Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice","authors":"Callie E. Scull ,&nbsp;Yawen Hu ,&nbsp;Scott Jennings,&nbsp;Guoshun Wang","doi":"10.1016/j.jcmgh.2024.101424","DOIUrl":"10.1016/j.jcmgh.2024.101424","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.</div></div><div><h3>Methods</h3><div>CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction.</div></div><div><h3>Results</h3><div>Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice.</div></div><div><h3>Conclusions</h3><div>CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101424"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607586","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":"Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic Steatosis","authors":"Xiao-lin Wang ,&nbsp;Jia-hao He ,&nbsp;Ping Xie,&nbsp;Yuan Wu,&nbsp;Ling-yue Dong,&nbsp;Wei An","doi":"10.1016/j.jcmgh.2024.101436","DOIUrl":"10.1016/j.jcmgh.2024.101436","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown.</div></div><div><h3>Methods</h3><div>Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in <em>in vivo</em> and <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis.</div></div><div><h3>Conclusions</h3><div>The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101436"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796457","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":"The Effect of FOXA3 Overexpression on Hepatocyte Differentiation and Liver Regeneration in a Fah cKO Mouse Model","authors":"Shao Li ,&nbsp;Chupeng Ou ,&nbsp;Jiajun Zhang ,&nbsp;Min Zeng ,&nbsp;Kangyan Liang ,&nbsp;Qing Peng ,&nbsp;Yi Gao","doi":"10.1016/j.jcmgh.2024.101438","DOIUrl":"10.1016/j.jcmgh.2024.101438","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Stimulated by injury or disease, hepatocytes can regenerate and repair liver tissues through proliferation and differentiation. Partial hepatectomy and liver transplantation are effective treatments for liver diseases. This study investigated the effect of FOXA3 on cell differentiation in HepaRG cell lines under 2- and 3-dimensional culture conditions.</div></div><div><h3>Methods</h3><div>Experiments were performed using a HepaRG cell line that stably overexpressed FOXA3 (RF3) and hepatocyte-specific functions. Moreover, a Fah conditional knockout mouse model (Fah cKO mice) was constructed using the CRISPR-Cas9 method and treated with RF3 spheroids for transplantation. Various molecular biology and immunostaining experiments were performed to assess liver function, hepatocyte structure, and expression levels of cell cycle–related proteins.</div></div><div><h3>Results</h3><div>HepaRG cells that overexpressed FOXA3 had hepatocyte-specific functions. RF3 spheroids expressed liver markers following gene and protein expression analysis. After RF3 spheroid transplantation, Fah cKO mice exhibited increased survival, reduced weight loss, normalization of liver function and hepatocyte structure, and enhanced expression of hepatocyte differentiation factors. However, the expression of cell cycle–related proteins, including p53 and p21, was decreased in vivo. Injection of an HNF4α antagonist revealed that inhibition of HNF4α effectively suppressed the regenerative capacity of the liver after RF3 spheroid transplantation, resulting in an increase in the number of p53- and p21-positive cells and a decrease in the expression levels of liver function–related genes.</div></div><div><h3>Conclusions</h3><div>FOXA3 plays an important role in hepatocyte function. RF3 spheroid transplantation had a therapeutic effect in the Fah cKO mouse model, improving liver function and promoting liver regeneration.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101438"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815193","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":"Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver Diseases","authors":"Lan Zhou ,&nbsp;Min Yan ,&nbsp;Qin Luo ,&nbsp;Wen Qiu ,&nbsp;Yu-Ru Guo ,&nbsp;Xiao-Qing Guo ,&nbsp;Hong-Bin Yu ,&nbsp;Jing-Ru Huo ,&nbsp;Yan-Lin Feng ,&nbsp;De-Ping Wang ,&nbsp;Teng Sun ,&nbsp;Kai-Fang Wang ,&nbsp;Jian-Yun Shi ,&nbsp;Xuan Shang ,&nbsp;Mei-Na Wu ,&nbsp;Lin Wang ,&nbsp;Ji-Min Cao","doi":"10.1016/j.jcmgh.2024.101439","DOIUrl":"10.1016/j.jcmgh.2024.101439","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies.</div></div><div><h3>Methods</h3><div>We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments.</div></div><div><h3>Results</h3><div>Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution.</div></div><div><h3>Conclusions</h3><div>Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101439"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820349","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":"Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells","authors":"Kentaro Tominaga ,&nbsp;Daniel O. Kechele ,&nbsp;J. Guillermo Sanchez ,&nbsp;Simon Vales ,&nbsp;Ingrid Jurickova ,&nbsp;Lizza Roman ,&nbsp;Akihiro Asai ,&nbsp;Jacob R. Enriquez ,&nbsp;Heather A. McCauley ,&nbsp;Keishi Kishimoto ,&nbsp;Kentaro Iwasawa ,&nbsp;Akaljot Singh ,&nbsp;Yuko Horio ,&nbsp;Jorge O. Múnera ,&nbsp;Takanori Takebe ,&nbsp;Aaron M. Zorn ,&nbsp;Michael A. Helmrath ,&nbsp;Lee A. Denson ,&nbsp;James M. Wells","doi":"10.1016/j.jcmgh.2024.101444","DOIUrl":"10.1016/j.jcmgh.2024.101444","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages.</div></div><div><h3>Methods</h3><div>HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro. Following 2 weeks of coculture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured in vivo for an additional 10–12 weeks.</div></div><div><h3>Results</h3><div>Macrophages were incorporated into developing HIOs and persisted for 2 weeks in vitro HIOs and for at least 12 weeks in HIOs in vivo. These cocultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10.</div></div><div><h3>Conclusions</h3><div>We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101444"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866518","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":"Mouse Models for Pancreatic Ductal Adenocarcinoma are Affected by the cre-driver Used to Promote KRASG12D Activation","authors":"Fatemeh Mousavi ,&nbsp;Joyce Thompson ,&nbsp;Justine Lau ,&nbsp;Nur Renollet ,&nbsp;Mickenzie B. Martin ,&nbsp;Jake McGue ,&nbsp;Oneeb Hassan ,&nbsp;Timothy Frankel ,&nbsp;Parisa Shooshtari ,&nbsp;Christopher L. Pin ,&nbsp;Filip Bednar","doi":"10.1016/j.jcmgh.2024.101428","DOIUrl":"10.1016/j.jcmgh.2024.101428","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS^G12D). One of the most commonly used models involves targeted insertion of a <em>cre</em>-recombinase into the <em>Ptf1a</em> gene. However, this approach disrupts the <em>Ptf1a</em> gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS^G12D). This study aims to determine if <em>Ptf1a</em> haploinsufficiency affected the acinar cell response to KRAS^G12D before and after induction of pancreatic injury.</div></div><div><h3>Methods</h3><div>We performed morphological and molecular analysis of 3 genetically engineered mouse models that express a tamoxifen-inducible <em>cre</em>-recombinase to activate <em>Kras</em>^{<em>G12D</em>} in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, <em>Ptf1a</em> or <em>Mist1/Bhlha15</em>, or expressed within a BAC-derived <em>Elastase</em> transgene. Histological and RNA-seq analyses were used to delineate differences between the models.</div></div><div><h3>Results</h3><div>Up to 2 months after tamoxifen induction of KRAS^G12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in <em>Ptf1a</em>^{<em>creERT</em>} pancreata within 7 days and maintained for at least 5 weeks post-injury, which was not seen in the models with 2 functional <em>Ptf1a</em> alleles. RNA-sequencing analysis prior to injury induction suggested <em>Ptf1a</em>^{<em>creERT</em>} and <em>Mist1</em>^{<em>creERT</em>} mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models.</div></div><div><h3>Conclusions</h3><div>These findings suggest <em>Ptf1a</em> haploinsufficiency in <em>Ptf1a</em>^{<em>creERT</em>} mouse models promotes KRAS^G12D priming of genes for promotion of pancreatic ductal adenocarcinoma.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101428"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640330","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":"Cytomegalovirus Worsens Necrotizing Enterocolitis Severity in Mice via Increased Toll-Like Receptor 4 Signaling","authors":"Daniel Scheese,&nbsp;Peng Lu,&nbsp;Hannah Moore,&nbsp;Koichi Tsuboi,&nbsp;Cody Tragesser,&nbsp;Johannes Duess,&nbsp;Zachariah Raouf,&nbsp;Maame F. Sampah,&nbsp;Daphne Klerk,&nbsp;Mahmoud El Baassiri,&nbsp;Hee-seong Jang,&nbsp;Sierra Williams-McLeod,&nbsp;Asuka Ishiyama,&nbsp;Steve N. Steinway,&nbsp;Sanxia Wang,&nbsp;Menghan Wang,&nbsp;Thomas Prindle Jr.,&nbsp;William B. Fulton,&nbsp;Chhinder P. Sodhi,&nbsp;David J. Hackam","doi":"10.1016/j.jcmgh.2025.101473","DOIUrl":"10.1016/j.jcmgh.2025.101473","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Necrotizing enterocolitis (NEC) is a life-threatening condition in premature infants, marked by acute intestinal necrosis. NEC develops in part after activation of the lipopolysaccharide receptor toll-like receptor 4 (TLR4) by intestinal microbes in the intestinal epithelium. Previous authors have shown an increased risk of NEC in human infants after cytomegalovirus (CMV) infection, which can affect mitochondrial function. We now seek to explore the impact and the mechanisms of CMV infection on NEC severity and its relationship with TLR4 signaling and mitochondria function.</div></div><div><h3>Methods</h3><div>NEC was induced in newborn mice with and without CMV infection. RNA sequencing and gene set enrichment analysis were performed to identify effects on inflammatory and metabolic pathways. The role of TLR4 signaling and mitochondrial function were investigated in wild-type and <em>Tlr4</em>-deficient mice. The adenosine receptor agonist 5'-N-ethylcarboxamido adenosine was tested for its ability to reduce CMV-induced effects on NEC severity.</div></div><div><h3>Results</h3><div>CMV infection significantly increased NEC severity in wild-type mice. Mechanistically, CMV infection triggered proinflammatory pathways, disrupted cellular metabolism, and upregulated <em>Tlr4</em> expression, leading to mitochondrial dysfunction and nuclear factor-kB translocation. These effects were notably absent in Tlr4-deficient mice. 5'-N-ethylcarboxamido adenosine treatment reversed CMV-induced NEC severity by reducing mitochondrial dysfunction and TLR4-driven nuclear factor-kB activation.</div></div><div><h3>Conclusions</h3><div>CMV infection worsens NEC severity in mice by amplifying TLR4 signaling, inflammation, and mitochondrial dysfunction. Targeting CMV and its influence on TLR4 may offer novel therapeutic approaches for NEC.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101473"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426689","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":"Attenuating ABHD17 Isoforms Augments the S-acylation and Function of NOD2 and a Subset of Crohn’s Disease-associated NOD2 Variants","authors":"Charneal L. Dixon ,&nbsp;Noah R. Martin ,&nbsp;Micah J. Niphakis ,&nbsp;Benjamin F. Cravatt ,&nbsp;Gregory D. Fairn","doi":"10.1016/j.jcmgh.2025.101491","DOIUrl":"10.1016/j.jcmgh.2025.101491","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational <em>S</em>-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, <em>S</em>-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.</div></div><div><h3>Methods</h3><div>To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.</div></div><div><h3>Results</h3><div>We identified <em>α</em>/<em>β</em>-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn’s disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn’s disease-associated NOD2 variants, offering a potential therapeutic strategy.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101491"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588322","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":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00047-5","DOIUrl":"10.1016/S2352-345X(25)00047-5","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101506"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825761","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":"Aquaporin-7 Deficiency Attenuates Liver Fibrosis by Inhibiting the Activation and Proliferation of Hepatic Stellate Cells","authors":"Junqi Zhang ,&nbsp;Yijun Ma ,&nbsp;Yu Wang ,&nbsp;Chi Zhang ,&nbsp;Peng Chen ,&nbsp;Qing Ye ,&nbsp;Yueyue Lei ,&nbsp;Yanghao Li ,&nbsp;Bo Zhang ,&nbsp;Tonghui Ma","doi":"10.1016/j.jcmgh.2024.101449","DOIUrl":"10.1016/j.jcmgh.2024.101449","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Aquaporin-7 (Aqp7) is an aquaglyceroporin that provides transmembrane gateway of water, glycerol, and hydrogen peroxide (H₂O₂). Analysis of the Gene Expression Omnibus (GEO) database revealed upregulation of hepatic AQP7 expression in liver fibrosis patients. This study aimed to elucidate the role of Aqp7 in the pathogenesis of liver fibrosis.</div></div><div><h3>Methods</h3><div>The GEO database analysis and TGF_β -induced human hepatic stellate cell (HSC) line LX-2 cells were used to study the relevance of AQP7 to human liver fibrosis. Bile duct ligation-induced and carbon tetrachloride-induced liver fibrosis models were employed to investigate the role of Aqp7 in liver fibrosis formation in conventional and HSC-specific Aqp7 knockout mice. Primary mouse HSCs were isolated to explore the role of Aqp7-mediated glycerol and H₂O₂ transport in HSC activation and proliferation.</div></div><div><h3>Results</h3><div>AQP7 mRNA and protein levels are remarkably upregulated in TGF_β-induced LX-2, as well as in primary mouse HSCs isolated from liver fibrosis models induced by bile duct ligation and peritoneal injection of carbon tetrachloride. Liver fibrosis formation was significantly alleviated in both conventional and HSC-specific Aqp7 knockout mice compared with their respective wild-type littermates, as evidenced by significantly decreased deposition of fibrous extracellular matrix. Aqp7 deletion resulted in the accumulation of intracellular glycerol, an increase in triglyceride content, the retention of intracellular lipid droplets, and dilatory activation of HSCs. Moreover, Aqp7 deficiency led to elevated intracellular H₂O₂ levels during activation, which impaired autophagy, proliferation, and survival of HSCs by disrupting relevant cell signaling pathways. Virus-mediated replacement with glycerol- or H₂O₂-transporting aquaporins Aqp3 or Aqp8, but not the strictly water-selective channel Aqp4, effectively rescued the impaired activation and proliferation in primary cultured Aqp7^-/- HSCs.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that Aqp7 plays a crucial role in the activation of HSCs and the formation of liver fibrosis by regulating triglyceride catabolism and maintaining reactive oxygen species homeostasis in HSCs.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101449"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637683","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}