American journal of physiology. Gastrointestinal and liver physiology最新文献

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Influence of isoflurane and propofol on gastric slow wave patterns and pacing efficacy in pigs. 异氟醚和异丙酚对猪胃慢波模式和起搏效果的影响。
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-09-01 Epub Date: 2025-08-13 DOI: 10.1152/ajpgi.00123.2025
Nipuni D Nagahawatte, Peng Du, Hanyu Zhang, Haley N Patton, Jack M Rogers, Niranchan Paskaranandavadivel, Leo K Cheng
{"title":"Influence of isoflurane and propofol on gastric slow wave patterns and pacing efficacy in pigs.","authors":"Nipuni D Nagahawatte, Peng Du, Hanyu Zhang, Haley N Patton, Jack M Rogers, Niranchan Paskaranandavadivel, Leo K Cheng","doi":"10.1152/ajpgi.00123.2025","DOIUrl":"10.1152/ajpgi.00123.2025","url":null,"abstract":"<p><p>Gut motility is partly driven by underlying rhythmic electrical activity called slow waves. The origin and propagation of these electrical events are studied extensively in anesthetized animal models. However, the effects of anesthesia on slow waves remain unclear. This study examined how propofol and isoflurane influence spatiotemporal features of gastric slow waves, anterior-posterior coupling, and the efficacy of gastric pacing. Pigs were anesthetized with propofol (<i>n</i> = 7) and isoflurane (<i>n</i> = 8), and baseline electrical activity was measured using high-resolution surface-contact electrode arrays placed on the anterior and posterior gastric serosa. Following baseline recordings, pacing was applied to assess its effects. Slow wave propagation patterns were quantified, and the efficacy of spatial entrainment during pacing was compared under propofol and isoflurane. Under propofol, antegrade propagation was observed with 86% symmetry between anterior and posterior gastric surfaces, whereas isoflurane reduced symmetry to 25% (<i>P</i> = 0.0187) with propagation patterns frequently changing. Slow wave period (18.8 ± 5.1 vs. 28.1 ± 14.3 s, <i>P</i> = 0.016), amplitude (1.5 ± 0.7 vs. 0.7 ± 0.4 mV, <i>P</i> = 0.002), and speed (4.4 ± 1.1 vs. 3.5 ± 0.7 mm/s, <i>P</i> = 0.018) differed significantly between anesthetic groups at baseline, whereas only amplitude and speed differed during pacing. Spatial entrainment success was higher with propofol (83%) than with isoflurane (57%), but pacing effects remained localized to the paced surface without propagation across the greater curvature. Isoflurane induced more gastric dysrhythmias than propofol, making propofol preferable for studying normal activity and isoflurane preferred for investigating therapies. The uncoupling of anterior and posterior surfaces suggests a potential electrical barrier at the greater curvature, warranting further investigation.<b>NEW & NOTEWORTHY</b> The influence of propofol and isoflurane on the spatial propagation of gastric slow wave activity under baseline and pacing conditions was defined for the first time. Slow waves were significantly ordered and coupled across the anterior and posterior surfaces of the stomach under propofol compared with isoflurane. Slow waves entrained during pacing were confined to the surface where pacing was applied, suggesting an electrical barrier along the greater curvature of the stomach.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G457-G468"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Female ethanolamine phosphate phospholyase knockout mice resisted high-fat diet-induced obesity with attenuated hepatic cholesterol deposition. 雌性乙醇胺磷酸磷酸化酶敲除小鼠通过降低肝脏胆固醇沉积来抵抗高脂肪饮食引起的肥胖。
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-09-01 Epub Date: 2025-07-18 DOI: 10.1152/ajpgi.00386.2024
Kholoud A Elmihi, Kelly-Ann Leonard, Randy Nelson, Aducio Thiesen, Robin D Clugston, René L Jacobs
{"title":"Female ethanolamine phosphate phospholyase knockout mice resisted high-fat diet-induced obesity with attenuated hepatic cholesterol deposition.","authors":"Kholoud A Elmihi, Kelly-Ann Leonard, Randy Nelson, Aducio Thiesen, Robin D Clugston, René L Jacobs","doi":"10.1152/ajpgi.00386.2024","DOIUrl":"10.1152/ajpgi.00386.2024","url":null,"abstract":"<p><p>Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phosphoethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) synthesis. Whole body knockout <i>Etnppl</i> mice were fed a high-fat diet (HFD) containing 45% kcal fat for 10 wk. <i>Etnppl</i><sup>-/-</sup> female mice were resistant to HFD-induced obesity and had decreased liver weight compared with <i>Etnppl</i><sup>+/+</sup> mice. Furthermore, <i>Etnppl</i><sup>-/-</sup> female mice had improved glucose sensitivity and increased energy expenditure compared with <i>Etnppl</i><sup>+/+</sup> mice. Plasma triglyceride (TG) levels were elevated in <i>Etnppl</i><sup>-/-</sup> female mice, although the rate of very low-density lipoprotein (VLDL) secretion was not increased. The hepatic expression of PCSK9 was elevated, indicating a possible decrease in VLDL uptake. Interestingly, both plasma and hepatic cholesterol levels were reduced in <i>Etnppl</i><sup>-/-</sup> relative to <i>Etnppl</i><sup>+/+</sup> mice. No difference in hepatic phosphatidylcholine, PE, or TG was detected between groups. Histopathological examination of hepatic tissues revealed decreased lipid deposition in <i>Etnppl</i><sup>-/-</sup> mice that may be explained by the lower hepatic cholesterol level. Additionally, RNA sequencing analysis showed upregulation in genes related to cholesterol metabolism in <i>Etnppl</i><sup>-/-</sup> female mice. In male mice, a slight decrease in weight gain was observed in <i>Etnppl</i><sup>-/-</sup> mice compared with <i>Etnppl</i><sup>+/+</sup> mice. No change in plasma and hepatic lipid levels was detected in <i>Etnppl</i><sup>-/-</sup> male mice. To conclude, ETNPPL impacts whole body energy expenditure, weight gain, cholesterol metabolism, and hepatic lipoprotein metabolism without altering hepatic phospholipid levels.<b>NEW & NOTEWORTHY</b> <i>Etnppl</i><sup>-/-</sup> female mice resisted diet-induced obesity with enhanced energy expenditure and less adipose tissue. In addition, <i>Etnppl</i><sup>-/-</sup> female mice fed an HFD showed decreased liver cholesterol deposition. RNA sequencing revealed changes in genes related to cholesterol and lipid metabolism in <i>Etnppl</i><sup>-/-</sup> female mice. <i>Etnppl</i><sup>-/-</sup> female mice fed an HFD supplemented with cholesterol had no difference in plasma and hepatic cholesterol levels compared with <i>Etnppl</i><sup>+/+</sup> mice.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G390-G402"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of Long Chain Acyl-CoA Synthetases in MASH-driven Hepatocellular Carcinoma and Ferroptosis. 长链酰基辅酶a合成酶在肝细胞癌和铁下垂中的作用。
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-28 DOI: 10.1152/ajpgi.00096.2025
Peyton Classon, Alexander Q Wixom, Natalia Calixto Mancipe, Rondell P Graham, Yu Zhao, Nguyen Tran, Timucin Taner, Davide Povero
{"title":"Role of Long Chain Acyl-CoA Synthetases in MASH-driven Hepatocellular Carcinoma and Ferroptosis.","authors":"Peyton Classon, Alexander Q Wixom, Natalia Calixto Mancipe, Rondell P Graham, Yu Zhao, Nguyen Tran, Timucin Taner, Davide Povero","doi":"10.1152/ajpgi.00096.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00096.2025","url":null,"abstract":"<p><p>Metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) incidence is rapidly rising worldwide. Lipid metabolic reprogramming is a hallmark of solid tumors to satisfy cancer high metabolic demand. However, it may confer sensitivity to ferroptosis, a cell death mode driven by iron-dependent lipid peroxidation. In this report, we describe the lipid metabolic landscape in MASH-HCC and characterize long chain acyl-CoA synthetases (ACSLs), a family of enzymes involved in synthesis of cellular lipids. Bulk RNA-sequencing, single-cell RNA-sequencing, spatial transcriptomics and immunohistochemistry analyses of human MASH-HCC were integrated to identify differentially expressed lipid metabolism genes. Ferroptosis <i>in vitro</i> was assessed in human HCC cell lines. A characterization of ACSLs was also conducted at the single-cell level in a diet-induced experimental murine model of MASH-HCC. Our analysis revealed that in human MASH-HCC, ACSLs exhibit a heterogeneous expression, with ACSL4 notably enriched in tumor tissues, contrasting with ACSL5 upregulation in non-cancerous MASH. We identified a unique lipid metabolic gene signature of MASH-HCC, which included genes associated with ferroptosis vulnerability. <i>In vitro</i>, high ACSL4 expression was associated with increased ferroptosis sensitivity in human HCC cell lines. Lastly, single-cell RNA-sequencing revealed elevated ACSL4 expression in immune cells in a murine MASH-HCC model, suggesting a role of ACSL4 in shaping the tumor immune microenvironment. Overall, this report offers new insights into lipid metabolic landscape and ferroptosis sensitivity for novel MASH-HCC treatments.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Treg-specific IL-6R signaling: a novel role in the regulation of the intestinal epithelium. treg特异性IL-6R信号:在肠上皮调节中的新作用
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-18 DOI: 10.1152/ajpgi.00131.2025
Emily E Klatt, Feda H Hamdan, Isaiah Pérez, Hannah M Smith, Kimberlee Kossick, Yaroslav Fedyshyn, Mary R Sagstetter, David Chiang, Lucas Cs Chini, Heidi M Davidson, Maria S Westphal, Naomi M Gades, Rohini Mopuri, Zhifu Sun, Wale O Bamidele, Brooke R Druliner, William A Faubion
{"title":"Treg-specific IL-6R signaling: a novel role in the regulation of the intestinal epithelium.","authors":"Emily E Klatt, Feda H Hamdan, Isaiah Pérez, Hannah M Smith, Kimberlee Kossick, Yaroslav Fedyshyn, Mary R Sagstetter, David Chiang, Lucas Cs Chini, Heidi M Davidson, Maria S Westphal, Naomi M Gades, Rohini Mopuri, Zhifu Sun, Wale O Bamidele, Brooke R Druliner, William A Faubion","doi":"10.1152/ajpgi.00131.2025","DOIUrl":"10.1152/ajpgi.00131.2025","url":null,"abstract":"<p><p>Mucosal homeostasis requires coordinated immune regulation and epithelial repair. Inflammatory bowel disease (IBD) arises from disrupted coordination between the immune system and intestinal epithelium, where resolution and repair must occur in parallel. Interleukin-6 (IL-6) plays a dual role: it promotes epithelial regeneration but destabilizes regulatory T cells (Tregs). We aimed to determine the contribution of Treg IL-6 receptor (IL-6R) signaling to intestinal inflammation and epithelial integrity. We developed a conditional knockout mouse model in which IL-6R was deleted from Tregs (Treg IL-6R knockout). These mice were subjected to dextran sodium sulfate (DSS)-induced colitis and a T cell transfer model of colitis. Soluble IL-6R production by Tregs was assessed in vitro, and transcriptional changes in epithelial cells were analyzed by RNA-seq. Human colonic organoids from IBD patients were treated with IL-6 or hyper-IL-6 (IL-6/sIL-6R fusion protein) to test downstream signaling effects. Tregs lacking IL-6R improved colitis to a similar extent as control Tregs in the adoptive transfer model, indicating intact suppressive function. However, Treg IL-6R knockout mice were more susceptible to DSS colitis than controls, suggesting a physiologic role for Treg IL-6R signaling in epithelial protection. In vitro, Tregs shed soluble IL-6R, enabling IL-6 trans-signaling to epithelial cells. Intestinal epithelial cells from Treg IL-6R knockout mice compared to WTcre controls revealed widespread transcriptional downregulation of genes related to survival and repair pathways at baseline, and impaired transcriptional responses following DSS treatment. In human organoids, IL-6 trans-signaling elicited stronger STAT3 activation than IL-6 alone. These findings reveal a previously unrecognized role for Treg-derived IL-6R in promoting epithelial resilience and maintaining mucosal homeostasis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Farnesoid X receptor inhibits proinflammatory cytokine-induced epithelial necroptosis in vitro: implications for preservation of intestinal barrier function. 法氏体X受体在体外抑制促炎细胞因子诱导的上皮坏死坏死:对肠道屏障功能保存的影响。
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-06-26 DOI: 10.1152/ajpgi.00086.2025
Caitriona E Curley, Natalia K Lajczak-McGinley, Luciano Adorini, Triona Ní Chonghaile, Stephen J Keely
{"title":"Farnesoid X receptor inhibits proinflammatory cytokine-induced epithelial necroptosis in vitro: implications for preservation of intestinal barrier function.","authors":"Caitriona E Curley, Natalia K Lajczak-McGinley, Luciano Adorini, Triona Ní Chonghaile, Stephen J Keely","doi":"10.1152/ajpgi.00086.2025","DOIUrl":"10.1152/ajpgi.00086.2025","url":null,"abstract":"<p><p>Epithelial cell death and compromised barrier function are key features of inflammatory bowel disease pathogenesis. Previous studies suggest that the nuclear bile acid receptor, farnesoid X receptor (FXR), promotes intestinal barrier function and protects against inflammation. Here, we investigated potential mechanisms involved. T<sub>84</sub> cell monolayers were treated with a combination of IFNγ and TNFα to model cytokine-induced barrier dysfunction in vitro. Apoptosis and necroptosis were assessed by measuring caspase 3/PARP cleavage and RIP3 phosphorylation, respectively. Epithelial permeability was determined by measuring 4-kDa fluorescein isothiocyanate-dextran (FD4) flux. Effects of FXR on barrier function in dextran sulfate sodium (DSS)-treated mice were assessed by measuring plasma levels of orally administered FD4. Treatment with IFNγ and TNFα enhanced FD4 flux and increased apoptosis in T<sub>84</sub> monolayers, as evidenced by increased cleaved PARP and caspase 3 levels. Pretreatment with the FXR agonist, GW4064, significantly inhibited cytokine-induced FD4 flux, but not apoptosis. Treatment with IFNγ and TNFα in the presence of the apoptosis inhibitor, Q-VD-OPh, induced necroptosis, as evidenced by increased RIP3 phosphorylation and enhanced FD4 flux, whereas a necroptosis inhibitor, necrostatin, inhibited these effects. GW4064 also inhibited cytokine-induced RIP3 phosphorylation and FD4 flux in the presence of Q-VD-OPh. In mice, treatment with the FXR agonist, obeticholic acid, attenuated DSS-induced disease activity and mucosal FD4 flux, but not levels of cleaved caspase 3 or phospho-RIP3. FXR activation inhibits cytokine-induced barrier dysfunction by inhibiting epithelial necroptosis rather than apoptosis in vitro. How such effects contribute to the protective actions of FXR in vivo requires further elucidation.<b>NEW & NOTEWORTHY</b> These studies demonstrate for the first time that FXR activation inhibits cytokine-induced necroptosis in vitro, an effect that may underlie protection against dysregulated barrier function in the setting of intestinal inflammation. These data support the potential for targeting FXR to promote epithelial barrier function in treatment of IBD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G261-G269"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lactiplantibacillus plantarum strengthens the intestinal barrier: involvement of the endocannabinoidome. 植物乳杆菌加强肠道屏障:内源性大麻素的参与。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-06-16 DOI: 10.1152/ajpgi.00142.2024
Bénédicte Allam-Ndoul, Elena Cristina Pulido-Mateos, Frédéric Bégin, Gabrielle St-Arnaud, Briscia Anaid Tinoco Mar, Thomas Mayer, Elizabeth Dumais, Nicolas Flamand, Frederic Raymond, Denis Roy, Yves Desjardins, Vincenzo Di Marzo, Alain Veilleux
{"title":"<i>Lactiplantibacillus plantarum</i> strengthens the intestinal barrier: involvement of the endocannabinoidome.","authors":"Bénédicte Allam-Ndoul, Elena Cristina Pulido-Mateos, Frédéric Bégin, Gabrielle St-Arnaud, Briscia Anaid Tinoco Mar, Thomas Mayer, Elizabeth Dumais, Nicolas Flamand, Frederic Raymond, Denis Roy, Yves Desjardins, Vincenzo Di Marzo, Alain Veilleux","doi":"10.1152/ajpgi.00142.2024","DOIUrl":"10.1152/ajpgi.00142.2024","url":null,"abstract":"<p><p>Probiotics have been suggested to ameliorate intestinal epithelial homeostasis and barrier function. They also modulate several mediators and receptors of the expanded endocannabinoid system, or endocannabinoidome (eCBome), potentially explaining their beneficial effects on intestinal function. We aimed to study the effects of probiotic strains on gut barrier functions and the possible involvement of the eCBome in these effects. We cocultured three strains of <i>Lactiplantibacillus plantarum</i> with murine small intestine epithelial organoids and explored the involvement of eCBome signaling and inflammation in mediating the beneficial effects of the probiotics on the epithelial barrier function. All three <i>L. plantarum</i> strains reduced the transepithelial permeability of organoids and increased mRNA expression of several tight junction proteins (<i>Clnd1</i>, <i>Clnd2</i>, <i>Ocln</i>, <i>Tjp1</i>, and <i>Cdh1</i>) and intestinal barrier proteins (<i>Muc2</i>, <i>Lyz1</i>, <i>Reg3a</i>, and <i>Defa20</i>). Concomitantly, the three strains increased the expression of genes encoding eCBome receptors while decreasing the expression of two catabolic enzymes (<i>Faah</i> and <i>Naaa</i>), and increasing one anabolic enzyme (<i>Daglb</i>). Altogether, these changes led to an overall increase in levels of eCBome mediators, namely <i>N</i>-acyl-ethanolamines (NAEs) and, particularly, 2-monoacylglycerols (2-MAGs), as measured by LC-MS/MS. URB 597 and JZL 184, two selective inhibitors of NAE and 2-MAG catabolism, reduced the transepithelial permeability of organoids, as observed with <i>L. plantarum</i> strains. Interestingly, both inhibitors also reversed inflammation-induced transepithelial permeability in organoids. Elevated endogenous levels of NAEs or 2-MAGs promote improvement in small intestine transepithelial permeability, and <i>L. plantarum</i> strains may exploit this mechanism to exert this same beneficial effect.<b>NEW & NOTEWORTHY</b> <i>Lactiplantibacillus plantarum</i> strains improve transepithelial permeability and concomitantly increase the levels of eCBome mediators in murine small intestine epithelial organoids. Pharmacological elevation of NAE or 2-MAG levels enhances the expression of intestinal epithelial barrier genes and reduces the transepithelial permeability of murine small intestine epithelial organoids, suggesting that <i>L. plantarum</i> may exploit eCBome signaling to exert its beneficial effects.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G245-G260"},"PeriodicalIF":3.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glia maturation factor-β in hepatocytes enhances liver regeneration and mitigates steatosis and ballooning in zebrafish. 斑马鱼肝细胞中的神经胶质成熟因子-β可促进肝脏再生,减轻脂肪变性和水肿。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-07-02 DOI: 10.1152/ajpgi.00407.2024
Hong-Yu Li, Wei-Lan Zeng, Yi-Wen Ye, Xin Chen, Ming-Ming Zhang, Yi-Si Chen, Cui-Ting Liu, Zhun-Qiang Zhong, Jing Li, Yan Wang
{"title":"Glia maturation factor-β in hepatocytes enhances liver regeneration and mitigates steatosis and ballooning in zebrafish.","authors":"Hong-Yu Li, Wei-Lan Zeng, Yi-Wen Ye, Xin Chen, Ming-Ming Zhang, Yi-Si Chen, Cui-Ting Liu, Zhun-Qiang Zhong, Jing Li, Yan Wang","doi":"10.1152/ajpgi.00407.2024","DOIUrl":"10.1152/ajpgi.00407.2024","url":null,"abstract":"<p><p>Glia maturation factor-β (Gmfb), an actin filament debrancher, was initially identified in brain and recently linked to liver diseases. To investigate the role of hepatocyte Gmfb (hep-Gmfb) in liver reparative regeneration, hepatocyte-specific <i>gmfb</i> knockout (HepGKO) and overexpression (HepGOE) zebrafish strains were constructed. Both transgenic and wild-type (WT) zebrafish underwent partial hepatectomy (PHX) or were fed high-fat, high-cholesterol diets to model metabolism-associated steatotic liver disease (MASLD). Under physiological conditions, the HepGKO, HepGOE, and WT fish displayed similar survival, gross appearance, and liver histology. Following PHX, WT liver gmfb levels positively correlated with cell proliferation and proinflammatory cytokine levels. HepGOE showed enhanced regeneration and reduced liver steatosis compared with WT, whereas HepGKO exhibited opposite effects. In MASLD, WT liver gmfb increased with disease progression. HepGKO experienced worsening liver enlargement, steatosis, ballooning, inflammation, and endoplasmic reticulum stress, whereas HepGOE showed improvements. HepGOE liver had the highest cell proliferation, but all three groups showed similar levels of cell apoptosis. Moreover, elevated proinflammatory cytokines were observed across MASLD groups, being the highest in HepGKO and lowest in HepGOE. However, signal transducer and activator of transcription 3 (stat3) activation was the lowest in HepGKO and highest in HepGOE, whereas jnk and mapk/extracellularly regulated kinase (erk) activation was consistent across the MASLD groups. In il6-treated primary hepatocytes, gmfb abundance influenced stat3 activation, and hep-gmfb abundance significantly affected actin filaments distribution in hepatocytes both in vivo and vitro. Hep-Gmfb boosts regenerative processes by enhancing hepatocyte proliferation, alleviating fatty liver histological abnormalities, and modulating the Il6/Stat3 signaling, potentially through remodeling of actin-filament network within hepatocytes.<b>NEW & NOTEWORTHY</b> Glia maturation factor-β (Gmfb) has shown important implications in liver disease. Using transgenic zebrafish models, our research demonstrates that Gmfb in hepatocytes confers protective benefits for liver regeneration and repair. It promotes hepatocyte proliferation, alleviates steatosis and ballooning, and modulates Il6/Stat3 signaling in response to liver injuries, potentially through remodeling of actin-filament network. This submission represents the first in vivo observation of the phenotypic effects of Gmfb in hepatocytes during liver injury.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G291-G306"},"PeriodicalIF":3.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic disruption of hnRNPI reveals a microbial-metabolic axis in colitis-associated cancer. hnRNPI的遗传破坏揭示了结肠炎相关癌症的微生物代谢轴。
IF 3.3 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-07-24 DOI: 10.1152/ajpgi.00236.2025
Yohannes Gemechu, Mengistu Lemecha
{"title":"Genetic disruption of <i>hnRNPI</i> reveals a microbial-metabolic axis in colitis-associated cancer.","authors":"Yohannes Gemechu, Mengistu Lemecha","doi":"10.1152/ajpgi.00236.2025","DOIUrl":"10.1152/ajpgi.00236.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G360-G362"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ASBT governs neonatal bile acid homeostasis early in life despite its strong ileal repression. 尽管ASBT具有强烈的回肠抑制作用,但它在生命早期控制新生儿胆汁酸稳态。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-05-16 DOI: 10.1152/ajpgi.00117.2025
Joyce Morales Aparicio, Zhengzheng Hu, Amy M Peiper, Lufuno Phophi, Haley M Wilt, Meera S Nair, Harrison B Winton, Katherine Blessing, Gabriela P Romero-Gonzalez, Stephanie M Karst
{"title":"ASBT governs neonatal bile acid homeostasis early in life despite its strong ileal repression.","authors":"Joyce Morales Aparicio, Zhengzheng Hu, Amy M Peiper, Lufuno Phophi, Haley M Wilt, Meera S Nair, Harrison B Winton, Katherine Blessing, Gabriela P Romero-Gonzalez, Stephanie M Karst","doi":"10.1152/ajpgi.00117.2025","DOIUrl":"10.1152/ajpgi.00117.2025","url":null,"abstract":"<p><p>Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the intestine after birth, yet its role in neonatal bile acid homeostasis remains unclear. Here, we demonstrate that ASBT plays a crucial role in limiting fecal bile acid loss and suppressing hepatic bile acid synthesis in neonates. ASBT-deficient pups exhibited a marked decrease in serum bile acids and concomitant increase in fecal bile acids, accompanied by upregulated hepatic bile acid synthesis genes, including CYP7A1, CYP7B1, and CYP27A1. We also illuminated a tissue-specific distinction in neonatal negative feedback regulation of bile acid synthesis, with intact hepatic regulation but impaired intestinal regulation. Our study identifies ASBT as a key regulator of neonatal bile acid homeostasis despite its strong repression early in life, highlighting its role in bile acid retention and synthesis regulation.<b>NEW & NOTEWORTHY</b> Despite being repressed after birth, ASBT is essential for neonatal bile acid homeostasis. This study reveals that ASBT limits fecal bile acid loss and suppresses hepatic bile acid synthesis in neonates. ASBT-deficient pups showed reduced serum bile acids, increased fecal loss, and upregulation of bile acid synthesis genes. Notably, feedback regulation of bile acid synthesis was intact in the liver but impaired in the intestine, uncovering tissue-specific control mechanisms in early life.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G307-G312"},"PeriodicalIF":3.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Investigating intestinal farnesoid X receptor functions at the intestinal mucosal barrier and in the intestinal microbiota in a biliary obstruction mouse model. 在胆道梗阻小鼠模型中研究肠法氏体X受体在肠粘膜屏障和肠道微生物群中的功能。
IF 3.9 3区 医学
American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2025-08-01 Epub Date: 2025-07-07 DOI: 10.1152/ajpgi.00223.2024
Yaoyao Cai, Xintong Chen, Hanfei Wang, Li Hou, Ruifei Zheng, Yue Wang, Weiwei Jiang, Weibing Tang
{"title":"Investigating intestinal farnesoid X receptor functions at the intestinal mucosal barrier and in the intestinal microbiota in a biliary obstruction mouse model.","authors":"Yaoyao Cai, Xintong Chen, Hanfei Wang, Li Hou, Ruifei Zheng, Yue Wang, Weiwei Jiang, Weibing Tang","doi":"10.1152/ajpgi.00223.2024","DOIUrl":"10.1152/ajpgi.00223.2024","url":null,"abstract":"<p><p>Intestinal barrier dysfunction and dysbiosis are critical intestinal alterations in biliary obstructive diseases, for which farnesoid X receptor (FXR) is a potential intestinal therapeutic target, but its role and mechanism in the intestinal tract remain poorly defined. Using gut-specific knockout mice, we demonstrate that intestinal <i>Fxr</i> deficiency caused intestinal barrier function impairment and dysbiosis, and in a biliary obstruction model, obeticholic acid (OCA)-dependent intestinal <i>Fxr</i> activation protected against intestinal barrier injury and dysbiosis after bile duct ligation (BDL) surgery. Furthermore, from single-cell sequencing data, <i>Fxr</i> may directly regulate regenerating islet-derived protein 3γ (<i>Reg3g</i>) to influence intestinal functions. In conclusion, we elucidated FXR actions in the intestine under physiological and biliary obstruction conditions and suggest possible molecular targets that provide new insights for the intestinal treatment of biliary obstructive diseases.<b>NEW & NOTEWORTHY</b> Intestinal barrier dysfunction and dysbiosis are critical in biliary obstructive diseases, making farnesoid X receptor (FXR) a potential therapeutic target. Our study shows that <i>Fxr</i> deficiency impairs barrier function and causes dysbiosis. In a biliary obstruction model, obeticholic acid (OCA) activation of <i>Fxr</i> protects against these effects. In addition, single-cell sequencing suggests that <i>Fxr</i> may regulate <i>Reg3g</i>, influencing intestinal functions. This research reveals the role of FXR and offers new molecular targets for the treatment of biliary obstructive diseases.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G313-G327"},"PeriodicalIF":3.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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