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

{"title":"Hypobaric hypoxia exposure impairs colonic goblet cell subpopulation via the HIF-1α signaling pathway.","authors":"Shaojie Zhang, Xiufang Jiang, Wangjingyi Zhang, Fansen Meng, Jiayue Gao, Xiang Cheng, Yazhuo Hu, Jing Liu, Tong Zhao, Lingling Zhu, Gangshi Wang","doi":"10.1152/ajpgi.00372.2024","DOIUrl":"10.1152/ajpgi.00372.2024","url":null,"abstract":"<p><p>Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maintaining this barrier. However, the effects of hypobaric hypoxia on goblet cell function and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of hypobaric hypoxia exposure (simulating an altitude of 6,000 m) and studied its effects on colonic goblet cells by transcriptomic analysis. In addition, the hypoxia-treated (1% O₂) goblet cell line Ls174t was used to investigate potential mechanisms underlying hypoxia-induced changes in goblet cells. In the present study, we discovered that hypobaric hypoxia exposure not only reduced the number of colonic goblet cells in mice by 27.6% but also impaired their mucus secretion. Transcriptome sequencing analysis of sorted goblet cells from the mice colon revealed significant changes in gene expression profiles, particularly in the expression of canonical goblet cell markers such as calcium-activated chloride channel regulator 1 (<i>Clca1</i>) and Fcγ-binding protein (<i>Fcgbp</i>). We confirmed the effects of hypobaric hypoxia/hypoxia exposure on CLCA1 and FCGBP expression at both mRNA and protein levels in mouse colonic tissues and in Ls174t cells. The expression of these canonical goblet cell marker genes was dependent upon hypoxia-inducible factor-1α (HIF-1α) activity; their expression decreased upon hypoxia-induced activation of HIF-1α and increased when HIF-1α was knocked down using siRNA. Thus, hypobaric hypoxia exposure regulates the distribution and function of colonic goblet cell subsets through the HIF-1α signaling pathway.<b>NEW & NOTEWORTHY</b> We investigated the role of hypoxia-inducible factor-1α (HIF-1α) in colonic goblet cell injury under hypobaric hypoxia exposure. Our results indicate that the elevation of HIF-1α caused by hypobaric hypoxia exposure can significantly reduce canonical goblet cells and disrupt intestinal mucosal barrier function. It provides a potential intervention strategy for restoring goblet cell function under hypobaric hypoxic conditions.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G465-G478"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707861","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}

{"title":"<i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> targets M cells in enteroid-derived monolayers through interactions with β1 integrins.","authors":"Grace Baruta, Kyle L Flannigan, Laurie Alston, Andrew Thorne, Hong Zhang, Jeroen De Buck, Pina Colarusso, Simon A Hirota","doi":"10.1152/ajpgi.00250.2024","DOIUrl":"10.1152/ajpgi.00250.2024","url":null,"abstract":"<p><p>Paratuberculosis is an infectious disease caused by the bacterium, <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> (MAP). MAP infection of ruminants triggers progressive wasting disease characterized by granulomatous lymphadenitis, enteritis, and severe intestinal pathology that often requires early culling of the animal. The resulting economic burden is significant, and MAP exposure in the workplace constitutes a significant zoonotic risk. Although it has been established that the MAP propagates within resident immune cells, less is known about how it traverses the epithelium. It is currently thought that MAP infects the small intestinal epithelium by targeting both enterocytes and M cells, with a potential tropism for the latter. In the current study, we developed and validated an enteroid-based in vitro assay containing functional M cells to identify the target cells for MAP's entry. Upon exposure to MAP, the bacteria were detected within both enterocytes and M cells; however, quantitative image analysis revealed significant tropism for the latter. Complementary studies using the Caco-2/Raji-B coculture system provided similar results. Since other mycobacteria have been shown to initiate cell attachment and entry by using a fibronectin-bridging process, we tested whether these interactions were involved in MAP's targeting of M cells. We found that MAP's M cell tropism was enhanced by fibronectin and that this effect was abolished when monolayers were pretreated with an integrin-blocking peptide. Our data demonstrate that MAP preferentially targets M cells and that this involves a fibronectin-bridging process. Furthermore, our study supports the utility of M cell-containing enteroids to study host-pathogen interaction at the intestinal epithelium.<b>NEW & NOTEWORTHY</b> We developed and validated a novel enteroid-based in vitro infection model with functional M cells and incorporated leading-edge imaging approaches to determine how MAP interacts with the intestinal epithelium. Using this model, we found that MAP preferentially enters M cells and that this process is enhanced by fibronectin opsonization and interactions with M cell-associated b1 integrins-the so-called fibronectin bridging mechanism that is used by other Mycobacterium to mediate cell attachment and entry.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G482-G501"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668903","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}

{"title":"The effect of corticotropin-release hormone on duodenal permeability and immune activation in healthy volunteers in a double-blind placebo-controlled study.","authors":"Jolien Schol, I-Hsuan Huang, Lukas Balsiger, Joran Tóth, Karen Van den Houte, Annelies Verheyden, Karlien Raymenants, Bert Broeders, Tim Vanuytsel, Jan Tack","doi":"10.1152/ajpgi.00130.2024","DOIUrl":"10.1152/ajpgi.00130.2024","url":null,"abstract":"<p><p>In functional dyspepsia, increased gut permeability, low-grade inflammation, and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone (CRH) have been shown to increase small bowel permeability in a mast-cell-dependent manner. Moreover, eosinophil-derived CRH has been implicated in mast cell activation. The aim of this study was to evaluate whether CRH administration alters duodenal permeability and immune activation in healthy volunteers (HVs). An intravenous bolus of 100-µg CRH or placebo was administered in HVs in a crossover, double-blind, randomized manner. Two hours later, a gastroscopy was performed to measure permeability in Ussing chambers and to count mast cells and eosinophils on duodenal biopsies. Supernatant was assessed for eosinophil-derived neurotoxin (EDN), tryptase, and chymase. In addition, CRH was administrated ex vivo to baseline biopsies pretreated with or without lodoxamide. Results are described as means ± SD. <i>P</i> values < 0.05 were considered significant. Twenty HVs completed the study. Mast cell or eosinophil counts were not significantly altered after CRH versus Placebo (respectively <i>P</i> = 0.31 and <i>P</i> = 0.069). Tryptase, but not chymase, significantly decreased after CRH (respectively <i>P</i> = 0.037 and <i>P</i> = 0.44) with a trend for a decrease in EDN (<i>P</i> = 0.053). Permeability was unaltered comparing both conditions. Ex vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared with baseline (<i>P</i> = 0.010), which was not prevented by pretreatment with lodoxamide. In vivo CRH administration reduced tryptase levels in the supernatant of duodenal biopsies without affecting permeability, whereas ex vivo duodenal permeability increased regardless of mast cell stabilization. These results suggest the involvement of mast cells in regulating gut permeability in HVs in response to CRH, possibly influenced by in vivo compensatory mechanisms.<b>NEW & NOTEWORTHY</b> Our investigation breaks new ground by directly examining the effects of corticotropin-release hormone (CRH) on duodenal alterations, including permeability and immune activation, in healthy subjects. Intriguingly, our findings highlight disparities between ex vivo and in vivo pathways affecting duodenal permeability, offering novel insights into the potential pathophysiology of CRH on the duodenum.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G457-G464"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750730","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}

{"title":"Optogenetic activation of the gut-brain axis in freely moving mice using a fully implantable wireless battery-free device.","authors":"Timothy J Hibberd, Andrew Efimov, Yue Wang, Mingzheng Wu, Lee Travis, Kaila Ting, Min-Kyu Lee, Joohee Kim, Jiheon Kang, Mohammad Riahi, Melinda Kyloh, Vladimir Zagorodnyuk, Hongzhen Hu, John A Rogers, Nick J Spencer, Abraham Vázquez-Guardado","doi":"10.1152/ajpgi.00330.2024","DOIUrl":"10.1152/ajpgi.00330.2024","url":null,"abstract":"<p><p>Considerable evidence suggests that the gut-brain axis can influence behavior. However, there has been a conspicuous lack of technology to provide targeted wireless activation of the gut-brain axis in conscious freely moving animals. We utilized a miniature fully implantable battery-free device to apply highly controlled optogenetic stimuli to the terminal region of gastrointestinal tract, in conscious freely moving mice. The optical stimulator was implanted and secured on the serosal surface of the distal colon and rectum to characterize the behavioral responses evoked by optogenetic stimulation of axons expressing channelrhodopsin (ChR2) driven by the Trpv1 promoter (Trpv1^Cre+ChR2 mice). In freely moving Trpv1^Cre+ChR2 mice, trains of blue light pulses to the distal colon and rectum induced increased abdominal grooming and reduced movement. In contrast to stimulation of the gut, trains of stimuli applied to the peritoneal cavity evoked writhing and abdominal contraction. Anterograde labeling from nodose ganglia revealed sparse vagal afferent axons and endings in the proximal and mid colon, with no labeled axons caudal of the mid colon (within 30 mm of the anus). The distal colon and rectum were densely innervated by spinal afferents. The findings demonstrate that wireless optogenetic stimulation of the gut-brain axis can induce specific behavioral patterns in conscious freely moving rodents, using fully implantable battery-free technology.<b>NEW & NOTEWORTHY</b> The findings demonstrate that distinct behavioral changes can be induced by wireless activation of the terminal region of the large intestine (distal colon and rectum) in freely moving rodents, using fully implantable battery-free devices.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G545-G557"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802222","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}

{"title":"Effects of potassium on laryngeal-induced swallowing rate in rats.","authors":"Satomi Kawada, Titi Chotirungsan, Charng-Rong Pan, Yuhei Tsutsui, Keiichiro Okamoto, Jin Magara, Takanori Tsujimura, Makoto Inoue","doi":"10.1152/ajpgi.00012.2025","DOIUrl":"10.1152/ajpgi.00012.2025","url":null,"abstract":"<p><p>The swallowing reflex can be induced by peripheral stimulation of the larynx. Although previous studies have suggested that potassium ions exert facilitatory effects on the initiation of swallowing, little information is available on the mechanism underlying the potassium ion-evoked swallowing reflex. In this study, we evaluated the effects of potassium ions on peripheral afferent responses and the initiation of swallowing in conscious and anesthetized rats. Furthermore, the possible receptors involved were explored. The topical application of potassium chloride (KCl) significantly facilitated the swallowing reflex; these facilitatory effects were more prominent than those of distilled water (DW) or sodium chloride (NaCl). This phenomenon depended not on the concentrations of anions but on those of potassium ions. The potassium ion-induced response in the superior laryngeal nerve was most prominent after treatment with KCl, especially at the early stage. In chronic rats, without differences in licking behavior between DW, NaCl, and KCl, the intervals between swallows were the smallest during KCl-associated licking. Inward rectifier potassium channel (Kir)3.1- and Kir6.2-positive cells were detected in the nodose ganglion and vocal folds. The rate of expression of these molecules in immunoreactive cells was relatively high at 74.1% for Kir3.1 and 75.3% for Kir6.2. Kir3.1 and Kir6.2 blockers significantly decreased the number of KCl-induced swallows. Possible mechanisms underlying potassium ion-induced swallowing are discussed. Our findings suggest that Kir3.1 and Kir6.2 are involved in K ion-induced swallowing in rats.<b>NEW & NOTEWORTHY</b> Potassium ion-containing solutions readily induce responses in the superior laryngeal nerve and swallowing reflexes, particularly at an early stage. Inward rectifier potassium channel (Kir)3.1 and Kir6.2 channel-positive cells were detected in the nodose ganglion and vocal folds. Kir3.1 and Kir6.2 blockers significantly decreased the number of KCl-induced swallows. Kir3.1 and Kir6.2 are involved in potassium ion-induced swallowing in rats.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G502-G512"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778849","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}

{"title":"Dimethyl fumarate attenuates bile acid retention and liver fibrosis in a mouse model of cholestasis.","authors":"Hana Lastuvkova, Ester Dohnalkova, Dina Faeq Manna, Jolana Cermanova, Jaroslav Mokry, Jaroslav Pejchal, Petra Hirsova, Petr Nachtigal, Ivona Pavkova, Maria Bajnokova, Lucie Smutna, Alzbeta Stefela, Rajamanikkam Kamaraj, Lenka Jandova, Martin Uher, Petr Pavek, Stanislav Micuda, Milos Hroch","doi":"10.1152/ajpgi.00262.2024","DOIUrl":"10.1152/ajpgi.00262.2024","url":null,"abstract":"<p><p>Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for 4 wk. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell and macrophage activation and by reducing c-Jun N-terminal kinase phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced <i>Bacteroidetes</i> phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse farnesoid X receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. In addition, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders.<b>NEW & NOTEWORTHY</b> Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 5","pages":"G558-G577"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956550","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}

{"title":"Deletion of H-ferritin in macrophages mitigates the development of steatohepatitis and hepatocellular carcinoma in mice.","authors":"Yasumasa Ikeda, Masafumi Funamoto, Haruka Itami, Mizuho Yamamoto, Hai Du Ly-Nguyen, Masaki Imanishi, Koichiro Tsuchiya","doi":"10.1152/ajpgi.00328.2024","DOIUrl":"10.1152/ajpgi.00328.2024","url":null,"abstract":"<p><p>Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one quarter of patients have nonalcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma. Several studies have shown the involvement of iron in NASH, but it remains unclear which cell of iron is at issue. This study aims to explore the role of iron in macrophages in NASH development. Conditional macrophage-specific H-ferritin knockout (LysM-Cre <i>Fth</i>KO) mice were divided into four groups: wild-type (WT) and LysM-Cre <i>Fth</i>KO mice fed a normal diet, and WT and LysM-Cre <i>Fth</i>KO mice with NASH model induced by diet and chemical. Histological analysis revealed that the NAFLD activity score and hepatic fibrosis were alleviated in the livers of LysM-Cre <i>Fth</i>KO mice with NASH compared with WT mice with NASH. The expression and signaling of inflammatory cytokines and fibrosis-related genes were increased in the livers of WT mice with NASH, but not elevated in the livers of LysM-Cre <i>Fth</i>KO mice with NASH. Similarly, macrophage infiltration and oxidative stress were augmented in the livers of WT mice with NASH but were inhibited in the livers of LysM-Cre <i>Fth</i>KO mice with NASH. In addition, hepatocellular carcinoma development was observed in 90% of WT mice and 62% of LysM-Cre <i>Fth</i>KO mice 30 wk after NASH induction, with tumor number and size being lower in LysM-Cre <i>Fth</i>KO mice. Deletion of macrophage H-ferritin alleviated NASH development by reducing inflammation, fibrosis, and oxidative stress. The findings of this study highlight macrophage iron levels as a potential therapeutic target in NASH.<b>NEW & NOTEWORTHY</b> NASH is a type of NAFLD with severe damage such as inflammation and fibrosis, which causes hepatocellular carcinoma. This study explores macrophage-specific iron involvement in NASH using LysM-Cre <i>Fth</i>KO mice. Results show that knocking out H-ferritin in macrophages reduces NASH-related inflammation, fibrosis, and oxidative stress compared with wild-type mice. Tumor occurrence was lower in LysM-Cre <i>Fth</i>KO mice. These findings suggest that macrophage iron modulation may be a therapeutic target for NASH treatment.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G533-G544"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778847","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}

{"title":"Hope for the gut: new evidence suggests Western diet damage can be undone.","authors":"Geetha Bhagavatula, Ian M Cartwright","doi":"10.1152/ajpgi.00073.2025","DOIUrl":"10.1152/ajpgi.00073.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G479-G481"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727530","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}

{"title":"Metabolic balance of human livers during long-term normothermic machine perfusion.","authors":"Bianca Lascaris, Linda C Woltjes, Silke B Bodewes, Robert J Porte, Vincent E de Meijer, Maarten W N Nijsten","doi":"10.1152/ajpgi.00404.2024","DOIUrl":"10.1152/ajpgi.00404.2024","url":null,"abstract":"<p><p>Normothermic machine perfusion (NMP) is used to preserve and assess the viability of (extended criteria) high-risk donor livers. Long-term NMP (LT-NMP; ≥24 h) is emerging as a method to improve or repair livers initially deemed unsuitable for transplantation. This study investigated metabolism during LT-NMP, focusing on hepatic energy consumption and nitrogen and electrolyte balances to better understand long-term perfusion requirements. In this study, we measured oxygen consumption (V̇o₂) and carbon dioxide production (V̇co₂) to determine the energy expenditure of 14 human livers during LT-NMP for 7 days. In addition, hepatic balances of glucose and lactate as well as of nitrogen and electrolytes were determined. Initial high metabolic rates during the first day of LT-NMP decreased and stabilized at nearly 50% on <i>day 3</i>, suggesting a quiescent state until <i>day 7</i>. Most energy was derived from glucose (75%-88%). Continuous amino acid supplementation was essential to maintain an anabolic state, whereas livers without supplementation became catabolic. Although net electrolyte balances were close to zero, significant uptake and release of electrolytes occurred throughout LT-NMP. During LT-NMP, livers reached a metabolically quiescent state after 3 days with decreased energy consumption. Tailoring perfusate composition and supplementation protocols to the specific needs of the liver could enhance organ preservation and potentially expand the pool of viable donor livers after LT-NMP.<b>NEW & NOTEWORTHY</b> A long-term normothermic machine perfusion platform is being developed for repairing and regenerating damaged livers to make them suitable for transplantation. The energy expenditure and the metabolic needs of 14 human donor livers were observed during NMP for up to a week. We noticed that livers become metabolically quiescent after 3 days and that a change in our nutrimental support protocol might be necessary to provide a better environment for the livers during NMP.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G522-G532"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778851","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}

{"title":"Chronic intermittent hypoxia alleviates alcohol-related liver injury via downregulation of hepatic hypoxia-inducible factor-2α.","authors":"Yunling Chen, Dongyuan Zhang, Yunxiao Wu, Wenshan Jiang, Luoting Guo, Di Pan, Qiao He, Zhaoqing Yin, Lichao Sun, Shuanglian Wang","doi":"10.1152/ajpgi.00283.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00283.2024","url":null,"abstract":"<p><p>Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors involved as well as the lack of information on the molecular mechanisms driving its progression. Interestingly, chronic, excessive alcohol intake has been reported to exacerbate the severity of obstructive sleep apnea (OSA), a respiratory disorder typically characterized by chronic intermittent hypoxia (CIH). However, this relationship between alcohol-enhanced OSA and ALD development/progression remains to be elucidated. As an approach to investigate this relationship, in vivo Gao-binge ALD and CIH mouse models were established. Alcohol-related liver injury, hepatic steatosis, inflammation, and oxidative stress were then assessed in these models. In addition, lipopolysaccharide (LPS) and ethanol-cotreated mouse normal hepatocyte cell line AML12 served as an in vitro model to investigate the mechanisms through which CIH affects ethanol-induced liver injury. CIH intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation and oxidative stress, and alleviated liver inflammation. Mechanistically, in the liver of these Gao-binge mice, CIH intervention inhibited alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α), a protein which plays a key role in hepatic lipid metabolism and liver injury. Similar to these effects observed in response to CIH intervention, treatment of Gao-binge mice with the selective inhibitor of HIF-2α, PT2385, alleviated alcohol-related liver injury and steatosis while inhibiting oxidative stress and inflammation. Additional findings from our in vitro model revealed that CIH downregulated HIF-2α by promoting calpains protein expression, thereby reducing the accumulation of lipid droplets and decreasing reactiveoxygenspecies (ROS) production in AML12 cells co-challenged with LPS and ethanol. The above results provide important, new evidence that reconceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD.<b>NEW & NOTEWORTHY</b> Chronic intermittent hypoxia (CIH) intervention mitigated hepatic lipid accumulation and reduced hepatic injury, inflammation, and oxidative stress in alcohol-related liver disease (ALD) mice. CIH alleviates ALD and is likely linked to the downregulation of hypoxia-inducible factor 2α (HIF-2α) expression mediated by calpains. This study presents a new possibility for ALD treatment and lays a theoretical foundation for the clinical treatment of ALD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 5","pages":"G610-G623"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963531","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}