Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"It Takes Guts: Interactions of Intestinal Stearoyl CoA Desaturase 1 and Bile Acids.","authors":"Jessica M Ferrell","doi":"10.1016/j.jcmgh.2024.101401","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101401","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333073","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":"Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization.","authors":"Xin Ding, Xiang Zhang, Jiafan Cao, Shiyun Chen, Yinghua Chen, Kai Yuan, Bo Chen, Guizhi Yang, Shengwen Li, Jundong Yang, Guixiang Wang, Frank Tacke, Tian Lan","doi":"10.1016/j.jcmgh.2024.101406","DOIUrl":"10.1016/j.jcmgh.2024.101406","url":null,"abstract":"<p><strong>Background & aims: </strong>Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis.</p><p><strong>Methods: </strong>Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1^-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation. The direct effects of SphK1 on macrophage polarization were also investigated in vitro. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples.</p><p><strong>Results: </strong>SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by carbon tetrachloride. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via C-C motif chemokine ligand 2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier-specific peptidase1 to decrease de-SUMOylation of Kruppel-like factor 4 to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers.</p><p><strong>Conclusions: </strong>Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301827","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":"Interindividual Variation in Gut Nitrergic Neuron Density Is Regulated By GDNF Levels and ETV1.","authors":"Heikki T Virtanen, Peyman Choopanian, L Lauriina Porokuokka, Richard Forsgård, Daniel R Garton, Soophie Olfat, Riitta Korpela, Mehdi Mirzaie, Jaan-Olle Andressoo","doi":"10.1016/j.jcmgh.2024.101405","DOIUrl":"10.1016/j.jcmgh.2024.101405","url":null,"abstract":"<p><strong>Background & aims: </strong>The size and function of the enteric nervous system (ENS) can vary substantially between individuals. Because ENS function is involved in the etiology of a growing number of common human diseases, understanding mechanisms that regulate ENS variation is important.</p><p><strong>Methods: </strong>We analyzed RNAseq data from 41 normal adult human colon biopsies and single-cell RNA-seq data from human and mouse developing gut. To establish cause-consequence relationship we used alleles in mice that allow levels change of the candidate effector molecule in the comparable range to human samples. We used siRNA and primary neuronal cultures to define downstream molecular events and characterized gut functional changes in mice where molecular phenotypes paralleled findings in humans.</p><p><strong>Results: </strong>We found that glial cell line-derived neurotrophic factor (GDNF) levels in the human colon vary about 5-fold and correlate strongly with nitrergic marker expression. In mice, we defined that GDNF levels are regulated via its 3' untranslated region (3' UTR) in the gastrointestinal tract and observed similar correlation between GDNF levels and nitrergic lineage development. We identified miR-9 and miR-133 as evolutionarily conserved candidates for negative regulation of GDNF expression in the gastrointestinal tract. Functionally, an increase in inhibitory nitrergic innervation results in an increase in gastrointestinal tract transit time, stool size, and water content accompanied with modestly reduced epithelial barrier function. Mechanistically, we found that GDNF levels regulate nitrergic lineage development via induction of transcription factor ETV1, corroborated by single-cell gene expression data in human and mouse developing enteric neurons.</p><p><strong>Conclusions: </strong>Our results reveal how normal variation in GDNF levels influence ENS size, composition, and gut function, suggesting a mechanism for well-known interindividual variation among those parameters.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301805","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":"RBM39 Enhances Cholangiocarcinoma Growth Through EZH2-mediated WNT7B/β-catenin Pathway.","authors":"Nianli Liu, Jinqiang Zhang, Weina Chen, Wenbo Ma, Tong Wu","doi":"10.1016/j.jcmgh.2024.101404","DOIUrl":"10.1016/j.jcmgh.2024.101404","url":null,"abstract":"<p><strong>Background & aims: </strong>The RNA-binding motif protein 39 (RBM39) functions as both an RNA-binding protein and a splicing factor in a variety of cancer types. However, the function of RBM39 in cholangiocarcinoma (CCA) remains undefined. In this study, we aimed to investigate the role of RBM39 in CCA and explore its potential as a therapeutic target.</p><p><strong>Methods: </strong>The expression of RBM39 in CCA was investigated by analyzing human CCA tumor specimens. CRISPR/Cas9 or shRNA-mediated depletion of RBM39 was performed in vitro and in vivo to document the oncogenic role of RBM39 in CCA. The anti-tumor effect of the RBM39 inhibitor, Indisulam, in combination with the EZH2 degrader MS177 was assessed in vitro and in vivo.</p><p><strong>Results: </strong>RBM39 is significantly increased in human CCA tissues and associated with a poor prognosis in patients with CCA. Depletion of RBM39 by CRISPR/Cas9 or shRNA inhibited CCA cell proliferation in vitro and prevented CCA development and tumor growth in mice. Mechanistically, our results showed that depletion of RBM39 suppressed EZH2 expression via disrupting its mRNA splicing. RBM39-regulated EZH2 controls WNT7B/β-catenin activity. Pharmacological co-targeting of RBM39 (with Indisulam) and EZH2 (with MS177) resulted in a synergistic antitumor effect, both in vitro and in vivo.</p><p><strong>Conclusion: </strong>This study discloses a novel RBM39-EZH2-β-catenin signaling axis that is crucial for CCA growth. Our findings suggest that simultaneous inhibition of RBM39 and EZH2 presents a promising therapeutic strategy for CCA treatment.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301807","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":"Intestinal Stearoyl-CoA Desaturase-1 Regulates Energy Balance via Alterations in Bile Acid Homeostasis.","authors":"Natalie Burchat, Jeanine Vidola, Sarah Pfreundschuh, Priyanka Sharma, Daniel Rizzolo, Grace L Guo, Harini Sampath","doi":"10.1016/j.jcmgh.2024.101403","DOIUrl":"10.1016/j.jcmgh.2024.101403","url":null,"abstract":"<p><strong>Background & aims: </strong>Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid assimilation and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here, we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance.</p><p><strong>Methods: </strong>To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine-specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, and metabolic phenotyping, including body composition, indirect calorimetry, glucose tolerance analyses, quantification of the composition of the gut microbiome, and assessment of bile acid signaling pathways.</p><p><strong>Results: </strong>iKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. In addition, the alpha and beta diversity of the gut microbiome was reduced in iKO mice, with several alterations in microbe species being associated with the observed increases in plasma bile acids. These increases in plasma bile acids were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice.</p><p><strong>Conclusion: </strong>Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid homeostasis and whole-body energy balance, likely via activation of TGR5.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301806","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":"XBP1 facilitating NF-κB-p65 nuclear translocation promotes macrophage-originated sterile inflammation via regulating MT2 transcription in the ischemia/reperfusion liver.","authors":"Jianhua Rao,Zeng Wang,Fei Yu,Junda Li,Wenzhu Li,Zhengfeng Xuan,Yongquan Chi,Feng Zhang,Liming Tang,Feng Cheng","doi":"10.1016/j.jcmgh.2024.101402","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.101402","url":null,"abstract":"BACKGROUND & AIMSXBP1, most conserved transcription factor of endoplasmic reticulum (ER) stress, plays important roles in physiological and pathological settings and has profound effects on disease progression and prognosis, so it's necessary to investigate XBP1 in macrophage-originated sterile inflammation during liver ischemia/reperfusion injury (IRI). Macrophage XBP1 expression and liver injury are analyzed in patients undergoing ischemia-related hepatectomy.METHODSA myeloid-specific male XBP1-knockout (XBP1M-KO) strain is created for function and mechanism of XBP1 on macrophage-derived sterile inflammation in murine liver IRI with in-vitro parallel research. Macrophages co-cultured with hypoxia-treated hepatocytes are applied to investigate impact of XBP1 in vitro, with analysis of RNA sequencing and databases.RESULTSClinically, macrophage XBP1 expression significantly increases in ischemic liver tissues and positively correlates with liver injury after hepatectomy. Less hepatocellular damage is presented in XBP1M-KO mice than in XBP1-proficient (XBP1FL/FL) controls. In vitro, XBP1 deficiency inhibits sterile inflammation and migration in macrophages co-cultured with hypoxia-treated hepatocytes. Analysis of RNA sequencing and databases determines Metallothionein 2 (MT2) as XBP1 target gene, negatively regulated by binding with its promoter. XBP1 deficiency increases MT2 and IKBα expression, but inhibits NF-κB-p65 phosphorylation, markedly neutralizing XBP1M-KO-related benefits by promoting sterile inflammation during liver IRI.CONCLUSIONSXBP1 promotes macrophage-originated sterile inflammation, increases liver IRI by binding to MT2 promoter, and regulates MT2/NF-κB pathway, potentially therapeutic for clinical liver IRI.","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266520","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":"▪▪▪","authors":"Michele A. Battle, Jonathan L. Katz","doi":"10.1016/j.jcmgh.2024.05.001","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.05.001","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141056444","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":"Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-Induced Immunotolerance.","authors":"Huiyuan Xie, Haiyan Deng, Xiaoping Yang, Xianxian Gao, Shanru Yang, Weiyi Chen, Yixuan Wang, Naibin Yang, Liang Yong, Xin Hou","doi":"10.1016/j.jcmgh.2024.05.008","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2024.05.008","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141051090","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":"“The Good, the Bad, and the Ugly” – About Diverse Phenotypes of Hepatic Stellate Cells in the Liver","authors":"Alexandra Bogomolova ,&nbsp;Asha Balakrishnan ,&nbsp;Michael Ott ,&nbsp;Amar Deep Sharma","doi":"10.1016/j.jcmgh.2024.01.002","DOIUrl":"10.1016/j.jcmgh.2024.01.002","url":null,"abstract":"<div><p>Hepatic stellate cells (HSCs) and their activated derivatives, often referred to as myofibroblasts (MFs), play a key role in progression of chronic liver injuries leading to fibrosis, cirrhosis, and hepatocellular carcinoma. Until recently, MFs were considered a homogenous cell type majorly due to lack of techniques that allow complex molecular studies at a single-cell resolution. Recent technical advancements in genetic lineage-tracing models as well as the exponential growth of studies with single-cell transcriptome and proteome analyses have uncovered hidden heterogeneities among the HSC and MF populations in healthy states as well as chronic liver injuries at the various stages of tissue deformation. The identification of different phenotypes along the HSC/MF axis, which either maintain essential liver functions (“good” HSCs), emerge during fibrosis (“bad” HSCs), or even promote hepatocellular carcinoma (“ugly” HSCs), may lay the foundation for targeting a particular MF phenotype as potential treatment for chronic liver injuries.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2400002X/pdfft?md5=5125ee8e287bd3ecb24133294c27807e&pid=1-s2.0-S2352345X2400002X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDKN2A-p16 Deletion and Activated KRASG12D Drive Barrett’s-Like Gland Hyperplasia-Metaplasia and Synergize in the Development of Dysplasia Precancer Lesions","authors":"Jing Sun ,&nbsp;Jorge L. Sepulveda ,&nbsp;Elena V. Komissarova ,&nbsp;Caitlin Hills ,&nbsp;Tyler D. Seckar ,&nbsp;Narine M. LeFevre ,&nbsp;Hayk Simonyan ,&nbsp;Colin Young ,&nbsp;Gloria Su ,&nbsp;Armando Del Portillo ,&nbsp;Timothy C. Wang ,&nbsp;Antonia R. Sepulveda","doi":"10.1016/j.jcmgh.2024.01.014","DOIUrl":"10.1016/j.jcmgh.2024.01.014","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Barrett’s esophagus is the precursor of esophageal dysplasia and esophageal adenocarcinoma. CDKN2A-p16 deletions were reported in 34%–74% of patients with Barrett’s esophagus who progressed to dysplasia and esophageal adenocarcinoma, suggesting that p16 loss may drive neoplastic progression. KRAS activation frequently occurs in esophageal adenocarcinoma and precancer lesions. LGR5⁺ stem cells in the squamocolumnar-junction (SCJ) of mouse stomach contribute as Barrett’s esophagus progenitors. We aimed to determine the functional effects of p16 loss and KRAS activation in Barrett’s-like metaplasia and dysplasia development.</p></div><div><h3>Methods</h3><p>We established mouse models with conditional knockout of CDKN2A-p16 (p16KO) and/or activated KRAS^G12D expression targeting SCJ LGR5⁺ cells in interleukin 1b transgenic mice and characterized histologic alterations (mucous-gland hyperplasia/metaplasia, inflammation, and dysplasia) in mouse SCJ. Gene expression was determined by microarray, RNA sequencing, and immunohistochemistry of SCJ tissues and cultured 3-dimensional organoids.</p></div><div><h3>Results</h3><p>p16KO mice exhibited increased mucous-gland hyperplasia/metaplasia versus control mice (<em>P</em> = .0051). Combined p16KO+KRAS^G12D resulted in more frequent dysplasia and higher dysplasia scores (<em>P</em> = .0036), with 82% of p16KO+KRAS^G12D mice developing high-grade dysplasia. SCJ transcriptome analysis showed several activated pathways in p16KO versus control mice (apoptosis, tumor necrosis factor-α/nuclear factor-kB, proteasome degradation, p53 signaling, MAPK, KRAS, and G1-to-S transition).</p></div><div><h3>Conclusions</h3><p>p16 deletion in LGR5⁺ cell precursors triggers increased SCJ mucous-gland hyperplasia/metaplasia. KRAS^G12D synergizes with p16 deletion resulting in higher grades of SCJ glandular dysplasia, mimicking Barrett’s high-grade dysplasia. These genetically modified mouse models establish a functional role of p16 and activated KRAS in the progression of Barrett’s-like lesions to dysplasia in mice, representing an <em>in vivo</em> model of esophageal adenocarcinoma precancer. Derived 3-dimensional organoid models further provide <em>in vitro</em> modeling opportunities of esophageal precancer stages.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000146/pdfft?md5=0aa29fe556e0ec453bca72e8f31695cb&pid=1-s2.0-S2352345X24000146-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139587531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}