Journal of Hepatology最新文献

{"title":"PNPLA3 rs738409, environmental factors and liver-related mortality in the U.S. Population","authors":"Eduardo Vilar-Gomez, Samer Gawrieh, Raj Vuppalanchi, Carla Kettler, Francis Pike, Niharika Samala, Naga Chalasani","doi":"10.1016/j.jhep.2024.09.043","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.043","url":null,"abstract":"<h3>Background &amp; Aims</h3>Little is known about the interplay between patatin-like phospholipase domain protein 3 <em>(PNPLA3</em> rs738409 C&gt;G), environmental factors, and the risk of liver-related death (LRD).<h3>Methods</h3>4,361 adults were selected from NHANES III, 1991–1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). LRD was the study outcome. Associations of <em>PNPLA3</em>, diet, light alcohol intake, smoking, and BMI (kg/m²) with LRD were examined using competing risk regression models.<h3>Results</h3><em>PNPLA3</em> G–allele was significantly associated with LRD (adjusted subhazard ratio [adj.sHR]: 2.9, 95% CI: 1.4-5.8). Non-heavy alcohol intake (adj.sHR: 2.2, 95% CI: 1.1-4.5), top quartiles of monounsaturated fat (MUFA) (adj.sHR: 0.43, 95% CI: 0.12-0.99), and cholesterol (adj.sHR: 2.6, 95% CI: 1.00-8.8) and coffee intake ≥3 cups/day (adj.sHR: 0.05, 95% CI: 0.06-0.10), former/current smoking (adj.sHR: 1.8, 95% CI: 1.2-2.6), BMI (adj.sHR: 1.1, 95% CI: 1.03-1.2), and healthy eating index (HEI) (adj.sHR: 0.96, 95% CI: 0.93-0.98) were associated with LRD.Joint effects between <em>PNPLA3</em> and environmental factors showed that the risk of LRD was significantly increased in carriers of the G-allele with non-heavy alcohol intake (adj.sHR: 3.7), higher consumption (top quartile) of cholesterol (adj.sHR: 4.1), former (adj.sHR: 4.3) or current (adj.sHR: 3.5) smoking, or BMI ≥30 (adj.sHR: 4.0) kg/m². The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of MUFA (adj.sHR: 0.5) or ≥3 cups/day of coffee (adj.sHR: 0.09). HEI was inversely associated with LRD across all <em>PNPLA3</em> genotypes (adj.sHR: 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively).<h3>Conclusions</h3><em>PNPLA3</em> is associated with LRD and this relationship is significantly modified by anthropometric and environmental factors.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"12 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.","authors":"Yajie Lu, Yunpeng Liu, Xiaoshuang Zuo, Guodong Li, Jianlin Wang, Jianshan Liu, Xiangxu Wang, Shuning Wang, Wangqian Zhang, Kuo Zhang, Xiaoying Lei, Qiang Hao, Weina Li, Lei Liu, Meng Li, Cun Zhang, Hongmei Zhang, Yingqi Zhang, Yuan Gao","doi":"10.1016/j.jhep.2024.09.044","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.044","url":null,"abstract":"<h3>Background</h3>The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.<h3>Methods</h3>We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.<h3>Results</h3>In this research, we identified a new subset of CXCL12⁺ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12⁺ TECs impede the differentiation of CD8⁺ naïve T cells into CD8⁺ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.<h3>Conclusions</h3>CXCL12⁺ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12⁺ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.<h3>Impact and implication</h3>This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12⁺ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12⁺ TECs as inhibitors of CD8⁺ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"14 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to “Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma” [J Hepatol 70 (1) 2019 66–77]","authors":"Yan Chen, Hai-Ning Chen, Kui Wang, Lu Zhang, Zhao Huang, Jiayang Liu, Zhe Zhang, Maochao Luo, Yunlong Lei, Yong Peng, Zong-Guang Zhou, Yuquan Wei, Canhua Huang","doi":"10.1016/j.jhep.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.002","url":null,"abstract":"The publisher regrets that the Supplementary Material on the original publication’s supplementary material, Figures S1, S2, S6 and S8 were incomplete. The correct and complete Figures and Supplementary Material are included herein.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"26 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: Obtaining first-line induction in autoimmune hepatitis: aren’t we underestimating prednisolone?","authors":"Charlotte D. Slooter, Anna E.C. Stoelinga, Romée J.A.L.M. Snijders","doi":"10.1016/j.jhep.2024.09.040","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.040","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Financial disclosure</h2>No financial support was received for this letter.</section></section><section><section><h2>Funding</h2>None</section></section><section><section><h2>Conflict-of-interest statement</h2>The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.</section></section><section><section><h2>Author contributions</h2>CS: manuscript drafting; AS, RS: critical expert review and revision of the manuscript.</section></section><section><section><h2>Declaration of generative AI and AI-assisted technologies in the writing process</h2>During the preparation of this work the author(s) used Curie (AJE) in order to improve style. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.</section></section><section><section><h2>Acknowledgements</h2>There are no additional acknowledgements.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"223 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STRIDE's Efficacy and Safety in Asian Hepatocellular Carcinoma","authors":"Zaoqu Liu, Dan Shan, Xinwei Han","doi":"10.1016/j.jhep.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Author’s contributions</h2>Zaoqu Liu: Study design &amp; Manuscript Writing.Dan Shan and Xinwei Han: Study design &amp; Manuscript Revision.</section></section><section><section><h2>Declaration of Competing Interest</h2>We declare there is no any conflict of interest.</section></section><section><section><h2>Acknowledgements &amp; Funding</h2>None</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"34 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highlighting the Impact of Hormonal Factors on Hepatic Cystogenesis: Implications for Pathophysiology and Clinical Practice","authors":"","doi":"10.1016/j.jhep.2024.09.041","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.041","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"12 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of de novo HCC in patients with MASLD following direct-acting antiviral-induced cure of HCV infection","authors":"Chen-Hua Liu, Pin-Nan Cheng, Yu-Jen Fang, Chi-Yi Chen, Wei-Yu Kao, Chih-Lin Lin, Sheng-Shun Yang, Yu-Lueng Shih, Cheng-Yuan Peng, Yu-Ping Chang, Shang-Chin Huang, Tung-Hung Su, Tai-Chung Tseng, Chun-Jen Liu, Pei-Jer Chen, Jia-Horng Kao","doi":"10.1016/j.jhep.2024.09.038","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.038","url":null,"abstract":"<h3>Background &amp; Aims</h3>Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after achieving sustained virologic response (SVR₁₂) using direct-acting antivirals (DAAs) for hepatitis C virus (HCV).<h3>Methods</h3>1598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC beyond achieving SVR₁₂. MASLD was defined as presence of controlled attenuation parameter (CAP) ≥ 248 dB/m and ≥ one cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping.<h3>Results</h3>The incidence rate of HCC was 1.44 per 100 person-years of follow-up (PYFU) [95% confidence interval (CI): 1.19-1.74]. Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p &lt; 0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, LSM, platelet count, and AFP, MASLD (adjusted hazard ratio (aHR): 2.07 [95% CI:1.36-3.16], p &lt; 0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution HR (sHR) of 2.07 (95% CI: 1.34-3.19, p &lt; 0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development.<h3>Conclusion</h3>After achieving SVR₁₂, patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect MASLD on HCC remain crucial for this population.<h3>Impact and implications</h3>The risk of de novo HCC among patients with MASLD, a novel nomenclature of steatotic liver disease (SLD), after the attaining of SVR₁₂ using DAAs remains to be confirmed. In this study recruiting 1598 patients in Taiwan, individuals with MASLD exhibited approximately a two-fold increased risk of de novo HCC, compared to those without MASLD after achieving SVR₁₂. MASLD significantly mediated CMRFs for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control CMRFs in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"39 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma exchange does not improve overall survival in patients with acute liver failure in a real world cohort","authors":"Laura Burke, William Bernal, Tasneem Pirani, Banwari Agarwal, Rajiv Jalan, Jennifer Ryan, Mansoor.Nawaz Bangash, Phillip El-Dalil, Nick Murphy, Mhairi Donnelly, Janice Davidson, Ken Simpson, Hannah Giles, Phyo Set Mone, Steven Masson, Andrew Davenport, Ian Rowe, Joanna Moore","doi":"10.1016/j.jhep.2024.09.034","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.034","url":null,"abstract":"<h3>Background and Aims</h3>Therapeutic plasma exchange (PEX) has emerged as a potential treatment option for patients with acute liver failure (ALF). The effect of PEX on survival outcomes outside of clinical trials is not yet well established. In this study we aimed to evaluate the real-world use and outcomes of PEX for the treatment of ALF.<h3>Methods</h3>This multicentre retrospective cohort study included consecutive <u>patients with ALF</u> admitted to all 7 tertiary liver transplant centres in the United Kingdom (UK) between June 2013 and December 2021. Changes in clinical variables following PEX treatment was assessed and overall survival and transplant free survival (TFS) to hospital discharge of patients receiving PEX were compared to those receiving standard medical therapy (SMT). Propensity score matching was performed to control for intergroup covariates and selection bias.<h3>Results</h3>We included 378 patients with ALF (median (IQR) age 36 (28-48), 64% (n=242) female) of which 120 received PEX. There was a significant improvement in most clinical variables following PEX, including median dose of noradrenaline (reduction from 0.35 μg/kg/min (0.19 - 0.70 μg/kg/min) to 0.16 μg/kg/min (0.08 - 0.49) (<em>p</em> = 0.001). There was no significant difference between PEX and SMT groups in overall survival (51.4 % v 62.6 % respectively, <em>p</em> = 0.12) or TFS (42.6 % v 53.1 %, <em>p</em> = 0.24).<h3>Conclusion</h3>PEX is now frequently used in the management of ALF patients in the UK. It is associated with significant improvement in haemodynamic parameters but there is no survival benefit.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"15 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FABP5⁺ lipid-loaded macrophages process tumour-derived unsaturated fatty acid signal to suppress T-cell antitumour immunity.","authors":"Xuguang Yang, Bo Deng, Weiwei Zhao, Yangyang Guo, Yaqi Wan, Zhihao Wu, Sheng Su, Jingyan Gu, Xiaoqian Hu, Wenxue Feng, Chencheng Hu, Jia Li, Yanyong Xu, Xiaowu Huang, Yuli Lin","doi":"10.1016/j.jhep.2024.09.029","DOIUrl":"10.1016/j.jhep.2024.09.029","url":null,"abstract":"<p><strong>Background & aims: </strong>Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear.</p><p><strong>Methods: </strong>Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ).</p><p><strong>Results: </strong>Single-cell RNA sequencing identified a subpopulation of FABP5⁺ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy.</p><p><strong>Conclusions: </strong>This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy.</p><p><strong>Impact and implications: </strong>Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy. This finding provides novel insights into the immunomodulatory roles of FABP5⁺ lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.</p>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice.","authors":"Emmanuel Dauda Dixon, Thierry Claudel, Alexander Daniel Nardo, Alessandra Riva, Claudia Fuchs, Veronika Mlitz, Georg Busslinger, Hubert Schnarnagl, Tatjana Stojakovic, Joana Senéca, Helga Hinteregger, Gernot F Grabner, Dagmar Kratky, Henkjan Verkade, Robert Zimmermann, Guenter Haemmerle, Michael Trauner","doi":"10.1016/j.jhep.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.09.037","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and aims: &lt;/strong&gt;Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Streptozotocin-injected male mice were fed an HFD to induce MASH. Mice receiving the ATGL inhibitor, Atglistatin (ATGLi), were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated its benefits on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic TAG-species containing PUFAs like linoleic acids as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signaling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BAs, interfering with dietary lipid absorption, and improving metabolic disturbances. The validation with NG-497 opens a new therapeutic perspective for MASLD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is a crucial public health concern. Since adherence to behavioural interventions is limited, pharmacological strategies are necessary, as highlighted by the recent FDA approval of resmetirom. However, since our current mechanistic understanding and pathophysiology-oriented therapeutic options for MASLD are still limited, novel mechanistic insights are urgently needed. Our present work uncovers that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis using Atglistatin (ATGLi), improves metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and associated key features of metabolic dysfunction in a mouse model of MASH and MCD-induced liver fibrosis. Mechanistical","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":" ","pages":""},"PeriodicalIF":26.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}