Liver International最新文献

{"title":"Oxidised Apolipoprotein Peptidome Characterises Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"Gabriele Mocciaro,&nbsp;Amy L. George,&nbsp;Michael Allison,&nbsp;Mattia Frontini,&nbsp;Isabel Huang-Doran,&nbsp;Frank Reiman,&nbsp;Fiona Gribble,&nbsp;Julian L. Griffin,&nbsp;Antonio Vidal-Puig,&nbsp;Vian Azzu,&nbsp;Richard Kay,&nbsp;Michele Vacca","doi":"10.1111/liv.16200","DOIUrl":"10.1111/liv.16200","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied the serum of 87 biopsy-confirmed MASLD patients and 20 age- and sex-matched control (CTRL) subjects. We first employed an untargeted LC-MS/MS peptidomics approach (9 CTRL, 32 MASLD) to identify key hits differentially modulated, and subsequently validated the most relevant findings through targeted peptidomics in an enlarged study population (87 MASLD and 20 CTRL).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Untargeted serum peptidomics identified several oxidised apolipoprotein peptide fragments, including ApoE and ApoC-III, significantly upregulated in MASLD compared to CTRL. Specifically focusing on the oxidative status of intact ApoC-III, studied through its major glycoforms (ApoC-III₀, ApoC-III_i and ApoC-III_ii), we observed a marked reduction in non-oxidised forms of these circulating peptides alongside substantially increased levels of their oxidised proteoforms in MASLD versus controls (but not within the disease stages). Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data reveals a previously unreported oxidised apolipoprotein profile associated with MASLD. The functional and clinical implications of these findings warrant further mechanistic investigation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-18a-5p/PXR/SREBP2 Was Involved in MAFLD Associated With Methyl Tert-Butyl Ether Among Petrol Station Workers","authors":"Hanyun Wang,&nbsp;Mingxiao Guo,&nbsp;Fengtao Cui,&nbsp;Mengdi Li,&nbsp;Xianan Zhang,&nbsp;Wei Gao,&nbsp;Xingqiang Fang,&nbsp;Li Chen,&nbsp;Ye Xin,&nbsp;Yucheng Sun,&nbsp;Piye Niu,&nbsp;Junxiang Ma","doi":"10.1111/liv.16246","DOIUrl":"10.1111/liv.16246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic associated fatty liver disease (MAFLD), previously defined as non-alcoholic fatty liver disease (NAFLD), has been shown to be closely related to many environmental pollutants. Lately, we found methyl tert-butyl ether (MTBE), a new environmental pollutant, could increase NAFLD risk in American adults, which still needs more population epidemiological studies to verify, and its pathogenic mechanism is not yet clear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a cross-sectional study among petrol station workers, diagnosed their MAFLD according to internationally recognised diagnostic criteria, assessed the potential association of MTBE exposure with MAFLD risk, and explored the miR-18a-5p/PXR/SREBP2 pathway as possible pathogenic mechanisms in male Wistar rats and HepaRG cells treated with MTBE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Blood MTBE levels were found to be significantly correlated with an increased risk of MAFLD, and MAFLD risk increased by 24.3% for every 0.1 μg/L increase in blood MTBE. Consistently, we found that MTBE exposure could induce MAFLD in rats and HepaRG cells, and activate pregnane X receptor (PXR) by inhibiting miR-18a-5p to upregulate the expression of sterol regulatory element-binding protein 2 (SREBP2) and its nuclear translocation, thereby upregulating the expression of its downstream target genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study demonstrated that MTBE exposure might be a significant risk factor for MAFLD, and MTBE could promote liver cholesterol synthesis and lipid deposition by activating the miRNA-18a-5p/PXR/SREBP2 pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to the Potential and Challenges of Autophagy in the Treatment of Liver Fibrosis","authors":"Li-Shuang Hou,&nbsp;Bang-Le Zhang","doi":"10.1111/liv.16238","DOIUrl":"10.1111/liv.16238","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maralixibat Reduces Serum Bile Acids and Improves Cholestatic Pruritus in Adolescents With Alagille Syndrome","authors":"Gideon Hirschfield,&nbsp;Shannon M. Vandriel,&nbsp;Douglas B. Mogul,&nbsp;Marshall Baek,&nbsp;Pamela Vig,&nbsp;Binita M. Kamath","doi":"10.1111/liv.16201","DOIUrl":"10.1111/liv.16201","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alagille syndrome (ALGS) is a multisystem cholestatic disorder. Maralixibat is approved for the treatment of cholestatic pruritus in ALGS with limited data in adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Participants were included if they received ≥ 2 doses of maralixibat at age ≥ 16 years in one of the three previously published maralixibat ALGS clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eleven initiated treatment &lt; 16 years old (median age, 13.0) with a median follow-up of 4.1 years. Three participants began maralixibat at ≥ 16 years old, with a median follow-up of 3.8 years. Participants starting maralixibat at age &lt; 16 had minimal-to-no itch (change from baseline [CFB]: −1.8; <i>p</i> = 0.002) persisting throughout the study. Serum bile acids (sBA) decreased (CFB: 29 μmol/L; <i>p</i> = 0.03), persisting throughout the study. Participants starting maralixibat ≥ 16 years old had pruritus improvements (CFB: −2.8, −0.6, −1.0). One had a large decrease in sBA (CFB: −112 μmol/L), and two had small increases (CFB: 8, 11 μmol/L). Maralixibat was well tolerated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Participants receiving maralixibat in adolescence demonstrated improvements in pruritus and sBA, which persisted through young adulthood.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viability Assessment During Normothermic Machine Liver Perfusion: A Literature Review","authors":"Heithem Jeddou,&nbsp;Stylianos Tzedakis,&nbsp;Mohamed Ali Chaouch,&nbsp;Laurent Sulpice,&nbsp;Michel Samson,&nbsp;Karim Boudjema","doi":"10.1111/liv.16244","DOIUrl":"10.1111/liv.16244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Objective</h3>\u0000 \u0000 <p>The discrepancy between donor organ availability and demand leads to a significant waiting-list dropout rate and mortality. Although quantitative tools such as the Donor Risk Index (DRI) help assess organ suitability, many potentially viable organs are still discarded due to the lack of universally accepted markers to predict post-transplant outcomes. Normothermic machine perfusion (NMP) offers a platform to assess viability before transplantation. Thus, livers considered unsuitable for transplantation based on the DRI can be evaluated and potentially transplanted. During NMP, various viability criteria have been proposed. These criteria are neither homogeneous nor consensual. In this review, we aimed to describe the viability criteria during NMP and evaluate their ability to predict hepatic graft function following transplantation. We conducted a PubMed search using the terms ‘liver transplantation’, ‘normothermic machine perfusion’ and ‘assessment’, including only English publications up to February 2024. Viability assessment during NMP includes multiple hepatocellular and cholangiocellular criteria. Lactate clearance and bile production are commonly used indicators, but their ability to predict post-transplant outcomes varies significantly. The predictive value of cholangiocellular criteria such as bile pH, bicarbonate and glucose levels remains under investigation. Novel markers, such as microRNAs and proteomic profiles, offer the potential to enhance graft evaluation accuracy and provide insights into the molecular mechanisms underlying liver viability. Combining perfusion parameters with biomarkers may improve the prediction of long-term graft survival. Future research should focus on standardising viability assessment protocols and exploring real-time biomarker evaluations, which could enhance transplantation outcomes and expand the donor pool.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Potential and Challenges of Autophagy in the Treatment of Liver Fibrosis","authors":"Jia Chen,&nbsp;Qichang Xing","doi":"10.1111/liv.16168","DOIUrl":"10.1111/liv.16168","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Validation of a Novel Model to Discriminate Idiosyncratic Drug-Induced Liver Injury and Autoimmune Hepatitis","authors":"Yu Wang,&nbsp;Xuhui Lin,&nbsp;Ying Sun,&nbsp;Jimin Liu,&nbsp;Jia Li,&nbsp;Qiuju Tian,&nbsp;Feng Guo,&nbsp;Xiaoli Hu,&nbsp;Liang Wang,&nbsp;Pingying Li,&nbsp;Jingshou Chen,&nbsp;Yan Wang,&nbsp;Zikun Ma,&nbsp;Jidong Jia,&nbsp;Jing Zhang,&nbsp;Zhengsheng Zou,&nbsp;Xinyan Zhao","doi":"10.1111/liv.16239","DOIUrl":"10.1111/liv.16239","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>Discriminating between idiosyncratic drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) is critical yet challenging. We aim to develop and validate a machine learning (ML)-based model to aid in this differentiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter cohort study utilised a development set from Beijing Friendship Hospital, with retrospective and prospective validation sets from 10 tertiary hospitals across various regions of China spanning January 2009 to May 2023. Different ML algorithms were tested using 24 routine laboratory parameters. The Shapley Additive exPlanations (SHAP) analysis was used to evaluate the contribution of each parameter in the ML model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 2554 patients (1750 for DILI and 804 for AIH) were included. Using Gradient Boost Decision Tree algorithm, five key parameters—aspartate transaminase, globulin, prealbumin, creatinine and platelet count—were selected to construct the ML model. Consequently, a web-based tool named Beijing-AID (BJ-AID) was developed (http://43.143.153.225:5000/). The BJ-AID model demonstrated excellent discrimination performance, with an area under the receiver operating characteristic curve (AUROC) of 0.94 (95% CI, 0.902–0.975) in the development set, 0.91 (95% CI, 0.900–0.928) in all external validation sets and 0.93 (95% CI, 0.889–0.974) in a prospective validation set. Notably, the BJ-AID model also effectively discriminated atypical cases, including drug-induced autoimmune-like hepatitis and AIH with the history of drug consumption, achieving an AUROC = 0.85 (95% CI, 0.742–0.949).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We successfully developed and validated a machine learning-based model, BJ-AID, which exhibits a strong discrimination performance. BJ-AID can assist practitioners and hepatologists in diagnosing both typical and atypical cases of DILI and AIH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier: NCT05532345</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper in PSVD: When Having the Tool Doesn't Mean Necessarily Using It","authors":"Zoe Mariño,&nbsp;Virginia Hernández-Gea","doi":"10.1111/liv.16228","DOIUrl":"10.1111/liv.16228","url":null,"abstract":"&lt;p&gt;We have read with great interest the paper by Balcar L, Dominik N, et al., titled ‘Elevated Hepatic Copper Content in Porto-Sinusoidal Vascular Disorder (PSVD): Leading Down a Wrong Track.’ The study evaluates copper liver content in patients with PSVD and intriguingly reports elevated hepatic copper levels, which were associated with a higher degree of decompensation. However, the study sample was poorly characterised, and the rationale for ruling out Wilson disease (WD) as a differential diagnosis remains particularly unclear.&lt;/p&gt;&lt;p&gt;This work could be considered a long-term addendum into Peter Ferenci's legacy manuscript from 2005 [&lt;span&gt;1&lt;/span&gt;] performed by the same group in Vienna 20 years ago. In that classic work, 359 liver biopsies from 114 patients WD, 219 non-cholestatic liver disease and 22 healthy controls had their intrahepatic copper measurement performed and compared, in an attempt to define intrahepatic copper value as a diagnostic tool for WD. Their main figure on that article could be complemented by the results from the present study (see adapted Figure 1), in which 92 patients with a known diagnosis of PSVD, had their intrahepatic copper content systematically evaluated as well. Despite the median copper values were low, as expected for a non-WD cohort (30 μg/g dry weight, IQR: 18–55), four patients (4.3%) presented with very increased intrahepatic copper levels (over the stablished cutoff for high suspicion of WD, ≥ 250 μg/g) and 29 (32%) with intermediate levels above normality (≥ 50 μg/g but &lt; 250 μg/g), leading the authors to suggest PSVD should be included in the differential diagnosis whenever a patient presents with high copper levels in hepatic tissue. The opposite lecture would be that high levels of intrahepatic copper content would suggest PSVD in the absence of WD confirmation, being copper a negative predictor for worse prognosis. A third lecture would account for the magnified value of potential outliers in this scenario. And a forth lecture would really question the need for such a measurement, only explained by unlimited access to this tool irrespectively of clinical suspicion in a highly experienced centre for WD.&lt;/p&gt;&lt;p&gt;Adapted Figure 1 from Ferenci et al. [&lt;span&gt;1&lt;/span&gt;] (figure 2 in the original manuscript).&lt;/p&gt;&lt;p&gt;A thorough clinical history would likely negate the need for measuring copper content in the majority of patients. In most cases, the diagnosis of WD could be excluded through ceruloplasmin levels and 24-h urinary copper measurements, at least in symptomatic patients with advanced liver disease [&lt;span&gt;2, 3&lt;/span&gt;], like those from the present work. In fact, the need for a liver biopsy (LB) in this clinical scenario of WD suspicion would be minimal for different reasons: (1) patients with WD have no pathognomonic signs on regular histology and often show ‘common signs of cirrhosis’ whenever cirrhosis is clinically evident [&lt;span&gt;4&lt;/span&gt;]—minimising the potential confusion between these two ","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Hepatic Copper Content in Porto-Sinusoidal Vascular Disorder (PSVD): Leading Down a Wrong Track","authors":"Lorenz Balcar,&nbsp;Nina Dominik,&nbsp;Behrang Mozayani,&nbsp;Georg Semmler,&nbsp;Emina Halilbasic,&nbsp;Mattias Mandorfer,&nbsp;Thomas Reiberger,&nbsp;Michael Trauner,&nbsp;Bernhard Scheiner,&nbsp;Albert Friedrich Stättermayer","doi":"10.1111/liv.16175","DOIUrl":"10.1111/liv.16175","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Porto-sinusoidal vascular disorder (PSVD) is a rare vascular liver disorder characterised by specific histological findings in the absence of cirrhosis, which is poorly understood in terms of pathophysiology. While elevated hepatic copper content serves as diagnostic hallmark in Wilson disease (WD), hepatic copper content has not yet been investigated in PSVD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with a verified diagnosis of PSVD at the Medical University of Vienna and available hepatic copper content at the time of diagnosis of PSVD were retrospectively included. Elevated hepatic copper content was correlated with cholestatic changes and WD diagnostics in PSVD and analysed for liver-related outcomes (first/further hepatic decompensation/liver-related death).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 92 patients were included into this study (mean age 49 ± 16; 57% male; median hepatic copper content was 30 [IQR: 18–55] μg/g) of whom 29 (32%) had moderately (≥ 50 μg/g) and 4 (4%) strongly (≥ 250 μg/g) elevated hepatic copper content.</p>\u0000 \u0000 <p>Elevated levels of hepatic copper were associated with younger age in multivariable linear regression analysis. After adjusting for age, decompensation status and albumin, hepatic copper content was significantly associated with the outcome of interest (log, per 10; aHR: 1.60 [95% CI: 1.14–2.25]; <i>p</i> = 0.007). A hepatic copper cut-off at ≥ 90 μg/g identified PSVD patients with considerable risk of liver-related outcomes (at 2 years: 51% vs. 12%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Elevated hepatic copper seems frequent in patients with PSVD even in the absence of cholestatic features, especially in young patients, which makes differential diagnosis to WD challenging. Since PSVD patients with elevated hepatic copper content had increased risk for liver-related outcomes, the pathomechanisms underlying hepatic copper accumulation in PSVD should be investigated as this may open new therapeutic avenues.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver GPBAR1 Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4−/− Mice","authors":"Cristina Di Giorgio,&nbsp;Ginevra Urbani,&nbsp;Silvia Marchianò,&nbsp;Michele Biagioli,&nbsp;Martina Bordoni,&nbsp;Rachele Bellini,&nbsp;Carmen Massa,&nbsp;Ginevra Lachi,&nbsp;Luigi Cari,&nbsp;Elva Morretta,&nbsp;Lucio Spinelli,&nbsp;Maria Chiara Monti,&nbsp;Valentina Sepe,&nbsp;Angela Zampella,&nbsp;Eleonora Distrutti,&nbsp;Jesus M. Banales,&nbsp;Ainhoa Lapitz,&nbsp;Piotr Milkiewicz,&nbsp;Malgorzata Milkiewicz,&nbsp;Stefano Fiorucci","doi":"10.1111/liv.16235","DOIUrl":"10.1111/liv.16235","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein-coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, <i>Abcb4</i>^{<i>−/−</i>} mice were treated with BAR501 for 12–24 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Single-cell analysis demonstrated that <i>GPBAR1</i> is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of <i>GPBAR1</i> increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In vitro treatment of NHCs with BAR501 reversed the acquisition of a pro-inflammatory phenotype and the downregulation of <i>GPBAR1</i> expression promoted by LPS in an NF-κB-dependent manner. Treating <i>Abcb4</i>^{<i>−/−</i>} mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis-associated gut permeability, and intestinal and systemic inflammation. Ex vivo experiments using conditioned media from BAR501-treated cholangiocytes mitigated the activation of macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation–associated cholestasis, warranting the evaluation of BAR501 in PSC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}