American Journal of Pathology最新文献_第9页

Alcohol-Mediated Skeletal Muscle Adaptations and Their Impact on Comorbidities 酒精介导的骨骼肌适应及其对合并症的影响

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-07-17 DOI: 10.1016/j.ajpath.2025.05.025

Keishla M. Rodríguez-Graciani, Paticia E. Molina, Liz Simon

{"title":"Alcohol-Mediated Skeletal Muscle Adaptations and Their Impact on Comorbidities","authors":"Keishla M. Rodríguez-Graciani, Paticia E. Molina, Liz Simon","doi":"10.1016/j.ajpath.2025.05.025","DOIUrl":"10.1016/j.ajpath.2025.05.025","url":null,"abstract":"<div><div>At-risk alcohol use has significant adverse effects on multiple tissue and organ systems, including the skeletal muscle. The pathophysiological mechanisms underlying alcohol-induced dysfunctional skeletal muscle (SKM) mass are multifactorial, involving decreased protein synthesis, increased protein degradation, impaired glucose homeostasis, bioenergetic dysregulation, aberrant extracellular matrix remodeling, impaired satellite cell function, circadian rhythm disruption, and epigenomic adaptations. This review provides a brief overview of these major alcohol-induced mechanisms of SKM dysfunction. Additionally, the review examines the current literature on alcohol-mediated SKM maladaptations in the context of comorbidities such as aging, alcohol-related liver disease, systemic and diet-induced metabolic dysregulation, cancer cachexia, and musculoskeletal pain. Although alcohol-induced skeletal muscle alterations may function as both the cause and consequence of these comorbid conditions, critical research gaps remain, particularly in the need for systematic clinical studies complemented by preclinical mechanistic research. Notably, 40% to 60% of people with at-risk alcohol use exhibit skeletal muscle maladaptations, yet data on associated healthcare or productivity loss costs are lacking. A comprehensive understanding of alcohol-induced SKM dysfunction is warranted for developing targeted interventions to reduce healthcare costs and improve quality of life in this population.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 92-103"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Liver Macrophage Changes during Early Adaptation to Alcohol Exposure 肝巨噬细胞在酒精暴露的早期适应过程中的变化。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-10-31 DOI: 10.1016/j.ajpath.2025.10.004

Kyle Yuquimpo , Janice Averilla , Zhuan Li , Priyanka Ghosh , Sheetalnath Rooge , Isabel A. Pulido Ruiz , Winston Dunn , Sumedha Gunewardena , Ann L. Wozniak , Irina Tikhanovich , Steven A. Weinman

{"title":"Liver Macrophage Changes during Early Adaptation to Alcohol Exposure","authors":"Kyle Yuquimpo , Janice Averilla , Zhuan Li , Priyanka Ghosh , Sheetalnath Rooge , Isabel A. Pulido Ruiz , Winston Dunn , Sumedha Gunewardena , Ann L. Wozniak , Irina Tikhanovich , Steven A. Weinman","doi":"10.1016/j.ajpath.2025.10.004","DOIUrl":"10.1016/j.ajpath.2025.10.004","url":null,"abstract":"<div><div>Liver macrophages consist of both Kupffer cells (KCs) and infiltrating macrophages (IMs), and both populations change during alcohol-associated liver disease. It has been suggested that KCs undergo a proinflammatory change after alcohol exposure, but the extent to which a proinflammatory shift results from IM rather than KC activation is unclear. The purpose of this study was to examine the early effects of alcohol exposure on KCs and IMs in a murine model and compare these effects with observations in human liver. Mice were fed the Lieber-Decarli ethanol diet, and total liver macrophage and KC-specific phenotypes were examined by flow cytometry, <em>ex vivo</em> cell culture, and KC single-cell RNA sequencing. Liver tissues from autopsy and transplant patients with different alcohol phenotypes were assessed. Early alcohol exposure caused a shift in the properties of total liver macrophages, with an initial proinflammatory effect that partially resolved by 10 days. KCs became steadily less inflammatory over the first 10 days of alcohol exposure. Alcohol exposure in the absence of liver disease also shifted macrophage phenotypes in human livers. These results show that early alcohol exposure is sufficient to cause KC adaptation in a way that maintains liver homeostasis and limits inflammation. Understanding the mechanisms of these changes and how to sustain them may help prevent the development of long-term liver injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 272-287"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145429962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Current Therapeutic Targets for Alcohol-Associated Liver Disease 当前酒精相关性肝病的治疗靶点

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-07-17 DOI: 10.1016/j.ajpath.2025.06.009

Mengmeng Zhang , Jingjing Ji , Jiayi Song , Chenchen An , Wangxiang Pei , Qianwen Fan , Li Zuo , Hua Wang

{"title":"Current Therapeutic Targets for Alcohol-Associated Liver Disease","authors":"Mengmeng Zhang , Jingjing Ji , Jiayi Song , Chenchen An , Wangxiang Pei , Qianwen Fan , Li Zuo , Hua Wang","doi":"10.1016/j.ajpath.2025.06.009","DOIUrl":"10.1016/j.ajpath.2025.06.009","url":null,"abstract":"<div><div>Alcohol-associated liver disease (ALD) is a progressive liver disorder induced by chronic excessive alcohol consumption, affecting approximately 3.5% of the global population. The clinical spectrum of ALD encompasses simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and the potential development of hepatocellular carcinoma. The pathogenesis of ALD involves a complex interplay of factors, including direct cell damage caused by alcohol and its metabolites, hepatic inflammation, immune dysregulation, and oxidative stress. Additionally, alcohol-induced dysbiosis and the subsequent imbalance of gut homeostasis further exacerbate the progression of ALD. While nutritional support and abstinence from alcohol remain the cornerstones of ALD management, growing evidence supports the therapeutic potential of targeting key pathologic processes such as inflammation, cellular oxidative stress, lipid metabolism, and strategies that promote liver regeneration and inhibit fibrosis. Emerging treatment approaches aimed at modulating the gut–liver–brain axis and targeting innate immune cells offer promising new avenues for ALD therapy. For patients with end-stage ALD, liver transplantation remains the only viable treatment option. This review summarizes the current epidemiology, pathogenesis, pathophysiology, natural history, and recent advancements in the therapeutic management of ALD, with the goal of providing further insight into the treatment of ALD and improve patient outcomes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 121-135"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of Preclinical Biomarkers of Metabolic Dysfunction–Associated Steatotic Liver Disease versus Metabolic Dysfunction and Alcohol-Associated Liver Disease and the Impact of Diet MASLD与MetALD临床前生物标志物的鉴定及饮食的影响。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-06-12 DOI: 10.1016/j.ajpath.2025.05.013

Tyler C. Gripshover , Rui S. Treves , Josiah E. Hardesty

{"title":"Identification of Preclinical Biomarkers of Metabolic Dysfunction–Associated Steatotic Liver Disease versus Metabolic Dysfunction and Alcohol-Associated Liver Disease and the Impact of Diet","authors":"Tyler C. Gripshover , Rui S. Treves , Josiah E. Hardesty","doi":"10.1016/j.ajpath.2025.05.013","DOIUrl":"10.1016/j.ajpath.2025.05.013","url":null,"abstract":"<div><div>Recent diagnostic advancements have defined metabolic dysfunction–associated steatotic liver disease (MASLD) and increased alcohol intake (MetALD) in cases of alcohol consumption ≥20 g/day in females and >30 g/day, in males. While current treatments can modify dietary behavior or treat organ-specific pathology, they have limited efficacy. There is a need for a preclinical animal model of MetALD that can assess concurrent diet and alcohol consumption on organ pathology to inform treatment strategies. Male C57BL/6J mice were randomly assigned to the following six dietary groups for 13 weeks: ±chow diet (CD), ±high-fat diet (HFD), and water or 10% (v/v) ethanol. Glucose tolerance test was performed at week 10. Physiological parameters were assessed, and cecal 16S rRNA and liver mRNA sequencing was conducted. HFD + ethanol (MetALD) mice had exacerbated dyslipidemia and gut dysbiosis relative to HFD + water (MASLD) mice. CD + HFD + ethanol mice had reduced glucagon-like peptide-1 relative to HFD + ethanol mice. MASLD and MetALD mice had altered transcription factor regulatory networks, which were further modulated with CD. Kupffer cell markers were lower in HFD + ethanol mice relative to those in other groups. Diet and ethanol had distinct physiological effects in this MetALD model. Mice on CD + HFD had worsened metabolic syndrome, but improved liver injury and microbiome diversity compared with mice on HFD. Hepatic gene markers and microbiome changes of MASLD were identified. This preclinical model may help identify novel therapeutics to treat MASLD and MetALD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 241-255"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The Link between Alcohol Consumption and Kidney Injury 饮酒与肾损伤之间的联系

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.011

Burhan Yokus , Luca Maccioni , Lihong Fu , György Haskó , Laura E. Nagy , Bin Gao , Pal Pacher

{"title":"The Link between Alcohol Consumption and Kidney Injury","authors":"Burhan Yokus , Luca Maccioni , Lihong Fu , György Haskó , Laura E. Nagy , Bin Gao , Pal Pacher","doi":"10.1016/j.ajpath.2025.05.011","DOIUrl":"10.1016/j.ajpath.2025.05.011","url":null,"abstract":"<div><div>Alcohol use disorder contributes to systemic organ dysfunction, but its direct effect on kidney health is unclear. Epidemiologic studies have shown inconsistent findings due to a reliance on conventional markers, such as serum creatinine and blood urea nitrogen, which are insensitive to early chronic kidney disease and influenced by factors such as muscle mass, diet, and hydration status. Experimental studies have indicated that alcohol may directly exacerbate renal damage through mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, indirect effects from alcohol-induced altered intestinal permeability and microbiome, liver injury, microcirculatory/cardiac dysfunction and muscle damage may also facilitate kidney damage. Notably, alcohol-related liver disease can lead to hepatorenal syndrome, a severe type of kidney dysfunction driven by circulatory disturbances and systemic inflammation. This overview explores the adverse effects of alcohol misuse on kidney health and disease, emphasizing the need for comprehensive epidemiologic studies with more sensitive kidney injury biomarkers. It also highlights the importance of using clinically relevant preclinical models to clarify the underlying mechanisms of alcohol-related kidney injury and to enhance the understanding of its long-term clinical consequences.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 78-91"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Microbiota in Alcohol-Associated Organ Damage 酒精相关器官损伤中的微生物群

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-06-11 DOI: 10.1016/j.ajpath.2025.05.012

Aenne Harberts , Bernd Schnabl

{"title":"Microbiota in Alcohol-Associated Organ Damage","authors":"Aenne Harberts , Bernd Schnabl","doi":"10.1016/j.ajpath.2025.05.012","DOIUrl":"10.1016/j.ajpath.2025.05.012","url":null,"abstract":"<div><div>Alcohol-associated organ damage is a major cause of morbidity and mortality worldwide, with the liver being the primarily affected organ. Emerging evidence highlights the gut microbiota as a key driver in alcohol-associated liver disease. Changes in the microbiota composition, microbial translocation, and a dysregulated immune response culminate in inflammation and tissue injury. Persistent liver injury eventually promotes disease progression from steatohepatitis to fibrosis and cirrhosis. In this review, an overview of microbiota alterations observed in patients with chronic alcohol consumption is provided and the mechanisms by which microbiota contributes to alcohol-associated damage across various organ systems are explored. Emphasis is placed on changes in the gut microbiota and its role in alcohol-associated liver disease, the disease condition with the most robust evidence linking microbiota-related changes to organ injury. Additionally, key areas where further research is needed to address unresolved questions are highlighted. Finally, emerging therapeutic strategies targeting the microbiota to treat alcohol use disorders and prevent alcohol-associated liver diseases are discussed.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 104-120"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Aldehyde Dehydrogenase 2 Deficiency Impairs Liver Progenitor Cell Proliferation in Alcohol-Fed Mice 醛脱氢酶2缺乏损害酒精喂养小鼠肝祖细胞增殖。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-09-03 DOI: 10.1016/j.ajpath.2025.08.004

Peng Xiao , Siting Yang , Shenghua Bi , Yawen Hao , Feiyu Zhang , Lin Ru , Tao Liu , Shengying Qian , Qiuhong Zai , Ningning Ma , Junqi Niu , Yong He , Yanhang Gao

{"title":"Aldehyde Dehydrogenase 2 Deficiency Impairs Liver Progenitor Cell Proliferation in Alcohol-Fed Mice","authors":"Peng Xiao , Siting Yang , Shenghua Bi , Yawen Hao , Feiyu Zhang , Lin Ru , Tao Liu , Shengying Qian , Qiuhong Zai , Ningning Ma , Junqi Niu , Yong He , Yanhang Gao","doi":"10.1016/j.ajpath.2025.08.004","DOIUrl":"10.1016/j.ajpath.2025.08.004","url":null,"abstract":"<div><div>Aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in the detoxification of acetaldehyde. Although numerous studies have demonstrated the significance of ALDH2 in alcohol-associated liver disease, its role in alcohol-induced activation of liver progenitor cells (LPCs) has not been thoroughly investigated. Proteomic analysis of serum samples from patients with either normal ALDH2 genotype or ALDH2 mutation following alcohol consumption revealed that ALDH2 deficiency may suppress LPC proliferation. To test this hypothesis, <em>Aldh2</em> knockout (<em>Aldh2</em>KO) mice were generated and fed a 3,5-diethoxycarbonyl1,4-dihydrocollidine–supplemented diet along with 10% ethanol in drinking water. A significant inhibition of LPC proliferation was observed in <em>Aldh2</em>KO mice after alcohol exposure, as indicated by reduced numbers of pan-cytokeratin (PanCK)– and Ki-67–positive cells in the liver. Bulk RNA sequencing revealed that differentially expressed genes (DEGs) in 3,5-diethoxycarbonyl1,4-dihydrocollidine plus ethanol-fed <em>Aldh2</em>KO mice were enriched in pathways related to inflammation (up-regulated DEGs) and cell cycle suppression (down-regulated DEGs) based on Reactome pathway analysis compared with wild-type mice. Mechanistically, alcohol exposure in <em>Aldh2</em>KO mice led to reduced LPC proliferation, likely mediated by enhanced hepatic pyroptosis and inflammatory responses. In conclusion, these findings suggest that ALDH2 deficiency appears to impair LPC proliferation in alcohol-associated liver disease, highlighting the critical role of ALDH2 in liver regeneration following alcohol-induced injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 256-271"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The Patatin-Like Phospholipase Domain–Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice PNPLA3 148M变异加重了小鼠酒精诱导的肝损伤和肿瘤发生。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-05-09 DOI: 10.1016/j.ajpath.2025.04.014

Jung-Hyo Cho , Hyeong-Geug Kim , Menghao Huang , Shen Wang , Sheng Liu , Alex Lu , Kyle McCrocklin , Yang Zhang , Zhigang Fang , Juexin Wang , Wanqing Liu , Jun Wan , X. Charlie Dong

{"title":"The Patatin-Like Phospholipase Domain–Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice","authors":"Jung-Hyo Cho , Hyeong-Geug Kim , Menghao Huang , Shen Wang , Sheng Liu , Alex Lu , Kyle McCrocklin , Yang Zhang , Zhigang Fang , Juexin Wang , Wanqing Liu , Jun Wan , X. Charlie Dong","doi":"10.1016/j.ajpath.2025.04.014","DOIUrl":"10.1016/j.ajpath.2025.04.014","url":null,"abstract":"<div><div>The patatin-like phospholipase domain–containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC). However, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3<sup>148M</sup> variant in alcohol-related HCC development. Control and humanized PNPLA3<sup>148M</sup> transgenic mice were fed with an ethanol-containing diet for 12 weeks and examined for liver tumors. After the alcohol feeding, the PNPLA3<sup>148M</sup> mice had twofold higher liver cancer incidence rates and larger tumor sizes than the control mice. Cancer stem cell markers in the PNPLA3<sup>148M</sup> mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3<sup>148M</sup> mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3<sup>148M</sup> mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1/TAZ) were activated in the PNPLA3<sup>148M</sup> mouse livers. The data suggest that the PNPLA3<sup>148M</sup> variant had a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3<sup>148M</sup> variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 209-222"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Chronic Alcohol Consumption Enhances the Differentiation Capacity of Hematopoietic Stem and Progenitor Cells into Osteoclast Precursors 慢性饮酒增强造血干细胞和祖细胞向破骨细胞前体的分化能力。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-07-17 DOI: 10.1016/j.ajpath.2025.06.010

Hami Hemati , Madison B. Blanton , Jude Koura , Rupak Khadka , Kathleen A. Grant , Ilhem Messaoudi

{"title":"Chronic Alcohol Consumption Enhances the Differentiation Capacity of Hematopoietic Stem and Progenitor Cells into Osteoclast Precursors","authors":"Hami Hemati , Madison B. Blanton , Jude Koura , Rupak Khadka , Kathleen A. Grant , Ilhem Messaoudi","doi":"10.1016/j.ajpath.2025.06.010","DOIUrl":"10.1016/j.ajpath.2025.06.010","url":null,"abstract":"<div><div>Chronic alcohol consumption (CAC) is associated with an enhanced risk of bone fracture, reduced bone density, and osteoporosis. In a rhesus macaque model of voluntary ethanol consumption, CAC induces functional, transcriptomic, and epigenomic changes in hematopoietic stem and progenitor cells (HSPCs) and their resultant monocytes/macrophages, skewing them toward a hyper-inflammatory response. In the present study, those studies were extended to investigate alterations in osteoclast development, which, in postnatal life, differentiate from HSPCs and play a critical role in maintaining bone homeostasis. Spectral flow cytometry revealed a skewing of HSPCs toward granulocyte-monocyte progenitors in the CAC group, consistent with an increased number of colony-forming unit-granulocyte/macrophage colonies. In addition, HSPCs from animals in the CAC group incubated with macrophage colony-stimulating factor and receptor activator of NF-κB ligand were more likely to differentiate into osteoclasts, as evidenced by increased tartrate-resistant acid phosphatase staining and bone resorption activity. Moreover, single-cell RNA sequencing of differentiated HSPCs identified osteoclast-related clusters in the CAC group, characterized by up-regulated gene expression in pathways associated with cellular response to stimuli, membrane trafficking, and vesicle-mediated transport. Collectively, these data demonstrate that CAC enhances the capacity of HSPCs to differentiate into osteoclast precursors. They provide critical insights into the mechanisms by which alcohol consumption contributes to reduced bone density and skeletal fragility.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 326-343"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Lipid Droplet Dynamics in Alcoholic Steatohepatitis 酒精性脂肪性肝炎的脂滴动力学。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-01-01 Epub Date: 2025-08-26 DOI: 10.1016/j.ajpath.2025.07.010

Delia Y. Omar , Mathilda M. Willoughby , Nourhan Mostafa , Kelly Otakhor , Saumya Bhatt , Mohammad A. Abbas Zaidi , Micah B. Schott

{"title":"Lipid Droplet Dynamics in Alcoholic Steatohepatitis","authors":"Delia Y. Omar , Mathilda M. Willoughby , Nourhan Mostafa , Kelly Otakhor , Saumya Bhatt , Mohammad A. Abbas Zaidi , Micah B. Schott","doi":"10.1016/j.ajpath.2025.07.010","DOIUrl":"10.1016/j.ajpath.2025.07.010","url":null,"abstract":"<div><div>Alcohol-associated liver disease poses a significant global health burden, with alcoholic steatohepatitis (ASH) representing a severe subtype driven by chronic alcohol consumption, hepatic inflammation, and limited treatment options. Central to ASH pathogenesis is the dysregulation of lipid droplet (LD) dynamics in hepatocytes. This review explores the critical role of LDs, focusing on alcohol-induced disruptions in LD biogenesis and catabolism. Chronic ethanol exposure enhances LD biogenesis from lipid import and <em>de novo</em> lipogenesis, while impairing LD catabolism by inhibiting lipolysis and lipophagy. Also, the review article examines alcohol's effect on remodeling the LD proteome and lipidome, including post-translational modifications. Additionally, LDs emerge as morphologic markers in hepatic stellate cells, where their loss drives fibrosis. Recent advances highlight potential therapeutic targets, such as restoring lipophagy or modulating LD biogenesis, offering hope for effective ASH treatments. This review underlines LDs as pivotal organelles in ASH progression and therapeutic innovation.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 20-34"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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