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

{"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}

{"title":"<i>Tritrichomonas muris</i> sensitizes the intestinal epithelium to doxorubicin-induced apoptosis.","authors":"Nicolas V Janto, Antoine R Gleizes, Siyang J Sun, Gurel Ari, Vivek Rao, Adam D Gracz","doi":"10.1152/ajpgi.00242.2024","DOIUrl":"10.1152/ajpgi.00242.2024","url":null,"abstract":"<p><p>Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. Although the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remains unexplored. We discovered <i>Tritrichomonas muris</i> (<i>Tmu</i>) in one of our mouse colonies exhibiting abnormal tuft cell hyperplasia, prompting an investigation into its impact on DXR-induced intestinal injury. Mice from <i>Tmu</i>-colonized and <i>Tmu</i>-excluded facilities were injected with DXR. Tissue morphology and gene expression were evaluated at acute injury (6 h) and regenerative (72 h and 120 h) phases. Changes to crypt and villus morphology were more subtle than previously reported and region-specific, with significantly shorter jejunal villi in <i>Tmu</i>⁺ mice at 72 h post-DXR compared with <i>Tmu</i>^- controls. Most notably, we observed elevated rates of DXR-induced apoptosis, measured by cleaved caspase 3 (CC3) staining, in <i>Tmu</i>⁺ intestinal crypts at 6 h post-DXR. <i>Tmu</i>⁺ mice also exhibited reduced expression of active intestinal stem cell (aISC) marker <i>Lgr5</i> and facultative ISC (fISC) marker <i>Ly6</i>a at 6 h post-DXR compared with <i>Tmu</i>^- controls. <i>Tmu</i>, but not DXR, was associated with increased inflammation and expression of type 2 cytokines IL-5 and IL-13. <i>Tmu</i>⁺ mice also exhibited a decreased fecal abundance of <i>Lactobacillus</i>, which promotes gut barrier integrity, and reduced claudin expression, indicating potential barrier dysfunction that could explain the increase in DXR-induced apoptosis. These findings highlight the significant influence of commensal microbiota, particularly eukaryotic organisms like <i>Tmu</i>, on intestinal biology and response to chemotherapy, underscoring the complexity of gut microbiota interactions in drug-induced mucositis.<b>NEW & NOTEWORTHY</b> Our study found that the eukaryotic commensal <i>Tritrichomonas muris</i> (<i>Tmu</i>) significantly increases DXR-induced intestinal apoptosis in mice. <i>Tmu</i> also reduces <i>Lgr5</i> expression post-DXR injury and elevates inflammation and type 2 cytokine expression in the absence of injury. 16S sequencing identifies decreased abundance of protective <i>Lactobacillus</i> in <i>Tmu</i> colonized mice, as well as decreased expression of barrier-forming claudins, which may explain increased apoptosis. These findings emphasize the complex role of microbiota in drug-induced intestinal damage.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 5","pages":"G594-G609"},"PeriodicalIF":3.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952303","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":"Mass cytometric analysis of circulating monocyte subsets in a murine model of diabetic gastroparesis.","authors":"Shefaa AlAsfoor, Erik Jessen, Suraj R Pullapantula, Jennifer R Voisin, Linda C Hsi, Kevin D Pavelko, Samera Farwana, Jack A Patraw, Xin-Yi Chai, Sihan Ji, Michael A Strausbauch, Gianluca Cipriani, Lai Wei, David R Linden, Ruixue Hou, Richard Myers, Yogesh Bhattarai, Jill Wykosky, Alan J Burns, Surendra Dasari, Gianrico Farrugia, Madhusudan Grover","doi":"10.1152/ajpgi.00229.2024","DOIUrl":"10.1152/ajpgi.00229.2024","url":null,"abstract":"<p><p>Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the dynamics of Mo in the development of DGE in an animal model are unknown. Using cytometry by time-of-flight and computational approaches, we show a high heterogeneity within the Mo population. In DGE mice, via unbiased clustering, we identified two reduced Mo clusters that exhibit migratory phenotype (Ly6C^hiCCR2^hi-intCD62L^hiLy6G^hiCD45R^hiMERTK^hiintLGALS3^intCD14^intCX3CR1^lowSiglec-H^int-low) resembling classical Mo (CMo-like). All markers enriched in these clusters are known to regulate cell differentiation, proliferation, adhesion, and migration. Trajectory inference analysis predicted these Mo as precursors to subsequent Mo lineages. In gastric muscle tissue, we demonstrated an increase in the gene expression levels of chemokine receptor C-C chemokine receptor type 2 (<i>Ccr2</i>) and its C-C motif ligand 2 (<i>Ccl2</i>), suggesting increased trafficking of classical-Mo. These findings establish a link between two CMo-like clusters and the development of the DGE phenotype and contribute to a better understanding of the heterogenicity of the Mo population.<b>NEW & NOTEWORTHY</b> Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the <i>Ccr2-Ccl2</i> axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the <i>Ccr2</i>-<i>Ccl2</i> axis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G323-G341"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412799","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":"Unique properties of proximal and distal colon reflect distinct motor functions.","authors":"Wilmarie Morales-Soto, Kristen M Smith-Edwards","doi":"10.1152/ajpgi.00215.2024","DOIUrl":"10.1152/ajpgi.00215.2024","url":null,"abstract":"<p><p>The gastrointestinal tract is made up of specialized organs that work in tandem to facilitate digestion. The colon regulates the final steps in this process where complex motor patterns in proximal regions facilitate the formation of fecal pellets that are propelled along the distal colon via self-sustaining neural peristalsis and temporarily stored before defecation. Historically, our understanding of colonic motility has focused primarily on distal regions, and the intrinsic reflex circuits of the enteric nervous system involved in neural peristalsis have been defined, but we do not yet have a clear grasp on the mechanisms orchestrating motor function in proximal regions. New approaches have brought to the forefront the unique structural, neurochemical, and functional characteristics that exist in distinct regions of the mouse and human colon. In this mini-review, we highlight key differences along the proximal-distal colonic axis and discuss how these differences relate to region-specific motor function.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G448-G454"},"PeriodicalIF":3.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12295705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646792","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":"Corrigendum for Öhnstedt et al., volume 327, 2024, p. G140-G153.","authors":"","doi":"10.1152/ajpgi.00022.2024_COR","DOIUrl":"10.1152/ajpgi.00022.2024_COR","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 4","pages":"G455"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810188","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":"Progressive impairment in gastric and duodenal slow waves and autonomic function during progression of type 2 diabetes in rats.","authors":"Gaojue Wu, Fei Li, Yan Li, Shiying Li, Md Jahangir Alam, Jiande D Z Chen","doi":"10.1152/ajpgi.00278.2024","DOIUrl":"10.1152/ajpgi.00278.2024","url":null,"abstract":"<p><p>The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis, which is highly prevalent in type 2 diabetes (T2D). Although relatively well-investigated in diabetic enteric neuropathy, abnormalities and progressive impairments of gastric slow waves (GSWs) and duodenal slow waves (DSWs) are underinvestigated during the progression of T2D. The aim of this study was to explore alterations in GSW and DSW during the development of diabetes induced by high-fat diet (HFD) followed by a low dose of streptozotocin (STZ). Weekly recordings of slow waves from healthy, prediabetic to diabetes stages exhibited a progressively decreased percentage of normal slow waves (%NSW) starting after HFD feeding (prediabetic stage) in the fasting state and starting after STZ injection (diabetic stage) in the postprandial state. The postprandial increase in the power of slow waves observed in normal control rats was absent starting from 2 wk after HFD and persisted after STZ. The mechanism might be attributed to both progressively increased blood glucose (BG) and impaired autonomic function in view of the following results: <i>1</i>) the %NSW was negatively correlated with the fasting BG; <i>2</i>) during the oral glucose tolerance test, %NSW of DSW and BG exhibited a positive correlation in rats with hemoglobin A1C (HbA1C) < 5.0%, but a negative correlation in rats with HbA1C ≥ 5.0%; and <i>3</i>) in comparison with baseline (healthy stage) of the same cohort, plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased, whereas plasma norepinephrine (reflecting sympathetic activity) was progressively increased.<b>NEW & NOTEWORTHY</b> This study recorded the progressive impairment in the regularity of gastric and duodenal slow waves in a rat model mimicking the progression to type 2 diabetes including the stage of health, prediabetic stage, and diabetes. The progressive impairment in gastric/duodenal slow waves might be attributed to the progressive increase in blood glucose and impairment in autonomic function.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G386-G398"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490388","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":"Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating aryl hydrocarbon receptor-dependent AMPK signaling.","authors":"Nikhil Y Patil, Iulia Rus, Felix Ampadu, Hassan M Abu Shukair, Sarah Bonvicino, Richard S Brush, Elena Eaton, Martin-Paul Agbaga, Tae Gyu Oh, Jacob E Friedman, Aditya D Joshi","doi":"10.1152/ajpgi.00337.2024","DOIUrl":"10.1152/ajpgi.00337.2024","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by the accumulation of fats in the liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance of hepatic aryl hydrocarbon receptor (AhR) signaling in cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers of high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific aryl hydrocarbon receptor knockout mice (AhR-hKO) exhibited aggravated steatosis, inflammation, and fibrosis compared with control AhR-floxed livers. Moreover, treatment with a tryptophan catabolite, CA, reduced body weight gain and significantly attenuated hepatic steatosis, inflammation, ballooning, fibrosis, and liver injury only in AhR-floxed but not in AhR-hKO mice, strongly indicating that the CA-mediated protection against steatohepatitis is AhR-dependent. Furthermore, protection against lipotoxicity by CA-activated AhR signaling was confirmed by utilizing an in vitro human hepatocyte model of MASLD. Mechanistically, CA-induced AhR-dependent signaling augmented AMP-activated protein kinase (AMPK), leading to the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1α) and attenuation of sterol regulatory element-binding protein-1 (SREBP1) to regulate hepatic lipid metabolism. Collectively, our findings indicate that CA-mediated protection against MASH is dependent on hepatic AhR signaling, and selective endogenous AhR agonists that regulate lipogenesis can serve as promising future therapeutics against MASLD.<b>NEW & NOTEWORTHY</b> The study showed that the absence of AhR in hepatocytes results in exacerbated metabolic dysfunction-associated steatohepatitis (MASH) in mice subjected to a Western-style high-fat, high-fructose, high-cholesterol diet. Moreover, treatment with a tryptophan catabolite, cinnabarinic acid (CA), mitigated hallmarks of MASH in an AhR-dependent manner. In conclusion, the study delineates the significance of hepatic AhR-dependent AMPK signaling in CA-mediated protection against MASH.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G433-G447"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584376","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}