Hepatology Communications最新文献

{"title":"Empowering patients with cirrhosis: Lessons from the Lima HepatoClub.","authors":"Daniela Goyes, Julio Santiago-Marcelo","doi":"10.1097/HC9.0000000000000825","DOIUrl":"10.1097/HC9.0000000000000825","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185724","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":"Plasma proteome correlations with liver stiffness in pediatric cholestasis implicate epithelial to mesenchymal transition.","authors":"Benjamin L Shneider, Rupa S Kanchi, Sandra L Grimm, Sridevi Devaraj, Juliet Emamaullee, Jeremy Schraw, Philip J Lupo, Jorge A Bezerra, Kathleen M Loomes, John C Magee, Ronald J Sokol, Kasper S Wang, Alyssa Kriegmeier, Evelyn Hsu, Jean P Molleston, Philip Rosenthal, Rohit Kohli, Saul J Karpen, Simon P Horslen, M Kyle Jensen, Arianna Barbetta, Cristian Coarfa","doi":"10.1097/HC9.0000000000000796","DOIUrl":"10.1097/HC9.0000000000000796","url":null,"abstract":"<p><strong>Background: </strong>Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).</p><p><strong>Methods: </strong>Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.</p><p><strong>Results: </strong>There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was found in ALGS relative to BA and A1AT. Weighted Correlation Network Analysis identified groups of proteins with strong LSM correlation (eg, in a BA module of interest, Pearson correlation coefficient 0.79, p=5´0-21). Machine learning developed models predicting LSM as a continuous variable (median R2=0.62 for BA). For BA, time to transplant could be predicted equally well by the proteome or clinical parameters (elastic net models achieved a C-index using proteome 0.91, clinical parameters 0.91, proteome and clinical parameters 0.90). Single-cell transcriptomics predicted the potential hepatic cell of origin for the most informative proteins, which included macrophage, mesenchymal, mesothelial, and endothelial cells. The epithelial-to-mesenchymal transition pathway was enriched in LSM correlated proteins in all 3 diseases.</p><p><strong>Conclusions: </strong>The plasma proteome is highly correlated in a disease-specific fashion with LSM in BA, A1AT, and ALGS. These correlations provide unique opportunities to identify biomarkers and focus attention on epithelial-to-mesenchymal transition in pediatric cholestasis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185810","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":"Albumin prevents kidney injury but is underutilized in a cohort of patients undergoing large-volume paracentesis.","authors":"Rahul Rajkumar, Nikki Duong, W Ray Kim, Elisabet Viayna, Thomas Ardiles, Cristina Coll-Ortega, E Anne Davis, Jonathan Lilley, Xuan Zhang, Nisha Wadhwani, Kunal Lodaya","doi":"10.1097/HC9.0000000000000760","DOIUrl":"10.1097/HC9.0000000000000760","url":null,"abstract":"<p><strong>Background: </strong>Cirrhosis and cirrhosis-related deaths have risen in the United States in recent years. Ascites is a common complication, often requiring large-volume paracentesis (LVP). The American Association for the Study of Liver Diseases (AASLD) recommends the administration of albumin in conjunction with LVP to prevent further complications of cirrhosis. Emerging research in cirrhosis care reveals significant variations in outcomes among different demographics. Therefore, we assessed the use of guideline-adherent albumin and outcomes in U.S. patients undergoing LVPs, particularly at the intersection of race, ethnicity, socioeconomic disparities, and cirrhosis.</p><p><strong>Methods: </strong>This retrospective study utilized Cerner Real World Data to identify adults with cirrhosis and ascites undergoing LVP between January 2016 and June 2022. We assessed albumin utilization patterns across racial and ethnic groups and payor types, and their overall impact on acute kidney injury (AKI)-related hospitalization using an adjusted generalized linear model (aGLM).</p><p><strong>Results: </strong>We identified 736 patients: 301 in the LVP + albumin group and 435 in the LVP-only group. Despite clinical recommendations, only 41% undergoing LVPs received albumin. White patients and commercially insured patients received albumin at higher rates (p=0.042 and p=0.009, respectively). The overall rate of AKI-related admissions within the 30-day post-procedure period was 26%. However, patients who received albumin during LVP had a 36% lower risk of short-term AKI-related hospitalization (OR: 0.64; p=0.03).</p><p><strong>Conclusions: </strong>These findings indicate a potential for broader albumin utilization in U.S. patients with refractory ascites undergoing repeated LVPs to reduce AKI-related admissions.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185699","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":"High biochemical remission rates in patients with primary biliary cholangitis treated with \"triple\" anticholestatic therapy.","authors":"Guilherme G L Cançado, Bo Chen, Madeline Cameron, Inbal Houri, Kristel K Leung, Aliya F Gulamhusein, Bettina Hansen, Gideon M Hirschfield","doi":"10.1097/HC9.0000000000000798","DOIUrl":"10.1097/HC9.0000000000000798","url":null,"abstract":"<p><strong>Background: </strong>Treatment goals in primary biliary cholangitis (PBC) are increasingly aspirational, aiming for normal serum liver tests. One of the add-on therapies to ursodeoxycholic acid (UDCA) is with the approved farnesoid X receptor (FXR) agonist obeticholic acid (OCA), alongside off-label use of fibrates (peroxisome proliferator-activated receptor [PPARs]). We report our experience of synergistic FXR-PPAR-UDCA combination therapy in PBC.</p><p><strong>Methods: </strong>A review of patients with PBC seen between July 2022 and July 2023 was performed across the autoimmune liver disease programme at the Toronto Centre for Liver Disease. Univariate and multivariate analyses were performed.</p><p><strong>Results: </strong>Four hundred seventy patients with PBC were seen, of which 71% were treated with UDCA only, 7% UDCA-OCA, 11.3% UDCA-fibrates, and 10.6% UDCA-OCA-fibrates. Among 50 patients on triple therapy, 82% had OCA as the first add-on therapy. Most patients (92%) received bezafibrate, while 8% had fenofibrate. Forty-eight patients were included in the final analysis. The mean follow-up time after triple therapy was 17.4 months. Triple therapy demonstrated median ALP reductions after 6 months of 33.3% (95% CI: 27.9%-37.6%) and 39.1% (95% CI: 30.7%-46.2%) at the last follow up; 30.2% of the patients had a normal serum ALP at 6 months, while 11.9% had normal ALP, AST, ALT, and bilirubin. Subgroup analysis of 28 patients followed for at least 12 months showed a 44.7% (95% CI: 33.3%-50.9%) median reduction in ALP. Liver stiffness remained relatively stable throughout the follow-up. Out of 34 patients with self-reported pruritus before triple therapy, 64.7% reported improvement, 11.8% worsened, and 23.5% had no change in itching intensity. On multivariable analysis, only older age at diagnosis (OR=1.12; 95% CI: 1.02-1.22) positively impacted ALP normalization.</p><p><strong>Conclusions: </strong>Our data confirm that FXR-PPAR-UDCA triple therapy significantly improves ALP with normalization for 30% of patients with PBC at 6 months.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185754","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":"iPSC-based hepatic organoids reveal a heterozygous MYO5B variant as driver of intrahepatic cholestasis.","authors":"Malte Sgodda, Evelyn Gebel, Lennart Dignas, Susanne Alfken, Reto Eggenschwiler, Amelie Stalke, Carola Dröge, Evo-Doreen Pfister, Ulrich Baumann, Tom Luedde, Irene Esposito, Verena Keitel, Tobias Cantz","doi":"10.1097/HC9.0000000000000812","DOIUrl":"10.1097/HC9.0000000000000812","url":null,"abstract":"<p><strong>Background: </strong>Hereditary intrahepatic cholestasis is caused by variants of various genes involved in enterohepatic bile circulation, metabolization, and conjugation. Originally classified into 3 groups, the number of contributing genes is still increasing, underlining the need for a deeper understanding of the molecular interaction during intrahepatic cholestasis.</p><p><strong>Methods: </strong>In the present study, we investigate the interplay of heterozygous variants in 3 cholestasis-associated genes (ABCB11, ABCB4, and MYO5B) by exploiting iPSC-based hepatic organoids from a patient suffering from recurrent intrahepatic cholestasis.</p><p><strong>Results: </strong>Functional characterization of MRP2-mediated cholyl-lysyl-fluorescein (CLF) and BSEP-mediated Tauro-nor-THCA-24-DBD transport demonstrated a marked reduction of transport in MYO5B-deficient organoids, in comparison to unaffected control organoids. Moreover, iPSC-based organoids derived from the patient carrying 3 heterozygous variants in ABCB11, ABCB4, and MYO5B also exhibited absence of BSEP-mediated Tauro-nor-THCA-24-DBD transport, but functional MRP2-mediated CLF-transport. Interestingly, CRISPR/Cas9-mediated correction of the mutated ABCB11 allele could not restore the impaired BSEP function, suggesting the heterozygous MYO5B variant as the main driver of the transport deficiency. In fact, CRISPR/Cas-mediated correction of the MYO5B variant finally resulted in a restoration of the BSEP-mediated Tauro-nor-THCA-24-DBD transport.</p><p><strong>Conclusions: </strong>iPSC-based organoids serve as an authentic model for functional assessment of the hepatobiliary transport with fluorescent substrates. This allows the characterization of variants of uncertain significance and other variants in cholestasis-associated genes and revealed that a heterozygous MYO5B variant increases the susceptibility to defective hepatobiliary BSEP-mediated transport.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185817","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":"TNAP-induced CD47 membrane expression enhances TGF-β1 conversion in liver fibrosis.","authors":"Lei Gao, Fengling Peng, Peng Qi, Hanqiu Zhang, Hao Chi, Liang Deng, Xin Liang, Min Sun, Wenkun Ma, Cheng Yang, Qiang Liu, Xiaoyu Wei, Yongguo Li, Jinqiu Zhao","doi":"10.1097/HC9.0000000000000781","DOIUrl":"10.1097/HC9.0000000000000781","url":null,"abstract":"<p><strong>Background: </strong>Tissue-nonspecific alkaline phosphatase (TNAP) expression increases after liver injury, but its role in liver fibrosis remains unclear. This study investigated the effect of TNAP on liver fibrosis and its mechanism in regulating TGF-β1 signaling.</p><p><strong>Methods: </strong>Human liver samples and a CCl4-induced liver fibrosis mouse model with adv-TNAP and a TNAP inhibitor (tetramisole, Tetra) were used to study the function of TNAP in liver fibrosis. Primary HSCs were used to study the mechanism of TNAP in regulating the TGF-β1 signal.</p><p><strong>Results: </strong>Elevated TNAP expression was observed in human and murine fibrotic liver tissues, correlating with increased fibrotic markers. In vivo experiments using TNAP overexpression and inhibition in a CCl4-induced liver fibrosis mouse model demonstrated that TNAP exacerbated, while its inhibition alleviated, liver fibrosis. In vitro studies revealed that TNAP regulated TGF-β1 conversion and HSCs activation through the TGF-β1/SMAD pathway. TNAP facilitated TGF-β1 conversion by promoting the interaction between CD47 and thrombospondin-1 (TSP1). Membrane expression of CD47 modulated by TNAP might contribute to the binding effect of CD47 and TSP1.</p><p><strong>Conclusions: </strong>TNAP plays a critical regulatory role in TGF-β1-mediated liver fibrosis, probably by promoting the binding of CD47/TSP1. Targeting TNAP-mediated pathways may offer new therapeutic strategies for liver fibrosis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185730","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":"Omics-driven networks herald a new era of multidimensional therapy for cholangiocarcinoma.","authors":"Yuming Liu, Ganggang Wang, Qiang Gao","doi":"10.1097/HC9.0000000000000809","DOIUrl":"10.1097/HC9.0000000000000809","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000471","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":"Changing landscape of steatotic liver diseases and liver fibrosis in the United States during the COVID-19 pandemic.","authors":"Abdelrahman M Attia, Mohammad Saeid Rezaee-Zavareh, Yee Hui Yeo, Minsun Kwak, Hyunseok Kim, Mazen Noureddin, Ju Dong Yang","doi":"10.1097/HC9.0000000000000806","DOIUrl":"10.1097/HC9.0000000000000806","url":null,"abstract":"<p><strong>Background: </strong>Steatotic liver diseases (SLDs) and their subcategories-metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD)-significantly contribute to liver-related and extrahepatic morbidity and mortality. This project aimed to assess the landscape of SLDs and clinically significant fibrosis (CSF) before (2017-2020) and during (2021-2023) the COVID-19 pandemic.</p><p><strong>Methods: </strong>Using National Health and Nutrition Examination Survey (NHANES) data, we analyzed 8965 prepandemic and 6337 pandemic participants aged ≥18 years. The main evaluated outcomes were changes in age-adjusted mean CSF, mean controlled attenuation parameter score, and age-adjusted prevalence of MASLD, MetALD, and ALD before and during the pandemic.</p><p><strong>Results: </strong>The age-adjusted prevalence of SLDs changed significantly (p=0.003) between the prepandemic and pandemic periods. ALD prevalence rose from 0.94% to 2.27%, MetALD from 2.60% to 4.42%, while MASLD declined from 30.13% to 25.46%. Vigorous and moderate physical activity decreased significantly (p<0.001), whereas moderate/excessive alcohol intake increased (p<0.001). The prevalence of CSF increased from 8.3% to 10.5% (p=0.028). Multivariable analyses showed the COVID-19 pandemic (adjusted OR: 1.47, 95% CI: 1.00-2.17) and moderate/excessive alcohol intake (adjusted OR: 2.13, 95% CI: 1.15-3.95) were associated with CSF. In addition, older age, higher body mass index, larger waist circumference, prediabetes/diabetes, and lower income were each independently associated with CSF.</p><p><strong>Conclusions: </strong>Our study highlights a shift in SLDs in the United States during the COVID-19 pandemic, showing a decrease in MASLD and increases in MetALD and ALD, with an alarming increase in the prevalence of CSF, likely reflecting lifestyle changes, including physical inactivity and alcohol consumption.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000463","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":"Identifying determinants of viral hepatitis and liver cancer care in Michigan Asian American communities through multilevel engagement.","authors":"Parnnate Wongsirisakul, Neehar Parikh, Yi-Chun Wang, Hannah Par, Thanvir Chowdhury, Qingqing Zhang, Tsu-Yin Wu, Ponni V Perumalswami","doi":"10.1097/HC9.0000000000000803","DOIUrl":"10.1097/HC9.0000000000000803","url":null,"abstract":"<p><strong>Background: </strong>In Michigan, Asian Americans are disproportionately infected with HBV and HCV. As many infections are first diagnosed when patients present with advanced liver disease or liver cancer, HBV and HCV screening, awareness, and early treatment are critical to improving outcomes.</p><p><strong>Methods: </strong>Using a theory-informed approach, we administered a bi-level qualitative study to identify determinants of viral hepatitis and liver cancer care and treatment in Michigan Asian American communities. We conducted a focus group involving representatives from public health agencies, cancer coalitions, and Asian diaspora organizations across the state. We then completed 1:1 interviews with leaders from the communities. Groups and interviews were taped, transcribed, and used to identify common and distinct themes according to the National Institute of Minority Health and Health Disparities framework.</p><p><strong>Results: </strong>According to community leaders, language barriers, costs, and a lack of viral hepatitis education appeared among the top shared screening barriers between the 3 communities. Conversely, common facilitators included pre-existing health programs, interpretation services, and community partnerships. Such sentiments were also echoed by the stakeholder focus group. However, the communities also raised distinct concerns about medical mistrust and positive health messaging.</p><p><strong>Conclusions: </strong>This qualitative report marks the first phase of a bi-level mixed methods study in Asian American Michigan communities to understand determinants of viral hepatitis and liver cancer care and treatment. This work lays the foundation for a quantitative survey that will gather data from community members to inform the development of a future intervention.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000443","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":"Deficiency of Ugcg in LSECs alleviates high-fat diet-induced MASLD.","authors":"Rui Han, Yanyan Li, Yuhui Liu, Manman Li, Liangliang Ren, Weiran Lin, Ying Jiang","doi":"10.1097/HC9.0000000000000793","DOIUrl":"10.1097/HC9.0000000000000793","url":null,"abstract":"<p><strong>Background: </strong>Hepatic glycosphingolipid biosynthesis is implicated in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). While UDP-glucose ceramide glucosyltransferase (UGCG) serves as the rate-limiting enzyme in glycosphingolipid synthesis, its cell-specific roles in MASLD pathogenesis remain undefined. Our study investigates the mechanistic contribution of LSEC-expressed UGCG to high-fat diet (HFD)-induced insulin resistance and MASLD progression.</p><p><strong>Methods: </strong>Primary cell sorting was used to analyze LSEC-specific enrichment of UGCG in wild-type mice under normal chow (NC) diet and high-fat diet (HFD) conditions. LSEC-specific Ugcg knockout mice (UgcgCdh5cre+) and littermate controls (UgcgCdh5cre-) were subjected to 12 weeks of HFD or NC feeding. Hepatic steatosis was assessed via histopathology; glucose tolerance and insulin sensitivity were evaluated functionally. Endothelial fenestration architecture was quantified using scanning electron microscopy (SEM). Ganglioside GM3 levels were measured via LC-MS. LSEC-hepatocyte cocultures were employed to investigate VLDL secretion and lipid metabolism-related gene/protein expression, with nitric oxide (NO) and endothelin-1 (ET-1) signaling verified by ELISA.</p><p><strong>Results: </strong>Ugcg deficiency in LSECs attenuated hepatic steatosis, improved glucose tolerance and insulin sensitivity, and restored endothelial fenestration architecture without compromising vascular integrity. It also reduced LSEC defenestration and CD31+ capillarization, promoting endothelial homeostasis. Mechanistically, insulin receptor-β (IRβ) was predominantly localized in LSECs; HFD-induced IRβ downregulation was reversed by UGCG inhibition (Genz-123346), correlating with reduced GM3 levels. GM3 was shown to suppress IRβ in a dose-dependent manner. In cocultures, Ugcg deficiency increased VLDL secretion and elevated the expression of hepatocyte lipid metabolism-related genes and proteins through NO/ET-1 signaling pathways.</p><p><strong>Conclusions: </strong>Our findings establish UGCG as a master regulator of LSEC metabolic functions through GM3-IRβ axis modulation. LSEC-targeted UGCG inhibition mitigates hepatic insulin resistance via NO/ET-1-mediated hepatocyte metabolic reprogramming, providing a novel therapeutic paradigm for MASLD.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"9 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000429","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}