Hepatology Communications最新文献

{"title":"Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure.","authors":"Sai Wang, Frederik Link, Stefan Munker, Wenjing Wang, Rilu Feng, Roman Liebe, Yujia Li, Ye Yao, Hui Liu, Chen Shao, Matthias P A Ebert, Huiguo Ding, Steven Dooley, Hong-Lei Weng, Shan-Shan Wang","doi":"10.1097/HC9.0000000000000483","DOIUrl":"10.1097/HC9.0000000000000483","url":null,"abstract":"<p><strong>Background: </strong>When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF.</p><p><strong>Methods: </strong>RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF.</p><p><strong>Results: </strong>Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-β-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without.</p><p><strong>Conclusions: </strong>During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633350","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":"Loss of β-catenin reveals a role for glutathione in regulating oxidative stress during cholestatic liver disease.","authors":"Oluwashanu Balogun, Daniel Shao, Matthew Carson, Thalia King, Karis Kosar, Rong Zhang, Gang Zeng, Pamela Cornuet, Chhavi Goel, Elizabeth Lee, Garima Patel, Eva Brooks, Satdarshan P Monga, Silvia Liu, Kari Nejak-Bowen","doi":"10.1097/HC9.0000000000000485","DOIUrl":"10.1097/HC9.0000000000000485","url":null,"abstract":"<p><strong>Background: </strong>Cholestasis is an intractable liver disorder that results from impaired bile flow. We have previously shown that the Wnt/β-catenin signaling pathway regulates the progression of cholestatic liver disease through multiple mechanisms, including bile acid metabolism and hepatocyte proliferation. To further explore the impact of these functions during intrahepatic cholestasis, we exposed mice to a xenobiotic that causes selective biliary injury.</p><p><strong>Methods: </strong>α-naphthylisothiocyanate (ANIT) was administered to liver-specific knockout (KO) of β-catenin and wild-type mice in the diet. Mice were killed at 6 or 14 days to assess the severity of cholestatic liver disease, measure the expression of target genes, and perform biochemical analyses.</p><p><strong>Results: </strong>We found that the presence of β-catenin was protective against ANIT, as KO mice had a significantly lower survival rate than wild-type mice. Although serum markers of liver damage and total bile acid levels were similar between KO and wild-type mice, the KO had minor histological abnormalities, such as sinusoidal dilatation, concentric fibrosis around ducts, and decreased inflammation. Notably, both total glutathione levels and expression of glutathione-S-transferases, which catalyze the conjugation of ANIT to glutathione, were significantly decreased in KO after ANIT. Nuclear factor erythroid-derived 2-like 2, a master regulator of the antioxidant response, was activated in KO after ANIT as well as in a subset of patients with primary sclerosing cholangitis lacking activated β-catenin. Despite the activation of nuclear factor erythroid-derived 2-like 2, KO livers had increased lipid peroxidation and cell death, which likely contributed to mortality.</p><p><strong>Conclusions: </strong>Loss of β-catenin leads to increased cellular injury and cell death during cholestasis through failure to neutralize oxidative stress, which may contribute to the pathology of this disease.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534283","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":"Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.","authors":"Rabab O Ali, James A Haddad, Gabriella M Quinn, Grace Y Zhang, Elizabeth Townsend, Lisa Scheuing, Kareen L Hill, Matthew Menkart, Jenna L Oringher, Regina Umarova, Shakuntala Rampertaap, Sergio D Rosenzweig, Christopher Koh, Elliot B Levy, David E Kleiner, Ohad Etzion, Theo Heller","doi":"10.1097/HC9.0000000000000478","DOIUrl":"10.1097/HC9.0000000000000478","url":null,"abstract":"<p><strong>Background: </strong>Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease.</p><p><strong>Methods: </strong>Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids.</p><p><strong>Results: </strong>Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2).</p><p><strong>Conclusions: </strong>Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534352","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":"Collagen in hepatocellular carcinoma: A novel biomarker and therapeutic target.","authors":"Dong-Yang Ding, Shu-Ya Jiang, Yun-Xi Zu, Yuan Yang, Xiao-Jie Gan, Sheng-Xian Yuan, Wei-Ping Zhou","doi":"10.1097/HC9.0000000000000489","DOIUrl":"10.1097/HC9.0000000000000489","url":null,"abstract":"<p><p>HCC is globally recognized as a major health threat. Despite significant progress in the development of treatment strategies for liver cancer, recurrence, metastasis, and drug resistance remain key factors leading to a poor prognosis for the majority of liver cancer patients. Thus, there is an urgent need to develop effective biomarkers and therapeutic targets for HCC. Collagen, the most abundant and diverse protein in the tumor microenvironment, is highly expressed in various solid tumors and plays a crucial role in the initiation and progression of tumors. Recent studies have shown that abnormal expression of collagen in the tumor microenvironment is closely related to the occurrence, development, invasion, metastasis, drug resistance, and treatment of liver cancer, making it a potential therapeutic target and a possible diagnostic and prognostic biomarker for HCC. This article provides a comprehensive review of the structure, classification, and origin of collagen, as well as its role in the progression and treatment of HCC and its potential clinical value, offering new insights into the diagnosis, treatment, and prognosis assessment of liver cancer.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534279","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":"Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.","authors":"Marit M Grimsrud, Michael Forster, Benjamin Goeppert, Georg Hemmrich-Stanisak, Irmi Sax, Krzysztof Grzyb, Peder R Braadland, Alphonse Charbel, Carmen Metzger, Thomas Albrecht, Tim Alexander Steiert, Matthias Schlesner, Michael P Manns, Arndt Vogel, Sheraz Yaqub, Tom H Karlsen, Peter Schirmacher, Kirsten M Boberg, Andre Franke, Stephanie Roessler, Trine Folseraas","doi":"10.1097/HC9.0000000000000461","DOIUrl":"10.1097/HC9.0000000000000461","url":null,"abstract":"<p><strong>Background: </strong>People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC.</p><p><strong>Methods: </strong>We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies.</p><p><strong>Results: </strong>We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival.</p><p><strong>Conclusions: </strong>In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534354","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":"Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.","authors":"Douglas Thorburn, Diana J Leeming, William T Barchuk, Ya Wang, Xiaomin Lu, Vladislav A Malkov, Kaori L Ito, Christopher L Bowlus, Cynthia Levy, Zachary Goodman, Morten A Karsdal, Andrew J Muir, Jun Xu","doi":"10.1097/HC9.0000000000000467","DOIUrl":"10.1097/HC9.0000000000000467","url":null,"abstract":"<p><strong>Background: </strong>Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events.</p><p><strong>Methods: </strong>Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test.</p><p><strong>Results: </strong>Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001).</p><p><strong>Conclusions: </strong>Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534351","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":"Gut microbial metabolites in MASLD: Implications of mitochondrial dysfunction in the pathogenesis and treatment.","authors":"Ruhan Zhang, Zhaobo Yan, Huan Zhong, Rong Luo, Weiai Liu, Shulin Xiong, Qianyan Liu, Mi Liu","doi":"10.1097/HC9.0000000000000484","DOIUrl":"10.1097/HC9.0000000000000484","url":null,"abstract":"<p><p>With an increasing prevalence, metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major global health problem. MASLD is well-known as a multifactorial disease. Mitochondrial dysfunction and alterations in the gut bacteria are 2 vital events in MASLD. Recent studies have highlighted the cross-talk between microbiota and mitochondria, and mitochondria are recognized as pivotal targets of the gut microbiota to modulate the host's physiological state. Mitochondrial dysfunction plays a vital role in MASLD and is associated with multiple pathological changes, including hepatocyte steatosis, oxidative stress, inflammation, and fibrosis. Metabolites are crucial mediators of the gut microbiota that influence extraintestinal organs. Additionally, regulation of the composition of gut bacteria may serve as a promising therapeutic strategy for MASLD. This study reviewed the potential roles of several common metabolites in MASLD, emphasizing their impact on mitochondrial function. Finally, we discuss the current treatments for MASLD, including probiotics, prebiotics, antibiotics, and fecal microbiota transplantation. These methods concentrate on restoring the gut microbiota to promote host health.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534281","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 impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications.","authors":"Divya Ayyala-Somayajula, Jennifer L Dodge, Kali Zhou, Norah A Terrault, Liyun Yuan","doi":"10.1097/HC9.0000000000000455","DOIUrl":"10.1097/HC9.0000000000000455","url":null,"abstract":"<p><strong>Background: </strong>Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications.</p><p><strong>Methods: </strong>Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p).</p><p><strong>Results: </strong>Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability.</p><p><strong>Conclusions: </strong>The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534353","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":"NUAK1 promotes metabolic dysfunction-associated steatohepatitis progression by activating Caspase 6-driven pyroptosis and inflammation.","authors":"Mingwei Sheng, Shuhan Huo, Lili Jia, Yiqi Weng, Weihua Liu, Yuanbang Lin, Wenli Yu","doi":"10.1097/HC9.0000000000000479","DOIUrl":"10.1097/HC9.0000000000000479","url":null,"abstract":"<p><strong>Background: </strong>lNUAK1 is strongly associated with organ fibrosis, but its causal mechanism for modulating lipid metabolism and hepatic inflammation underlying MASH has not been fully clarified.</p><p><strong>Method: </strong>In our study, human liver tissues from patients with MASH and control subjects were obtained to evaluate NUAK1 expression. MASH models were established using C57BL/6 mice. Liver damage and molecular mechanisms of the NUAK1-Caspase 6 signaling were tested in vivo and in vitro.</p><p><strong>Results: </strong>In the clinical arm, NUAK1 expression was upregulated in liver samples from patients with MASH. Moreover, increased NUAK1 was detected in mouse MASH models. NUAK1 inhibition ameliorated steatohepatitis development in MASH mice accompanied by the downregulation of hepatic steatosis and fibrosis. Intriguingly, NUAK1 was found to facilitate Caspase 6 activation and trigger pyroptosis in MASH-stressed livers. Disruption of hepatocytes Caspase 6 decreased MASH-induced liver inflammation with upregulated TAK1 but diminished RIPK1. Moreover, we found that NUAK1/Caspase 6 axis inhibition could accelerate the interaction between TAK1 and RIPK1, which in turn led to the degradation of RIPK1.</p><p><strong>Conclusions: </strong>In summary, our study elucidates that NUAK1-Caspase 6 signaling controls inflammation activation in MASH through the interaction between TAK1 and RIPK1, which is crucial for controlling pyroptosis and promoting the progression of MASH.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534350","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 macrophages revisited: The expanding universe of versatile responses in a spatiotemporal context.","authors":"Adrien Guillot, Frank Tacke","doi":"10.1097/HC9.0000000000000491","DOIUrl":"10.1097/HC9.0000000000000491","url":null,"abstract":"<p><p>The liver is a vital organ that continuously adapts to a wide and dynamic diversity of self-antigens and xenobiotics. This involves the active contribution of immune cells, particularly by the liver-resident macrophages, the Kupffer cells (KCs), which exert a variety of central functions in liver homeostasis and disease. As such, KCs interact with their microenvironment to shape the hepatic cellular landscape, control gut-derived signal integration, and modulate metabolism. On injury, the rapid recruitment of bone marrow monocyte-derived macrophages alters this status quo and, when unrestrained, drastically compromises liver homeostasis, immune surveillance, and tissue organization. Several factors determine the functional roles of liver macrophages in these processes, such as their ontogeny, activation/polarization profile and, importantly, spatial distribution within the liver. Loss of tolerance and adaptability of the hepatic immune environment may result in persistent inflammation, hepatic fibrosis, cirrhosis, and a tumorigenic niche promoting liver cancer. In this review, we aim at providing the most recent breakthroughs in our understanding of liver macrophage biology, particularly their diversity and adaptability in the hepatic spatiotemporal context, as well as on potential therapeutic interventions that may hold the key to tackling remaining clinical challenges of varying etiologies in hepatology.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534282","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}