi Cheng , Saifei Lei , Junjie Zhu , Jie Lu , Mary F. Paine , Wen Xie , Xiaochao Ma","doi":"10.1016/j.livres.2022.11.007","DOIUrl":"10.1016/j.livres.2022.11.007","url":null,"abstract":"<div><h3>Background and aims</h3><p>The herbal supplement Gancao, also known as licorice, belongs to the genus <em>Glycyrrhiza</em> and has been used worldwide for its hepatoprotective effect. Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor (PXR)-mediated induction of hepatic cytochrome P450 3A4 (CYP3A4). The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.</p></div><div><h3>Methods</h3><p>DPX2 cells were used for cell-based PXR reporter assays. The phytochemicals in Gancao extract were identified using a metabolomics approach. The effects of PXR activators identified from <em>in vitro</em> studies were further investigated in PXR- and CYP3A4-humanized mouse models.</p></div><div><h3>Results</h3><p>Gancao was verified to be a PXR-activating herb. Two major phytochemicals in Gancao, glycyrrhizin (GZ) and glycyrrhetinic acid (GA), did not activate PXR in the cell-based reporter assays. However, glabridin was shown to activate PXR in a dose-dependent manner. <em>In vivo</em> studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator. Although GA did not active PXR <em>in vitro</em>, it induced CYP3A4 expression in a PXR-dependent manner in the PXR- and CYP3A4-humanized mice.</p></div><div><h3>Conclusions</h3><p>GZ is not a PXR activator. GA could not activate PXR in cell-based reporter assays but it could activate PXR <em>in vivo</em>. Glabridin is a weak PXR activator. This work provides novel insights into the underlying mechanisms of Gancao-related herb-drug interactions via PXR.</p></div>","PeriodicalId":36741,"journal":{"name":"Liver Research","volume":"6 4","pages":"Pages 251-257"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S254256842200068X/pdfft?md5=bff88fec13aebaa46dadfe043b6ab64e&pid=1-s2.0-S254256842200068X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44955475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Pathogenesis of fatty liver diseases and hepatocellular carcinoma 脂肪肝和肝细胞癌的发病机制

Q2 Medicine

Liver Research

Pub Date : 2022-12-01 DOI: 10.1016/j.livres.2022.12.001

John Y.L. Chiang, Tiangang Li

引用次数: 0

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