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Yashaswini C, Kiran NS, Chatterjee A. Zebrafish navigating the metabolic maze: insights into human disease - assets, challenges and future implications. J Diabetes Metab Disord 2025; 24:3. [PMID: 39697864 PMCID: PMC11649609 DOI: 10.1007/s40200-024-01539-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 09/26/2024] [Indexed: 12/20/2024]
Abstract
Zebrafish (Danio rerio) have become indispensable models for advancing our understanding of multiple metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome. This review provides a comprehensive analysis of zebrafish as a powerful tool for dissecting the genetic and molecular mechanisms of these diseases, focusing on key genes, like pparγ, lepr, ins, and srebp. Zebrafish offer distinct advantages, including genetic tractability, optical transparency in early development, and the conservation of key metabolic pathways with humans. Studies have successfully used zebrafish to uncover conserved metabolic mechanisms, identify novel disease pathways, and facilitate high-throughput screening of potential therapeutic compounds. The review also highlights the novelty of using zebrafish to model multifactorial metabolic disorders, addressing challenges such as interspecies differences in metabolism and the complexity of human metabolic disease etiology. Moving forward, future research will benefit from integrating advanced omics technologies to map disease-specific molecular signatures, applying personalized medicine approaches to optimize treatments, and utilizing computational models to predict therapeutic outcomes. By embracing these innovative strategies, zebrafish research has the potential to revolutionize the diagnosis, treatment, and prevention of metabolic disorders, offering new avenues for translational applications. Continued interdisciplinary collaboration and investment in zebrafish-based studies will be crucial to fully harnessing their potential for advancing therapeutic development.
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Affiliation(s)
- Chandrashekar Yashaswini
- Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, Karnataka 560064 India
| | | | - Ankita Chatterjee
- Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, Karnataka 560064 India
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Han L, Pan Y, Luo L, Shen J, Yu Y. Advances in fluorescent probes of non-alcoholic fatty liver disease. Talanta 2025; 287:127694. [PMID: 39923673 DOI: 10.1016/j.talanta.2025.127694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant chronic liver disease worldwide, with 20-30 % of individuals going on to develop non-alcoholic steatohepatitis (NASH), which could result in serious complications such as fibrosis, liver cirrhosis, and hepatocellular carcinoma. Since NAFLD is reversible in its early stages, early diagnosis is necessary. By using particular structural and functional designs, fluorescent probes can be made to detect NAFLD-related chemicals or biological processes with a high degree of sensitivity and selectivity. In this work, we summarize the existing fluorescent probes for identifying biomarkers in NAFLD, including microenvironment (viscosity, polarity), ROS, RNS, RSS, metal ions, enzymes, and RNA. Furthermore, future directions are envisioned to inform the creation of more accurate and reliable fluorescent probes for NAFLD diagnosis, emphasizing the benefits and challenges of fluorescence probes.
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Affiliation(s)
- Lijun Han
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China; Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan, 430070, China
| | - Yalong Pan
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China; Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan, 430070, China
| | - Li Luo
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China; Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan, 430070, China
| | - Junxue Shen
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China; Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan, 430070, China
| | - Yao Yu
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China; Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan, 430070, China.
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3
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Xie C, Jiang X, Yin J, Jiang R, Zhu J, Zou S. Bisphenol S accelerates the progression of high fat diet-induced NAFLD by triggering ferroptosis via regulating HMGCS2. JOURNAL OF HAZARDOUS MATERIALS 2025; 487:137166. [PMID: 39799675 DOI: 10.1016/j.jhazmat.2025.137166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
Bisphenol S (BPS) is a widely detected environmental toxin with the potential to increase the risk of non-alcoholic fatty liver disease (NAFLD). However, the effects of BPS on the progression of high fat diet (HFD)-induced NAFLD remain unclear. This study aimed to explore the role and underlying mechanisms of action of BPS in HFD-induced NAFLD. Our results showed that BPS exposure (50 and 500 μg/kg bodyweight/day) promoted the progression of NAFLD, which was evidenced by increased liver/body weight ratio, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and more and larger lipid droplets in liver tissues. These phenomena were accompanied by abnormal expression levels of fatty acid uptake (Cd36), fatty acid synthesis (Pparγ, Scd-1, and Fasn), fatty acid oxidation (Pparα), and cytokines (TNFα, IL-1β, and IL-6). In vitro and in vivo studies showed that BPS exposure caused hepatic ferroptosis by regulating ferroptosis-related markers (GPX4, xCT, FTH, and ACSL4). Moreover, BPS exposure caused ROS overproduction, mitochondrial dysfunction, lipid peroxidation, and GSH suppression, all of which were restored by ferrostatin-1, a ferroptosis inhibitor. Moreover, BPS significantly upregulated HMGCS2 expression in the hepatocytes and liver tissues. 3-hydroxy-3-methylglutaryl coenzyme A synthetase 2 (HMGCS2) knockdown mitigated the effects of BPS on hepatocytes and reversed the expression of ferroptosis-related markers. Thus, BPS exposure aggravates HFD-induced NAFLD by regulating HMGCS2-mediated ferroptosis. Collectively, our study indicates that BPS exposure at environmentally relevant concentrations may aggravate NAFLD phenotypes under HFD conditions, highlighting the health risks of BPS to the liver.
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Affiliation(s)
- Chunfeng Xie
- Medical School, Nanjing University, Nanjing 210093, China; Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Xinyao Jiang
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China
| | - Juan Yin
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China
| | - Runqiu Jiang
- Medical School, Nanjing University, Nanjing 210093, China.
| | - Jianyun Zhu
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China.
| | - Shenshan Zou
- Department of General Surgery, Changzhou TCM Hospital, No. 25, Heping North Road, Changzhou City, Jiangsu Province 213003, China.
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Wang Q, Li D, Zhang Z, Shen L, Xu H, Wang Z, Redshaw C, Zhang Q. Polarity-Sensitive fluorescent probes based on triphenylamine for fluorescence lifetime imaging of lipid droplets. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 330:125694. [PMID: 39754836 DOI: 10.1016/j.saa.2024.125694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease closely associated with metabolic abnormalities. Lipid droplets (LDs) serve as organelles that store intracellular neutral lipids and maintain cellular energy homeostasis. Their abnormalities can cause metabolic disorders and disease, which is also one of the distinctive characteristics of NAFLD patients. However, the correlation between the polarity of LDs and NAFLD is easily overlooked. To monitor the polarity changes in LDs in order to assess the progression of NAFLD, triphenylamine was used as the electron donor (D), pyridine as the electron acceptor (A) and thiazolo[5,4-d]thiazole (TTz) as π bridge in this study. The structure was modified by introducing different substituents at the triphenylamine to obtain a series of D-π-A structural polar-responsive asymmetric thiazolo[5,4-d]thiazole (aTTz) fluorescent probes with different push-pull electron effects and steric hindrance. The fluorescent probes, which exhibit distinct fluorescence emission spectra in solutions with varying polarities, demonstrate excellent polarity-sensitive properties, and the displacement of the maximum emission wavelength varies from 125 to 150 nm. Meanwhile, the fluorescent probes exhibited low dark toxicity of cells and can specifically image lipid droplets, with a localization coefficient of more than 0.84 when imaging, and can be applied to the fluorescence imaging of C. elegans. Furthermore, the polar response properties of the fluorescent probes were used to distinguish normal liver tissue and nonalcoholic fatty liver tissue by fluorescence lifetime microscopic imaging (FLIM), thus providing a molecular tool for the diagnosis of NAFLD.
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Affiliation(s)
- Qian Wang
- Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, PR China
| | - Dongmei Li
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, PR China
| | - Ze Zhang
- School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical, University, Guiyang 550025, China
| | - Lingyi Shen
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, PR China
| | - Hong Xu
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, PR China.
| | - Zhiyong Wang
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, PR China.
| | - Carl Redshaw
- Chemistry, School of Natural Sciences, University of Hull, Hull, Yorkshire HU6 7RX, UK
| | - Qilong Zhang
- School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, PR China.
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Gao Z, Cao S, Yuan H, Wu JZ, Zou G. Broad antifibrotic activities of AK3280 in pulmonary, hepatic, cardiac, and skin fibrosis animal models. Int Immunopharmacol 2025; 151:114337. [PMID: 40015207 DOI: 10.1016/j.intimp.2025.114337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/06/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025]
Abstract
Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.
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Affiliation(s)
- Zhao Gao
- Shanghai Ark Biopharmaceutical Co., Ltd, Shanghai 201203, China
| | - Sushan Cao
- Shanghai Ark Biopharmaceutical Co., Ltd, Shanghai 201203, China
| | - Haiqing Yuan
- Shanghai Ark Biopharmaceutical Co., Ltd, Shanghai 201203, China
| | - Jim Zhen Wu
- Shanghai Ark Biopharmaceutical Co., Ltd, Shanghai 201203, China
| | - Gang Zou
- Shanghai Ark Biopharmaceutical Co., Ltd, Shanghai 201203, China.
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Wang M, Wei T, Sun L, Zhen Y, Bai R, Lu X, Ma Y, Hou Y. Incremental predictive value of liver fat fraction based on spectral detector CT for major adverse cardiovascular events in T2DM patients with suspected coronary artery disease. Cardiovasc Diabetol 2025; 24:151. [PMID: 40176017 DOI: 10.1186/s12933-025-02704-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/23/2025] [Indexed: 04/04/2025] Open
Abstract
BACKGROUND The purpose of this study was to explore the incremental predictive value of liver fat fraction (LFF) in forecasting major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM). METHODS We prospectively enrolled 265 patients with T2DM who presented to our hospital with symptoms of chest distress and pain suggestive of coronary artery disease (CAD) between August 2021 and August 2022. All participants underwent both coronary computed tomography angiography (CCTA) and upper abdominal dual-layer spectral detector computed tomography (SDCT) examinations within a 7-day interval. Detailed clinical data, CCTA imaging features, and LFF determined by SDCT multi-material decomposition algorithm were meticulously recorded. MACE was defined as the occurrence of cardiac death, acute coronary syndrome (ACS), late-phase coronary revascularization procedures, and hospital admissions due to heart failure. RESULTS Among 265 patients (41% male), 51 cases of MACE were documented during a median follow-up of 30 months. The LFF in T2DM patients who experienced MACE was notably higher compared to those without MACE (p < 0.001). The LFF was divided into tertiles using the cutoffs of 4.10 and 8.30. Kaplan-Meier analysis indicated that patients with higher LFF were more likely to develop MACE, regardless of different subgroups in framingham risk score (FRS) or coronary artery calcium score (CACS). The multivariate Cox regression results indicated that, compared with patients in the lowest tertile, those in the second tertile (hazard ratio [HR] = 3.161, 95% confidence interval [CI] 1.163-8.593, P = 0.024) and third tertile (HR = 4.372, 95% CI 1.591-12.014, P = 0.004) had a significantly higher risk of MACE in patients with T2DM. Even after adjusting for early revascularization, both LFF tertile and CACS remained independently associated with MACE. Moreover, compared with the traditional FRS model, the model that included LFF, CACS, and FRS showed stable clinical net benefit and demonstrated better predictive performance, with a C-index of 0.725, a net reclassification improvement (NRI) of 0.397 (95% CI 0.187-0.528, P < 0.01), and an integrated discrimination improvement (IDI) of 0.100 (95% CI 0.043-0.190, P < 0.01). CONCLUSIONS The elevated LFF emerged as an independent prognostic factor for MACE in patients with T2DM. Incorporating LFF with FRS and CACS provided incremental predictive power for MACE in patients with T2DM. RESEARCH INSIGHTS WHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: T2DM is associated with increased MACE rates, underscoring the need for improved risk prediction. CACS is a well-established tool for MACE risk assessment but may not capture all risk factors. Hepatic steatosis is a common comorbidity in metabolic syndrome and T2DM. WHAT IS THE KEY RESEARCH QUESTION?: Does the incorporation of LFF derived from SDCT into existing risk prediction models enhance the accuracy of MACE forecasting in patients with T2DM? WHAT IS NEW?: SDCT-LFF measurement introduces a more accurate method for assessing hepatic steatosis. LFF as an independent predictor of MACE in T2DM patients is a novel finding. The study presents LFF as an additional tool for risk stratification, complementing FRS and CACS. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: Study findings may guide personalized prevention for T2DM patients at higher MACE risk.
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Affiliation(s)
- Min Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Tanglin Wei
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Li Sun
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yanhua Zhen
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Ruobing Bai
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Xiaomei Lu
- CT Clinical Science CT, Philips Healthcare, Shenyang, People's Republic of China
| | - Yue Ma
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yang Hou
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
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Xu K, Corona-Avila I, Frutos MD, Núñez-Sánchez MÁ, Makhanasa D, Shah PV, Guzman G, Ramos-Molina B, Priyadarshini M, Khan MW. Hepatic HKDC1 deletion alleviates western diet-induced MASH in mice. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167746. [PMID: 40020530 DOI: 10.1016/j.bbadis.2025.167746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/05/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
The global prevalence of Metabolic Dysfunction-Associated Steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1's potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1LKO) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.
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Affiliation(s)
- Kai Xu
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America
| | - Irene Corona-Avila
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America
| | - María Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain
| | - María Ángeles Núñez-Sánchez
- Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain
| | - Dhruvi Makhanasa
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America
| | - Pratham Viral Shah
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Bruno Ramos-Molina
- Obesity, Diabetes and Metabolism Research Group, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain
| | - Medha Priyadarshini
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America.
| | - Md Wasim Khan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America.
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Lu F, Liu J, She B, Yang H, Ji F, Zhang L. Global Trends and Inequalities of Liver Complications Related to Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis From 1990 to 2021. Liver Int 2025; 45:e16120. [PMID: 39387341 DOI: 10.1111/liv.16120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/11/2024] [Accepted: 09/20/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction-associated steatotic liver disease (LC-MASLD) by geographical region, age and sex during 1990-2021. METHODS Global Burden of Diseases Study 2021 data were analysed to assess LC-MASLD incidence, prevalence, mortality and disability-adjusted life years (DALYs). Temporal trends during 1990-2021 were measured by 'estimated annual percentage change' (EAPC). Inequalities of LC-MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI). RESULTS During 1990-2021, LC-MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC-MASLD incidence was earliest in the 15-19 age group, both prevalence and DALY rates peaked at 75-79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990-2021, demonstrated by a decline in SII from -0.09 to -0.56 per 100 000 for mortality and from 1.41 to -7.74 per 100 000 for DALYs. RCI demonstrated similar findings. CONCLUSION The LC-MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990-2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations.
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Affiliation(s)
- Fang Lu
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Jinli Liu
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Bingyang She
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Hailin Yang
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Fanpu Ji
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lei Zhang
- China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia
- Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia
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Yao Y, Hong Q, Ding S, Cui J, Li W, Zhang J, Sun Y, Yu Y, Yu M, Zhang C, Chen L, Jiang J, Hu Y. An umbrella review of meta-analyses on the effects of microbial therapy in metabolic dysfunction-associated steatotic liver disease. Clin Nutr 2025; 47:1-13. [PMID: 39978229 DOI: 10.1016/j.clnu.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/09/2024] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Current pharmacological treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) are often accompanied by adverse side effects. Consequently, probiotics, prebiotics, and synbiotics, which are bioactive compounds from fermented foods and offer fewer side effects, have garnered significant attention as alternative therapeutic strategies. OBJECTIVE This study aims to assess the efficacy of microbial therapies-probiotics, prebiotics, and synbiotics-in managing MASLD and to identify the optimal treatment modality for various clinical indicators through a comprehensive umbrella review of meta-analyses. METHODS A thorough literature search was conducted across PubMed, Web of Science, EMBASE, Cochrane Library, and Scopus to identify 23 meta-analyses over 18,999 MASLD patients as of November 2024. RESULTS The findings indicate that microbial treatments positively influence levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), homeostasis model assessment of insulin resistance (HOMA-IR), insulin, tumour necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and body mass index (BMI) in MASLD patients. Notably, probiotics were most effective in reducing TC, ALT, AST, GGT, insulin, TNF-α, and BMI; prebiotics were most effective in reducing TG; and synbiotics were most effective in reducing LDL-C, HOMA-IR, and CRP. CONCLUSION Our study provides robust evidence for microbial treatments of MASLD, enabling targeted interventions for different indicators.
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Affiliation(s)
- Yuanyue Yao
- College of Biological and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Qing Hong
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai, 200436, China
| | - Siqi Ding
- College of Biological and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Jie Cui
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Wenhui Li
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Jian Zhang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Ye Sun
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Yiyang Yu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Mingzhou Yu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
| | - Chengcheng Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, 214122, Wuxi, Jiangsu, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, China
| | - Lianmin Chen
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China; Nanjing Medical University, Nanjing, 21100, China
| | - Jinchi Jiang
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China.
| | - Yonghong Hu
- College of Food Science and Light Industry, Nanjing Tech University, Nanjing, 211816, China; State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, China
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Li Z, Guo H, He H, Wang S, Pei S, Xie L. The relationship between smoking cessation history and significant liver fibrosis among the population with metabolic dysfunction-associated steatotic liver disease in the United States. PLoS One 2025; 20:e0320573. [PMID: 40168280 PMCID: PMC11960941 DOI: 10.1371/journal.pone.0320573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/19/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Smoking was identified as a risk factor for the development of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the association between smoking cessation history and the development of liver fibrosis remains unclear. This study was intended to analyze the association between smoking cessation history and significant liver fibrosis in adult MASLD participants in the United States. METHODS This study utilized data from 2643 patients with MASLD from the National Health and Nutrition Examination Survey (NHANES). Significant liver fibrosis was detected based on transient elastography measurements. According to the smoking questionnaire data, patients were categorized as non-smokers, ex-smokers and current smokers. A multivariate logistic regression analysis, adjusted for weights, was performed to investigate the relationship between smoking cessation history and the presence of significant liver fibrosis in participants with MASLD. RESULTS A total of 2643 patients with MASLD were included in this study. Compared with non-smokers, ex-smokers had a slightly elevated risk of developing significant liver fibrosis (OR: 1.07, 95% CI: 1.02-1.13). Specifically, a positive correlation was observed between patients who quit smoking for < 20 years and significant liver fibrosis (OR: 1.07, 95% CI: 1.01-1.15). Furthermore, MASLD patients who started regularly smoking at an age of ≤ 20 years (OR: 1.09, 95% CI: 1.02-1.16) and had a smoking duration of ≥ 10 years before quitting (OR: 1.10, 95% CI: 1.02-1.18) were also highly correlated with an increased likelihood of developing significant liver fibrosis. CONCLUSIONS This study revealed that individuals with MASLD who have ceased smoking exhibit an elevated risk for significant liver fibrosis when compared to those who never smoked. It is highly emphasized that MASLD patients who quit smoking for < 20 years, started regularly smoking at an age of ≤ 20 years, and had a smoking duration of ≥ 10 years before quitting should be extremely vigilant regarding the risk of significant liver fibrosis.
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Affiliation(s)
- Zhongtao Li
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Hao Guo
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Hongyu He
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
| | - Shu Wang
- Department of Urology Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Shufen Pei
- Department of Otolaryngology-Head and Neck Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Liang Xie
- Department of General Surgery (Wenhua Road Campus), The Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Hepatobiliary Pancreatic and Intestinal Diseases, North Sichuan Medical College, Nanchong, China
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11
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Kovynev A, Charchuta MM, Begtašević A, Ducarmon QR, Rensen PCN, Schönke M. Combination of dietary fiber and exercise training improves fat loss in mice but does not ameliorate MASLD more than exercise alone. Am J Physiol Gastrointest Liver Physiol 2025; 328:G399-G410. [PMID: 40033967 DOI: 10.1152/ajpgi.00317.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 01/02/2025] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber and exercise on the modulation of gut-liver axis and MASLD amelioration. Here, we studied the impact of the combination of exercise training and a fiber-rich diet on the amelioration of MASLD. Male APOE*3-Leiden.CETP mice were fed a high-fat high-cholesterol diet with or without the addition of fiber (10% inulin) and exercise trained on a treadmill, or remained sedentary. Exercise training and fiber supplementation reduced fat mass gain and lowered plasma glucose levels. Only the combination treatment, however, induced fat loss and decreased plasma triglyceride and cholesterol levels compared with sedentary control mice. Exercise training with and without the addition of fiber had a similar ameliorating effect on the MASLD score. Only exercise without fiber decreased the hepatic expression of inflammatory markers. Fiber diet was mainly responsible for remodeling the gut microbial composition, with an increase in the relative abundance of the short-chain fatty acid (SCFA)-producing genera Anaerostipes and Muribaculaceae, whereas, surprisingly, exercise training alone and with fiber resulted in the highest increase of SCFA production. Overall, the combination of exercise training and dietary fiber decreases fat mass and improves glucose and lipid homeostasis but does not have an additional synergistic positive effect on liver health compared with exercise training alone.NEW & NOTEWORTHY The combination of dietary fiber intake and exercise training has a synergetic beneficial effect on the metabolic health, resulting in fat loss, lowered blood glucose, and lowered plasma lipid levels in mice with steatotic liver disease. However, fiber supplementation, despite a positive remodulation of the gut-liver axis, does not have an additional positive effect on liver health compared with exercise training alone.
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Affiliation(s)
- Artemiy Kovynev
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Mikołaj M Charchuta
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Amina Begtašević
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Quinten R Ducarmon
- Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Milena Schönke
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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12
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Kumar A, Arora A, Choudhury A, Arora V, Rela M, Jothimani DK, Mahtab MA, Devarbhavi H, Eapen CE, Goel A, Yaghi C, Ning Q, Chen T, Jia J, Zhongping D, Hamid SS, Butt AS, Jafri W, Shukla A, Tan SS, Kim DJ, Saraya A, Hu J, Sood A, Goyal O, Midha V, Pati GK, Singh A, Lee GH, Treeprasertsuk S, Thanapirom K, Mandot A, Maghade R, Lesmana RC, Ghazinyan H, Mohan Prasad VG, Dokmeci AK, Sollano JD, Abbas Z, Shrestha A, Lau GK, Payawal DA, Shiha GE, Duseja A, Taneja S, Verma N, Rao PN, Kulkarni AV, Karim F, Saraswat VA, Alam S, Chowdhury D, Kedarisetty CK, Saigal S, Sharma P, Yattoo GN, Koshy A, Patwa AK, Elbasiony M, Rathi PM, Maharshi S, Dayal VM, Jha AK, Kalista KF, Gani RA, Yuen MF, Singh V, Sargsyan VA, Huang CH, Mukewar SS, Xin S, Rajaram RB, Panackel C, Dadhich S, Sachdeva S, Kumar A, Behera S, Kamani L, Saithanyamurthi HV, Prasad B, Sarin SK. Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in Metabolic Dysfunction Associated Fatty Liver Disease-Related Acute-on-Chronic Liver Failure. Am J Gastroenterol 2025; 120:816-826. [PMID: 39016385 DOI: 10.14309/ajg.0000000000002951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 05/09/2024] [Indexed: 07/18/2024]
Abstract
INTRODUCTION The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. DISCUSSION Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF.
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Affiliation(s)
- Ashish Kumar
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Anil Arora
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | | | - Vinod Arora
- Institute of Liver and Biliary Sciences, New Delhi, India
| | | | | | - Mamun A Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | | | | | | | - Qin Ning
- Tongji Hospital, Wuhan/Capital Medical University, Beijing, China
| | | | - Jidong Jia
- Tongji Hospital, Wuhan/Capital Medical University, Beijing, China
| | - Duan Zhongping
- Youan Hospital Capital Medical University, Beijing, China
| | | | - Amna S Butt
- Aga Khan University Hospital, Karachi, Pakistan
| | - Wasim Jafri
- Aga Khan University Hospital, Karachi, Pakistan
| | - Akash Shukla
- Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Seok S Tan
- Selayang Hospital University of Malaysia, Malaya, Malaysia
| | - Dong J Kim
- Chuncheon Sacred Heart Hospital, Chuncheon, Korea
| | - Anoop Saraya
- Institute of liver and Biliary Sciences, New Delhi, India
| | - Jinhua Hu
- The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China
| | - Ajit Sood
- Dayanand Medical College, Ludhiana, India
| | | | | | | | - Ayaskant Singh
- SUM Ultimate Medicare and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Guan H Lee
- National University Hospital, Kent Ridge, Queenstown, Singapore
| | | | | | | | | | - Rinaldi C Lesmana
- Digestive Disease and Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | | | | | - Abdul K Dokmeci
- Ankara University School of Medicine, Hacettepe, Ankara, Turkey
| | - Jose D Sollano
- Cardinal Santos Medical Center, Metro Manila, Philippines
| | - Zaigham Abbas
- Dr. Ziauddin University Hospital, Clifton, Karachi, Pakistan
| | | | - George K Lau
- Humanity and Health Medical Centre, Hong Kong, SAR, China
| | | | - Gamal E Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Egypt
| | - Ajay Duseja
- Post Graduate Institute of Medical Education and Research Chandigarh, India
| | - Sunil Taneja
- Post Graduate Institute of Medical Education and Research Chandigarh, India
| | - Nipun Verma
- Post Graduate Institute of Medical Education and Research Chandigarh, India
| | - Padaki N Rao
- Asian Institute of Gastroentrology, Somajiguda, Hyderabad, India
| | - Anand V Kulkarni
- Asian Institute of Gastroentrology, Somajiguda, Hyderabad, India
| | - Fazal Karim
- Sir Salimullah Medical College, Mitford Hospital, Dhaka, Bangladesh
| | - Vivek A Saraswat
- Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Shahinul Alam
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | | | - Sanjiv Saigal
- Max Super Speciallity Hospital, Saket, New Delhi, India
| | - Praveen Sharma
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Ghulam N Yattoo
- Sher-e-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Abraham Koshy
- VPS Lakeshore Hospital and Research Center Ltd, Kochi, Kerala, India
| | | | | | - Pravin M Rathi
- Topi Wala National (TN) Medical College and BYL Nair Charitable Hospital, Mumbai, India
| | | | - Vishwa M Dayal
- Indira Gandhi Institute of Medical Sciences (IGIMS), Bailey Road, Patna, Bihar, India
| | - Ashish K Jha
- Indira Gandhi Institute of Medical Sciences (IGIMS), Bailey Road, Patna, Bihar, India
| | | | - Rino A Gani
- Cipto Mangunkusumo General Hospital, Jakarta , Indonesia
| | - Man F Yuen
- Department of Medicine , University of Hong Kong, Hong Kong, China
| | - Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
| | | | - Chien H Huang
- Chang Gung Medical Foundation Linkou Chang Gung Memorial Hospital, Taoyuan City, Taiwan
| | | | | | | | | | - Sunil Dadhich
- Dr. Sampuranand Medical College (SNMC), Jodhpur, Rajasthan, India
| | | | - Ajay Kumar
- Govind Ballabh Pant Hospital, New Delhi, India
| | | | | | | | - Babita Prasad
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Institute of Liver and Biliary Sciences, New Delhi, India
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Uluk D, Pein J, Herda S, Schliephake F, Schneider CV, Bitar J, Dreher K, Eurich D, Zhang IW, Schaffrath L, Auer TA, Collettini F, Engelmann C, Tacke F, Pratschke J, Lurje I, Lurje G. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Impacts Long-Term Outcomes After Curative-Intent Surgery for Hepatocellular Carcinoma. Aliment Pharmacol Ther 2025; 61:1318-1332. [PMID: 39964081 PMCID: PMC11950813 DOI: 10.1111/apt.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/18/2024] [Accepted: 01/17/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Curative surgery for hepatocellular carcinoma (HCC) includes liver resection (LR) and orthotopic liver transplantation (OLT). Due to the obesity epidemic, metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent HCC aetiology that often coincides with increased alcohol consumption, termed MetALD, or even alcohol-associated liver disease (ALD). METHODS Patients undergoing LR or OLT for HCC at Charité-Universitätsmedizin Berlin (2010-2020) were included in this retrospective cohort study investigating disease aetiology, time to recurrence (TTR), overall survival (OS) and CT-based body composition. RESULTS Out of 579 patients with HCC, 417 underwent LR and 162 OLT. Tumour aetiologies were viral n = 191 (33.0%), MASLD n = 158 (27.3%), MetALD n = 51 (8.8%), ALD n = 68 (11.7%) and other/cryptogenic n = 111 (19.2%). Patients with MASLD and MetALD had more intramuscular (p < 0.001, p = 0.015) and visceral fat (both p < 0.001) than patients with non-metabolic dysfunction aetiologies. Patients with MASLD-HCC had comparable TTR (median 26 months, [95% CI: 23-31] vs. 30 months [95% CI: 4-57], p = 0.425) but shorter OS than patients with other HCC aetiologies (63 months [95% CI: 42-84] vs. 80 months [95% CI: 60-100], hazard ratio: 1.53 [95% CI: 1.050-2.229], p = 0.026) after LR. Multivariate analysis confirmed MASLD aetiology, portal vein thrombosis and MELD score ≥ 10 as independent prognostic factors for OS in LR (adjusted p = 0.021,p < 0.001,p = 0.003), even after excluding in-hospital mortality (adjusted p = 0.016,p = 0.002,p = 0.002). Causes of death were similar in MASLD and non-MASLD aetiology. CONCLUSIONS Patients with HCC undergoing LR and meeting the new MASLD criteria have significantly shorter OS. This study provides empirical prognostic evidence for the novel MASLD/MetALD classification in a large European cohort of patients undergoing curative-intent HCC therapy.
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Affiliation(s)
- Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Justus Pein
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Sophia Herda
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Frederik Schliephake
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | | | - Jude Bitar
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Katharina Dreher
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Ingrid W. Zhang
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Lukas Schaffrath
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Timo A. Auer
- Department of RadiologyCharité – Universitätsmedizin BerlinBerlinGermany
| | | | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Isabella Lurje
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow KlinikumCharité‐Universitätsmedizin BerlinBerlinGermany
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
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Dai JJ, Deng Y, Wang GF, Lin KQ, He JR, Hu XG. Relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with non-alcoholic fatty liver disease: Diagnostic value for liver fibrosis. Shijie Huaren Xiaohua Zazhi 2025; 33:192-198. [DOI: 10.11569/wcjd.v33.i3.192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/15/2025] [Accepted: 03/16/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in China. Vitamin D and pentraxin 3 (PTX3) participate in the occurrence and development of NAFLD by regulating calcium and phosphorus metabolism and inflammation. This study analyzed the relationship of serum 25-hydroxy vitamin D3 [25(OH)D3] and PTX3 levels with liver fat content and liver fibrosis in patients with NAFLD.
AIM To analyze the relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with NAFLD, as well as their diagnostic value for liver fibrosis.
METHODS A total of 120 NAFLD patients in our hospital from June 2022 to September 2023 were selected as a study group, and another 120 healthy individuals in the same period were selected as a control group. General information and serum levels of 25(OH)D3 and PTX3 were compared between and two groups, and the levels of 25(OH)D3 and PTX3 were compared in patients with different liver fat contents in the study group. The correlation between serum levels of 25(OH)D3 and PTX3 and liver fat content in NAFLD patients was analyzed. The levels of serum 25(OH)D3, PTX3, liver fibrosis, and liver function indicators [hyaluronic acid (HA), procollagen type Ⅲ (PCⅢ), procollagen type Ⅳ (PCIV), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] were compared among patients with different degrees of liver fibrosis in the study group. The correlation of serum 25(OH)D3 and PTX3 levels with liver fibrosis and liver function indicators was examined, and their value for diagnosing liver fibrosis was assessed.
RESULTS Serum 25(OH)D3 level in the study group was lower than that of the control group, while PTX3 level was higher than that of the control group (P < 0.05). There was a statistically significant difference in serum 25(OH)D3 and PTX3 levels among patients with different liver fat contents in the study group (P < 0.05). As the liver fat content increased, serum 25(OH)D3 levels significantly decreased, while PTX3 levels significantly increased. Serum 25(OH)D3 levels were negatively correlated with liver fat content in NAFLD patients, while PTX3 levels were positively correlated with liver fat content in NAFLD patients (P < 0.05). Serum 25(OH)D3 levels in patients at risk of liver fibrosis in the study group were lower than those in patients without liver fibrosis, while the levels of PTX3, HA, PC Ⅲ, PC Ⅳ, ALT, and AST were higher than those of patients without liver fibrosis (P < 0.05). Serum 25(OH)D3 levels in NAFLD patients were negatively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels, while PTX3 levels were positively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels (P < 0.05). The area under the curve (AUC) of serum 25(OH)D3 and PTX3 alone for diagnosing liver fibrosis in patients with NAFLD was 0.713 and 0.781, respectively, while the AUC of their combination was 0.908, which was greater than the AUC of either of them alone (P < 0.05).
CONCLUSION Serum 25(OH)D3 level in NAFLD patients is negatively correlated with liver fat content, while serum PTX3 level is positively correlated with liver fat content. The two have appreciated diagnostic value in liver fibrosis.
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Affiliation(s)
- Jian-Ji Dai
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Yi Deng
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Guo-Feng Wang
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Kai-Qin Lin
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Jian-Rong He
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Xiao-Gang Hu
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
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15
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Jain P, Jain A, Deshmukh R, Samal P, Satapathy T, Ajazuddin. Metabolic dysfunction-associated steatotic liver disease (MASLD): Exploring systemic impacts and innovative therapies. Clin Res Hepatol Gastroenterol 2025; 49:102584. [PMID: 40157567 DOI: 10.1016/j.clinre.2025.102584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/01/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), which includes the inflammatory subtype metabolic dysfunction-associated steatohepatitis, is a prominent cause of chronic liver disease with systemic effects. Insulin resistance, obesity, and dyslipidaemia produce MASLD in over 30 % of adults. It is a global health issue. From MASLD to MASH, hepatic inflammation and fibrosis grow, leading to cirrhosis, hepatocellular cancer, and extrahepatic complications such CVD, CKD, and sarcopenia. Effects of MASLD to MASH are mediated through mechanisms that include inflammation, oxidative stress, dysbiosis, and predisposition through genetic makeup. Advances in diagnostic nomenclature in the past few years have moved the emphasis away from NAFLD to MASLD, focusing on the metabolic etiology and away from the stigma of an alcoholic-related condition. Epidemiological data show a large geographical variability and increasing prevalence in younger populations, particularly in regions with high carbohydrate-rich diets and central adiposity. Lifestyle modification is considered as the main management of MASLD currently. This may include dietary intervention, exercise, and weight loss management. Pharmaceutical management is primarily aimed at metabolic dysfunction with promising findings for GLP-1 receptor agonists, pioglitazone and SGLT-2 inhibitors, which can correct both hepatic and systemic outcome. However, it still depends on well-integrated multidisciplinary care models by considering complex relationships between MASLD and its effects on extrahepatic organs. Determining complications at an early stage; developing precision medicine strategies; exploring new therapeutic targets will represent crucial factors in improving their outcomes. This review discuss the systemic nature of MASLD and calls for multiple collaborations to reduce its far-reaching health impacts and our quest for understanding its pathological mechanisms. Thus, collective efforts that are required to address MASLD are under the public health, clinical care, and research angles toward effectively containing its rapidly increasing burden.
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Affiliation(s)
- Parag Jain
- Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Bhilai, C.G., India, 490024.
| | - Akanksha Jain
- Department of Biotechnology, Bharti University, Durg, C.G., India
| | - Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, India, 281406
| | - Pradeep Samal
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur, C.G., India
| | - Trilochan Satapathy
- Department of Pharmacy, Columbia Institute of Pharmaceutical Sciences, Raipur, C.G., India, 493111
| | - Ajazuddin
- Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research, Bhilai, C.G., India, 490024
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Xie J, He Q, Fisher D, Pronyuk K, Musabaev E, Zhao L. Association of platelet to albumin ratio with metabolic dysfunction-associated steatotic liver disease based on the National Health and Nutrition Survey 2017-2018. Sci Rep 2025; 15:10573. [PMID: 40148478 PMCID: PMC11950324 DOI: 10.1038/s41598-025-92837-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 03/03/2025] [Indexed: 03/29/2025] Open
Abstract
The prevalence and incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) are significantly increasing globally, but the index of non-invasive disease is limited. Platelet-albumin ratio(PAR) is a non-invasive biomarker of inflammation, the aim of this study was to evaluate the relationship between PAR and MASLD. This population-based cross-sectional retrospective study analyzed data extracted from the National Health and Nutrition Survey (NHANES) database from 2017 to 2018. Multivariate logistic regression analysis was used to evaluate the correlation between PAR and MASLD in different models. Model I was unadjusted, model II adjusted for race, sex and age, and model III was adjusted based on model II plus smoking status, hypertension, and diabetes. Further subgroup analysis was carried out according to sex, age, hypertension and diabetes status. The study involved 3287 participants, of whom 873 (26.5%) were diagnosed with MASLD. The PAR level in MASLD group was significantly higher than non-MASLD group (P < 0.05). Multivariate logistic regression revealed that high PAR level was an independent risk factor for MASLD (OR = 2.58, 95%CI: 1.26-5.27, P = 0.03), which adjusted for sex, age, race, smoking status, hypertension, and diabetes.The same results were observed in multiple subgroups of further subgroup analysis, and it can effectively predict the risk of MASLD (AUC = 0.842, 95% CI: 0.826-0.859). In conclusion, the new biomarker PAR shows a positive correlation with the risk of MASLD in the population, and can be used as a biomarker of MASLD to help clinicians identify people at high risk of MASLD.
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Affiliation(s)
- Jiao Xie
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qingliu He
- Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - David Fisher
- Department of Medical Biosciences, Faculty of Natural Sciences, University of The Western Cape, Cape Town, South Africa
| | - Khrystyna Pronyuk
- Infectious Diseases Department, O.Bogomolets National Medical University, Kyiv, Ukraine
| | - Erkin Musabaev
- The Research Institute of Virology, Ministry of Health, Tashkent, 100122, Uzbekistan
| | - Lei Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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17
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Wang D, Zhang X, Cai Y, Dong H, Zhang Y. Multidimensional sleep impairment predicts steatotic liver disease spectrum risk. Sci Rep 2025; 15:10405. [PMID: 40140484 PMCID: PMC11947187 DOI: 10.1038/s41598-025-95336-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 03/20/2025] [Indexed: 03/28/2025] Open
Abstract
To evaluate the correlation between various sleep and the risk of NAFLD\MAFLD\MASLD. This study included 4772 subjects from the National Health and Nutrition Examination Survey data from 2017 to 2020. Poor sleep factors were defined as: ①abnormal sleep duration (< 7 h or > 8 h); ②snoring; ③sleep apnea; ④self-reported sleep disorder; ⑤ daytime sleepiness. The frequency of each sleep factor was scored, and the scores of all components were summed to obtain a sleep score ranging from 0 to 12. The higher the score, the less healthy the sleep pattern. Then we divided the overall sleep pattern into mild (sleep score 0-3 points), moderate (sleep score 4-7 points) or severe (sleep score 8-12 points) sleep pattern according to the distribution of sleep scores. Multiple logistic regression and restricted cubic spline graph analysis were used to determine the association between sleep and NAFLD\MAFLD\MASLD. In Model 1 and Model 2, sleep score as a continuous or categorical variable had an effect on NAFLD\MAFLD\MASLD(p <0.05). The risk of NAFLD\MAFLD\MASLD was higher in subjects with severe sleep patterns (p < 0.05). Snoring and sleepy during day was associated with NAFLD\MAFLD\MASLD (p < 0.05). We then drew a restricted cubic spline plot and found that sleep duration was nonlinearly associated with MAFLD\MASLD (p < 0.01), and the risk of MAFLD\MASLD was lower when the sleep duration was 7.5 ~ 9.5 h/d. In this nationally representative survey, severe sleep patterns were associated with an increased risk of NAFLD/MAFLD/MASLD. It is worth noting that sleep duration was nonlinearly associated with MAFLD and MASLD.
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Affiliation(s)
- Dongling Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiao Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yujie Cai
- Shanxi University of Chinese Medicine, Taiyuan, China
| | - Haihang Dong
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yinqiang Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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18
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Sun J, Shi R, Zhou Z, Xu W, Huai J, Cao Y, Zhang W, Nie L, Wang G, Yan Q, Wang X, Li M, Fang Z, Zhou X. Identification of CACNB1 protein as an actionable therapeutic target for hepatocellular carcinoma via metabolic dysfunction analysis in liver diseases: An integrated bioinformatics and machine learning approach for precise therapy. Int J Biol Macromol 2025; 308:142315. [PMID: 40139615 DOI: 10.1016/j.ijbiomac.2025.142315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
In addition to histological evaluation for nonalcoholic fatty liver disease (NAFLD), a comprehensive analysis of the metabolic landscape is urgently needed to categorize patients into distinct subgroups for precise treatment. In this study, a total of 806 NAFLD and 267 normal liver samples were comprehensively analyzed. Alterations in 114 metabolic pathways were investigated and two distinct metabolic clusters were identified. Single-cell RNA sequencing (scRNA-seq) analysis was utilized to decipher the metabolic activities within the microenvironment of NAFLD-derived liver cirrhosis. A refined fibrosis prediction model was developed using a Gaussian Mixture Model (GMM), demonstrating superior performance in fibrosis discrimination across multiple independent cohorts. Additionally, using The Cancer Genome Atlas (TCGA), CACNB1 protein was identified as a promising therapeutic target for hepatocellular carcinoma (HCC) patients with elevated metabolic dysfunction scores (MBDS). Machine learning algorithms were applied to MBDS-related genes to select an optimal prognostic model for HCC. All the models were trained in an HCC cohort obtained from the Gene Expression Omnibus (GEO), and the best model was validated in two independent HCC datasets: the TCGA-HCC cohort and LIRI-JP cohort. Overall, we provide insights of metabolic molecular subtyping and its potential clinical applicability in risk stratification for NAFLD and HCC individuals.
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Affiliation(s)
- Jing Sun
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Run Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaokai Zhou
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Weilong Xu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiaxuan Huai
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yutian Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenhui Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lijuan Nie
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Gaoxiang Wang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qianhua Yan
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Department of Pharmacology, Renmin Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China.
| | - Minglun Li
- Department of Radiation Oncology, Lueneburg Municipal Hospital, Lueneburg, Germany.
| | - Zhuyuan Fang
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
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Wang B, Yang Y, Yin Z, Yang W. The causal impact of body mass index on metabolic biomarkers and nonalcoholic fatty liver disease risk. Sci Rep 2025; 15:10314. [PMID: 40133380 PMCID: PMC11937590 DOI: 10.1038/s41598-024-84165-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/20/2024] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern linked to obesity. METHODS This study employed a Mendelian randomization approach to explore the causal influence of BMI on metabolic biomarkers and the subsequent risk of NAFLD. We analyzed data from multiple sources, including 249 metabolic traits, to establish direct and mediating relationships among BMI, metabolic factors, and NAFLD risk. RESULTS Our findings revealed a significant positive correlation between BMI and NAFLD across various datasets. We identified 176 metabolites associated with BMI, of which 106 were also linked to NAFLD. Importantly, 86 metabolites were found to mediate the relationship between BMI and NAFLD risk. Specifically, elevated levels of branched-chain amino acids, triglycerides, and certain cholesterol esters were notably associated with increased NAFLD risk, whereas changes in free cholesterol and phospholipid levels also played critical roles. CONCLUSION This study highlights the complex interactions between BMI, metabolic biomarkers, and NAFLD risk. By elucidating these relationships, we highlight potential targets for interventions aimed at reducing NAFLD incidence in populations with elevated BMI, ultimately contributing to improved metabolic health.
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Affiliation(s)
- Bo Wang
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Yanjiang Yang
- Department of Rheumatology and Immunology, The People's Hospital of Qiandongnan Autonomous Prefecture, Kaili, 556000, Guizhou Province, China
| | - Zhaoqiang Yin
- Department of Minimally Invasive and Biliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
| | - Wenwen Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu Province, China.
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20
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Allen MJ, Tulleners R, Brain D, O'Beirne J, Powell EE, Barnett A, Valery PC, Kularatna S, Hickman IJ. Implementation of a nurse-delivered, community-based liver screening and assessment program for people with metabolic dysfunction-associated steatotic liver disease (LOCATE-NAFLD trial). BMC Health Serv Res 2025; 25:421. [PMID: 40121480 PMCID: PMC11929169 DOI: 10.1186/s12913-025-12580-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 03/15/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND With the high burden of Metabolic dysfunction-associated steatotic liver disease (MASLD), (previously known as Non-Alcoholic Fatty Liver Disease - NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of the LOCATE model. METHODS The evaluation used mixed methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care. RESULTS The LOCATE model was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk MASLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in MASLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support. CONCLUSION Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting. TRIAL REGISTRATION The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12620000158965.
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Affiliation(s)
- Michelle J Allen
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
| | - Ruth Tulleners
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - David Brain
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - James O'Beirne
- University of the Sunshine Coast, Maroochydore DC, QLD, Australia
- Sunshine Coast University Hospital, Birtinya, QLD, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Adrian Barnett
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | | | - Sanjeewa Kularatna
- Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- Health Services and Systems Research, Duke - NUS Medical School, Singapore, Singapore
| | - Ingrid J Hickman
- Clinical Trials Capability, Centre for Clinical Research, The University of Queensland ULTRA Team, Herston, QLD, 4006, Australia
- Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
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21
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Zhang J, Wang Q, Zhou N, Liu J, Tao L, Peng Z, Hu G, Wang H, Fu L, Peng S. Fluorofenidone attenuates choline-deficient, l-amino acid-defined, high-fat diet-induced metabolic dysfunction-associated steatohepatitis in mice. Sci Rep 2025; 15:9863. [PMID: 40118958 PMCID: PMC11928590 DOI: 10.1038/s41598-025-94401-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/13/2025] [Indexed: 03/24/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves hepatic lipid accumulation, inflammation, and fibrosis. It can progress to cirrhosis or hepatocellular carcinoma without timely treatment. Current treatment options for MASH are limited. This study explores the therapeutic effects of fluorofenidone (AKF-PD), a novel small-molecule compound with antifibrotic and anti-inflammatory properties, on MASH in mouse model. Mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) were treated with AKF-PD, resulting in reduced serum ALT, AST, hepatic lipid accumulation, liver inflammation, and fibrosis. Network pharmacology and RNA-sequencing analyses suggested that AKF-PD influenced multiple metabolic, inflammatory, and fibrosis-related pathways. Further experiments verified that AKF-PD activated hepatic AMPK signaling, leading to the inhibition of the downstream SREBF1/SCD1 pathway and the activation of autophagy. Additionally, AKF-PD suppressed the expression of various inflammatory factors, reduced macrophage infiltration, and inhibited NLRP3 inflammasome activation. Moreover, AKF-PD attenuated liver fibrosis by inhibiting TGFβ1/SMAD signaling. In conclusion, this study reveals that AKF-PD effectively decreases hepatic lipid accumulation, liver inflammation and fibrosis in a CDAHFD-induced MASH model, positioning AKF-PD as a promising candidate for the treatment of MASH.
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Affiliation(s)
- Jian Zhang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Qianbing Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Nianqi Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jinqing Liu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Zhangzhe Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Gaoyun Hu
- Faculty of Pharmaceutical Sciences, Central South University, Changsha, 410008, Hunan, China
| | - Huiwen Wang
- Department of Infection Control Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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22
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Xia D, Jiang X, Xie X, Zhou H, Yu D, Jin G, Ye X, Zhu S, Guo Z, Liang X. Identification of a Novel NPC1L1 Inhibitor from Danshen and Its Role in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2025; 26:2793. [PMID: 40141435 PMCID: PMC11942890 DOI: 10.3390/ijms26062793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Danshen, a well-known traditional Chinese medicine (TCM), has gained increasing attention for its protective effects on nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying these effects remain to be elucidated. Niemann-Pick C1-like 1 (NPC1L1), a key transporter mediating intestinal cholesterol absorption, has emerged as a critical target for NAFLD treatment. This study aimed to screen for NPC1L1 inhibitors from Danshen and investigate their therapeutic effects on NAFLD. We established a high-throughput screening platform using stable Caco2 cell lines expressing human NPC1L1 (hL1-Caco2) and discovered that tanshinones (Tans), the liposoluble components of Danshen, inhibited NPC1L1-mediated cholesterol absorption in hL1-Caco2 cells. Additionally, Tans treatment reduced hepatic steatosis in high-fat diet (HFD)-fed mice. To identify the active compounds in Tans, activity-oriented separation was performed by integrating the high-throughput screening platform and two-dimensional chromatographic techniques. Ultimately, cryptotanshinone (CTS) was identified as a novel NPC1L1 inhibitor and significantly decreased hepatic steatosis in HFD-fed mice. Molecular docking and dynamics simulation showed that CTS stably bound with NPC1L1, where TRP383 acted as the key amino acid. Taken together, this study demonstrates, for the first time, that CTS, a liposoluble compound from Danshen, is a novel NPC1L1 inhibitor. Our findings suggest that the inhibitory effect of CTS against NPC1L1-mediated intestinal cholesterol absorption may be a potential mechanism, contributing to its alleviation of NAFLD in mice.
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Affiliation(s)
- Donghai Xia
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuan Jiang
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Xiaomin Xie
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Han Zhou
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Dongping Yu
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Gaowa Jin
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Xianlong Ye
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Zhimou Guo
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Xinmiao Liang
- Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (D.X.)
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
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Feng Q, Wu M, Mai Z. Emerging horizons: clinical applications and multifaceted benefits of SGLT-2 inhibitors beyond diabetes. Front Cardiovasc Med 2025; 12:1482918. [PMID: 40182430 PMCID: PMC11965600 DOI: 10.3389/fcvm.2025.1482918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/05/2025] Open
Abstract
SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.
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Affiliation(s)
- Qing Feng
- Department of Cardiology, Kaiping Central Hospital, Kaiping, China
| | - Miaoqiong Wu
- Department of Endocrinology, Kaiping Central Hospital, Kaiping, China
| | - Zizhao Mai
- School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China
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24
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Yu C, Chen L, Hu W, Lei X, Liu X, Xu Z, Chen C, Zhao H. The role of the advanced lung cancer inflammation index (ALI) in the risk of liver fibrosis and mortality among US adult MAFLD patients: a cross-sectional study of NHANES 1999-2018. BMC Gastroenterol 2025; 25:190. [PMID: 40114055 PMCID: PMC11927276 DOI: 10.1186/s12876-025-03762-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 03/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver disease globally, with inflammation and nutrition playing key roles in its progression. The Advanced Lung Cancer Inflammation Index (ALI) is a novel biomarker reflecting nutritional and inflammatory status. This study aims to explore the association between ALI and the risk of liver fibrosis and prognosis in MAFLD patients. METHODS This cross-sectional study analyzed NHANES data from the 1999-2018 on adult participants in the US. Weighted logistic regression assessed the association between ALI and liver fibrosis risk. Mortality outcomes, including all-cause, cardiovascular disease (CVD), and cancer mortality, analyzed using weighted Kaplan-Meier and Cox proportional hazards models. Restricted cubic splines (RCS) and threshold effect analyses were uesd to explore non-linear relationships. Receiver operating characteristic (ROC) curve evaluated the prognostic value of ALI, and stratified analyses examined subgroup differences. RESULTS A total of 6,858 MAFLD patients (mean age 51.38 ± 17.22 years, 54% male) were included. A non-linear relationship was found between ALI and liver fibrosis risk, with a threshold at 5.68, beyond which the risk increased significantly (OR = 2.35, 95% CI: 1.89-2.95). Stronger associations were observed in subgroups with central obesity and prediabetes (P for interaction < 0.05). ALI was inversely associated with all-cause mortality (HR = 0.64, 95% CI: 0.56-0.72) and CVD mortality (HR = 0.57, 95% CI: 0.46-0.65), but not cancer mortality. RCS analysis showed an L-shaped non-linear relationship with all-cause mortality (threshold at 5.36) and a linear relationship with CVD mortality. Low HDL cholesterol and excessive alcohol consumption influenced the association between ALI and all-cause mortality (P for interaction < 0.05). ALI demonstrated the highest predictive accuracy for CVD mortality. CONCLUSION ALI is associated with an increased risk of liver fibrosis and reduced all-cause and CVD mortality, highlighting its potential value in assessing MAFLD prognosis, particularly CVD-related mortality.
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Affiliation(s)
- Chunchun Yu
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lefu Chen
- Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA
| | - Wanting Hu
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiong Lei
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiling Liu
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhixiao Xu
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Chengshui Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Zhejiang Province Engineering Research Center for Endoscope Instruments and Technology Development, Department of Pulmonary and Critical Care Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, 324000, China.
| | - Hongjun Zhao
- Zhejiang Province Engineering Research Center for Endoscope Instruments and Technology Development, Department of Pulmonary and Critical Care Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, 324000, China.
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Park Y, Ko KS, Rhee BD. Non-Alcoholic Fatty Liver Disease (NAFLD) Management in the Community. Int J Mol Sci 2025; 26:2758. [PMID: 40141404 PMCID: PMC11943420 DOI: 10.3390/ijms26062758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has frequently been associated with obesity, type 2 diabetes (T2D), and dyslipidemia, all of which are shared by increased insulin resistance. It has become the most common liver disorder in Korea as well as in developed countries and is therefore associated with an increased health burden of morbidity and mortality. It has an association with T2D, and T2D increases the risk of cirrhosis and related complications. NAFLD encompasses a disease continuum from simple steatosis to non-alcoholic steatohepatitis which is characterized by faster fibrosis progression. Although its liver-related complication is estimated to be, at most, 10%, it will be a leading cause of cirrhosis and hepatocellular carcinoma soon in Korea. Although the main causes of death in people with NAFLD are cardiovascular disease and extra-hepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and can be assessed with combinations of non-invasive tests in the community. A number of components of metabolic syndrome involved could be another important prognostic information of NAFLD assessed easily in the routine care of the community. There is a few approved therapies for NAFLD, although several drugs, including antioxidants, attract practitioners' attention. Because of the modest effect of the present therapeutics, let alone complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is a viable option for many patients with NAFLD in the Korean community. Comprehensive approach taking healthy lifestyle and weight reduction into account remain a mainstay to the prevention and treatment of NAFLD.
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Affiliation(s)
- Yongsoo Park
- Department of Internal Medicine, Sanggye Paik Hospital, College of Medicine, Inje University, 1342 Dongil-ro, Nowon-gu, Seoul 01757, Republic of Korea; (K.S.K.); (B.D.R.)
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Chen K, Yang M, Li G, Wang W. Liver transplantation for NASH-related hepatocellular carcinoma versus non-NASH etiologies of hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One 2025; 20:e0317730. [PMID: 40106456 PMCID: PMC11922278 DOI: 10.1371/journal.pone.0317730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 01/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) has been emerging a predominant reason for liver transplantation (LT). The complexity of comorbidities in this population increases the possibility of poor transplant outcomes. The purpose of this study was to evaluate the differences in survival after transplantation among patients with NASH HCC and those with non-NASH HCC. METHOD We conducted systematic searches of the PubMed, Embase, Web of Science, and Cochrane Library databases. To analyze the data, both fixed and random-effects models were employed to aggregate hazard ratios (HRs) along with 95% confidence intervals (CIs) for recurrence-free survival (RFS) and overall survival (OS) outcomes. This study is registered with PROSPERO as CRD42024578441. RESULTS A total of seven studies were included in this study. This study revealed that there was no significant difference in OS between liver transplant recipients with NASH HCC and those with non-NASH HCC. The RFS of NASH HCC patients were significantly longer. The HRs were 0.70 (95% CI: 0.51-0.97, P = 0.03) for RFS and 0.88 (95% CI: 0.72-1.07, P = 0.21) for OS, respectively. CONCLUSION This study indicates that patients with NASH HCC who undergo LT have comparable OS as those with non-NASH HCC, while NASH HCC was associated with increased RFS. However, further research in randomized trials is necessary to verify these results and address potential selection biases.
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Affiliation(s)
- Kunlin Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guangjun Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wentao Wang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
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Liu S, Li F, Cai Y, Sun L, Ren L, Yin M, Cui H, Pan Y, Gang X, Wang G. Gout drives metabolic dysfunction-associated steatotic liver disease through gut microbiota and inflammatory mediators. Sci Rep 2025; 15:9395. [PMID: 40102566 PMCID: PMC11920238 DOI: 10.1038/s41598-025-94118-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/11/2025] [Indexed: 03/20/2025] Open
Abstract
This study explores the relationship between gout and metabolic dysfunction-associated steatotic liver disease (MASLD), two metabolic conditions linked to worsening health outcomes. While hyperuricemia's association with MASLD is established, the specific connection between gout and MASLD remains less explored. Using data from the UK Biobank, the study employs COX proportional hazard models, multi-state survival analysis, and Mendelian randomization to assess the independent and mutual risks of gout and MASLD. Findings indicate a mutual risk increase: male gout patients, those younger than 60, and those with high BMI are particularly susceptible to MASLD, while female MASLD patients are at heightened risk for gout. Shared risk factors for both conditions include high BMI, hypertension, diabetes, and hyperuricemia. The study further identifies a bidirectional causal link, with gout leading to MASLD, mediated by gut microbiota Ruminococcaceae and proteins like IL-2 and GDF11, implicating specific metabolic pathways. The findings highlight a clinical and mechanistic correlation, emphasizing the need for targeted interventions to address these overlapping metabolic pathways in future treatments.
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Affiliation(s)
- Siyuan Liu
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Fan Li
- Department of Hepatobiliary and Pancreatic Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Yunjia Cai
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Lin Sun
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Linan Ren
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Mengsha Yin
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Huijuan Cui
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Yujie Pan
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
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Chu Y, Yang S, Chen X. Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2025; 269:108844. [PMID: 40113178 DOI: 10.1016/j.pharmthera.2025.108844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/08/2025] [Accepted: 02/20/2025] [Indexed: 03/22/2025]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.
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Affiliation(s)
- Yi Chu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Su Yang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiaodong Chen
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
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Liu Z, Hou J, Tian M, Zhang Y, Huang D, Zhao N, Ma Y, Cui S. Hypoxia ameliorates high-fat-diet-induced hepatic lipid accumulation by modulating the HIF2α/PP4C signaling. Cell Signal 2025; 131:111751. [PMID: 40112904 DOI: 10.1016/j.cellsig.2025.111751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 03/03/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
Hepatic lipid accumulation is a hallmark of metabolically associated fatty liver disease (MAFLD), which contributes to the progression of cirrhosis and even hepatoma. However, the underlying mechanisms remain poorly understood. Protein phosphatase 4C (PP4C) is an important enzyme that exists widely in the body and participates in cell metabolism. Hypoxia can affect the development of metabolic diseases. In this study, we investigated the role of PP4C in hepatic lipid metabolism under hypoxia in vivo and in vitro. Hypoxia-inducible factor 2α (HIF2α), PP4C, phosphorylated AU-rich element RNA-binding factor 1(pAUF1), acetyl-CoA carboxylase 1 (ACC1), and carnitine palmitoyl transferase-1 (CPT1) were analyzed via western blotting and immunofluorescence. The mechanism by which PP4C affects hepatic lipid accumulation under hypoxia was evaluated in stable transfected cell lines. Compared with those in the 2200 m HFD group, body weight, triglyceride (TG), total cholesterol (TC), amino alanine transferase (ALT), aspartate transaminase (AST), and lipid accumulation were lower in the 4500 m HFD group (P < 0.05). Compared with those in the 4500 m ND group, ACC1 and PP4C levels were lower than in the 4500 m HFD group, but HIF2α, pAUF1, and CPT1 levels were greater (P < 0.05). Knockdown of HIF2α prevented the hypoxia-induced reduction of PP4C, confirming the regulatory role of the HIF2α-PP4C axis in hepatic lipid metabolism. PP4C could affect the phosphorylation and expression localization of AU-rich element RNA-binding factor 1 (AUF1). PP4C enhanced lipid accumulation by reducing pAUF1, while the knockdown of PP4C had the opposite effect; pAUF1 had no change. Compared with those in the control group, ACC1 levels were decreased and CPT1 levels were increased in the AUF1 overexpression group, whereas ACC1 and CPT1 levels were not altered in the AUF1 knockdown group (P < 0.05). In conclusion, hypoxia might improve lipid accumulation by downregulating PP4C via HIF2a. PP4C is involved in hepatic lipid metabolism by regulating AUF1 phosphorylation under different oxygen concentrations. PP4C might be a promising target for treating hepatic lipid accumulation.
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Affiliation(s)
- Zhe Liu
- Research Center for High Altitude Medicine, Qinghai University, Xining 810000, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province, Xining 810000, China; Department of Gynecology, Affiliated Hospital of Qinghai University, Xining 810000, China
| | - Jing Hou
- Central Laboratory/Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810000, China
| | - MeiYuan Tian
- Central Laboratory/Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810000, China
| | - YaoGang Zhang
- Central Laboratory/Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810000, China
| | - DengLiang Huang
- Central Laboratory/Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810000, China
| | - Na Zhao
- Graduate School of Qinghai University, Qinghai University, Xining 810000, China
| | - Yanyan Ma
- Central Laboratory/Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810000, China; Department of Scientific Research Office, Affiliated Hospital of Qinghai University, Xining 810000, China.
| | - Sen Cui
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining 810000, China.
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Liu WY, Huang S, Ji H, Kim SU, Yip TCF, Wong GLH, Petta S, Tsochatzis E, Nakajima A, Bugianesi E, Goh BBG, Chan WK, Romero-Gomez M, Sanyal AJ, Boursier J, Hagström H, Calleja JL, de Lédinghen V, Newsome PN, Fan JG, Lai M, Castéra L, Lee HW, Pennisi G, Yoneda M, Armandi A, Teh KKJ, Gallego-Durán R, Asgharpour A, de Saint-Loup M, Shang Y, Llop E, Fournier C, Mahgoub S, Lara-Romero C, Canivet CM, Chan MSW, Lin H, Chen LL, Targher G, Byrne CD, Du M, Wai-Sun Wong V, Zheng MH. From "Burnt-Out" to "Burning-Out": Capturing Liver Fat Loss in Patients With Advanced Metabolic Dysfunction-Associated Steatotic Liver Disease From a Dynamic Perspective. Gastroenterology 2025:S0016-5085(25)00523-2. [PMID: 40113099 DOI: 10.1053/j.gastro.2025.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND AND AIMS The absence of hepatic fat in advanced fibrosis has been documented in metabolic dysfunction-associated steatotic liver disease (''burnt-out" MASLD). However, whether hepatic fat loss occurs continuously with fibrosis progression is controversial. We proposed a "burning-out" concept to describe this process and analyze the long-term outcomes of "burnt-out" and "burning-out" MASLD. METHODS We included a MASLD cohort from 16 centers, including 3273 individuals with baseline histology and 5455 with serial vibration-controlled transient elastography measurements during the follow-up. "Burnt-out" MASLD was defined by steatosis grade ≤S1 and fibrosis stage ≥F3. Trajectory analysis identified "burning-out" patients with continuous trends of decreasing controlled attenuation parameter and increasing liver stiffness measurement values. RESULTS Of 3273 patients with histologic evaluation included, 435 had "burnt-out" MASLD. Compared with those with pronounced steatosis in advanced fibrosis, patients with "burnt-out" had higher risks of all-cause mortality (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.14-4.02), liver-related events (LREs; HR, 1.77; 95% CI, 1.12-2.78), and hepatic decompensation (HR, 1.83; 95% CI, 1.11-3.01). Of 5455 patients with vibration-controlled transient elastography included for trajectory analysis, 176 were identified as "burning-out" MASLD. The incidence rates of all-cause mortality, LREs, and decompensation were 7.28, 26.47, and 21.92 per 1000 person-years in "burning-out" patients, respectively. The "burning-out" group had higher cumulative incidences of adverse outcomes than patients with consistently high controlled attenuation parameter and moderate/low liver stiffness measurement values (P < .0001). CONCLUSIONS Continuous hepatic fat loss accompanied by fibrosis progression, referred to as "burning-out," was observed in advanced MASLD and associated with high rates of all-cause mortality, LREs, and hepatic decompensation.
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Affiliation(s)
- Wen-Yue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Key Laboratory of Diabetes Research, Wenzhou, China
| | - Shanshan Huang
- Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongsheng Ji
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Salvatore Petta
- Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy
| | - Emmanuel Tsochatzis
- University College London Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Boon-Bee George Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Malaysia
| | - Manuel Romero-Gomez
- Digestive Diseases Unit and CIBERehd, Virgen Del Rocío University Hospital, Seville, Spain
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Jérôme Boursier
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Sweden; Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - José Luis Calleja
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | | | - Philip Noel Newsome
- Institute of Hepatology, Faculty of Life Sciences & Medicine, King's College London and King's College Hospital, London, UK
| | - Jian-Gao Fan
- Department of Gastroenterology and Hepatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Michelle Lai
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Laurent Castéra
- Université Paris Cité, UMR1149 (CRI), INSERM, Paris, France; Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Clichy, France
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Grazia Pennisi
- Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Angelo Armandi
- Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Kevin Kim-Jun Teh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Rocio Gallego-Durán
- Digestive Diseases Unit and CIBERehd, Virgen Del Rocío University Hospital, Seville, Spain
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Marc de Saint-Loup
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
| | - Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Sweden
| | - Elba Llop
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | | | - Sara Mahgoub
- Institute of Hepatology, Faculty of Life Sciences & Medicine, King's College London and King's College Hospital, London, UK
| | - Carmen Lara-Romero
- Digestive Diseases Unit and CIBERehd, Virgen Del Rocío University Hospital, Seville, Spain
| | - Clemence M Canivet
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
| | | | - Huapeng Lin
- Department of Gastroenterology and Hepatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, China
| | - Li-Li Chen
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy; Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Mulong Du
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Sun M, Ma H, Miao Y, Zhang M. Quinoa bran polyphenol extract attenuates high-fat diet induced non-alcoholic fatty liver disease in mice. Food Funct 2025; 16:2291-2302. [PMID: 39981953 DOI: 10.1039/d4fo02647k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Quinoa bran is a by-product of quinoa processing and is rich in polyphenolic bioactives. Previous studies have shown that polyphenol compounds can help alleviate metabolic diseases, but studies on quinoa bran polyphenols intervening in non-alcoholic fatty liver disease (NAFLD) have not yet been reported. In this study, a C57BL/6J mouse NAFLD model was established using a high-fat diet (HFD) to explore the interventional effects of quinoa bran polyphenol extract (QBP) on NAFLD in mice. The results showed that QBP was effective in attenuating abnormal lipid metabolism and hepatic fat accumulation and reducing inflammation in NAFLD mice. 16S rRNA sequencing analysis showed that QBP regulated the composition of the gut microbiota by increasing the abundance of beneficial bacteria Clostridium_innocuum_group, Clostridium_sensu_stricto_13, Ruminococcus_gnavus_group, Coriobacteriaceae_UCG_002 and UBA1819. Untargeted metabolomics identified 51 differential metabolites due to QBP supplementation. Functional predictions indicated that starch and sucrose metabolism and pentose and gluconate interconversion are key metabolic pathways for QBP to attenuate NAFLD, which may be influenced by the gut microbiota. These results demonstrated the potential application of QBP interventions for NAFLD.
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Affiliation(s)
- Minjun Sun
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Haoyuan Ma
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Ying Miao
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Meili Zhang
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
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Zheng L, Lei H, Tang X, Zheng Y, Wu Q, Chen P, Chen Y, Cai L. Association Between Hepatic Steatosis Index and Endometrial Cancer Risk: A Cross-Sectional Study. Int J Womens Health 2025; 17:825-833. [PMID: 40123758 PMCID: PMC11927498 DOI: 10.2147/ijwh.s497621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Purpose To investigate the relationship between hepatic steatosis index (HSI) and endometrial cancer (EC) and its diagnostic value for EC. Patients and Methods A total of 114 patients with pathologically diagnosed EC in Mindong Hospital, Ningde City, Fujian Province from 2016 to 2022 were retrospectively included as the EC group. A total of 175 patients with pathologically confirmed benign endometrial lesions (endometrial polyps and uterine submucosal fibroids) in the same hospital during the same period were selected as the control group. Non-parametric test were used to compare the differences in HSI and non-alcoholic fatty liver disease (NAFLD) between the two groups, and the diagnostic value of HSI and NAFLD levels on EC was analysed. The cut-off point of continuous variables was determined by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to calculate odds ratios (ORs). Results The results showed that compared with the control group, serum GGT, CA125, HDL-C and HSI were significantly increased in the EC group (P<0.05). 27.19% of the EC patients (31/114) and 12% of the control group (21/175) had NAFLD, and the difference between the two groups was statistically significant (P<0.05). The results of univariate logistic regression analysis showed that GGT, CA125, HDL-C, HSI and NAFLD were significantly correlated with the occurrence of EC (P<0.05). Further multivariate logistic regression analysis showed that CA125 and HSI elevation were independent risk factors for EC (P<0.05). Conclusion NAFLD is closely associated with EC, and elevated HSI is an independent risk factor for EC.
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Affiliation(s)
- Lili Zheng
- Department of Gynecology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Huifang Lei
- Department of Gynecology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Xiaoyi Tang
- Department of Laboratory, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Yuanyin Zheng
- Department of Pathology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Qiuzhen Wu
- Department of Pathology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Peixuan Chen
- Department of Gynecology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Yanhong Chen
- Department of Gynecology, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China
| | - Liangzhi Cai
- Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China
- Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fuzhou, People’s Republic of China
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Li Y, Li L, Zhang Y, Lu J, Tang X, Bi C, Qu Y, Chai J. Clinical and pathological characteristics of metabolic dysfunction-associated steatotic liver disease and the key role of epigenetic regulation: implications for molecular mechanism and treatment. Ther Adv Endocrinol Metab 2025; 16:20420188251321602. [PMID: 40098726 PMCID: PMC11912175 DOI: 10.1177/20420188251321602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 01/31/2025] [Indexed: 03/19/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), also called metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent syndrome marked by liver fat accumulation in the absence of significant alcohol consumption, encompassing simple fatty liver, nonalcoholic steatohepatitis (NASH), and advanced stages such as fibrosis and cirrhosis. Its incidence has surged globally, impacting up to 40% of the population, with a doubling of cases in China over a decade. NASH, a severe form, can progress to liver cirrhosis and cancer, posing a substantial health burden, especially among individuals with type 2 diabetes. Projections indicate a steep rise in NASH cases, necessitating urgent interventions beyond lifestyle modifications, such as innovative pharmaceuticals. Early diagnosis is crucial, yet current tools have limitations, highlighting the need for noninvasive, scalable diagnostic approaches. Advances in imaging and biomarker identification offer hope for early detection. Epigenetic factors play a significant role in MASLD pathogenesis, regulating key molecular mechanisms. Addressing MASLD requires a multifaceted approach, integrating lifestyle interventions, pharmacotherapy, and emerging therapeutics, against the backdrop of an evolving landscape in disease management.
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Affiliation(s)
- Yijing Li
- College of Basic Medical Sciences, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Lijie Li
- Department of Pulmonology, Third Affiliated Clinical Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yishuo Zhang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jing Lu
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xiaolei Tang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Chaoran Bi
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Yanan Qu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jingmei Chai
- Medical College, Yanbian University, 3 Gongyuan Road, Yanji, Jilin 133002, China
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Wang JJ, Chen XY, Zhang YR, Shen Y, Zhu ML, Zhang J, Zhang JJ. Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease. Front Physiol 2025; 16:1562848. [PMID: 40166716 PMCID: PMC11955510 DOI: 10.3389/fphys.2025.1562848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.
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Affiliation(s)
- Jun-Jie Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Xiao-Yuan Chen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Yi-Rong Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Yan Shen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Meng-Lin Zhu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun-Jie Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
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Lin B, Wu T, Nasb M, Li Z, Chen N. Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver. Free Radic Biol Med 2025; 230:163-176. [PMID: 39954868 DOI: 10.1016/j.freeradbiomed.2025.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/20/2025] [Accepted: 02/13/2025] [Indexed: 02/17/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms-such as biogenesis, mitophagy, fusion, and fission-within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.
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Affiliation(s)
- Baoxuan Lin
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Tong Wu
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Mohammad Nasb
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Zeyun Li
- Department of Rehabilitation Medicine, Xiangtan Central Hospital, Xiangtan, China.
| | - Ning Chen
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan, China.
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Zhang JW. Role of 1,25-dihydroxyvitamin D 3 in alleviating hepatic steatosis: Targeting M1 macrophage polarization in non-alcoholic fatty liver disease. World J Gastrointest Oncol 2025; 17:102424. [PMID: 40092934 PMCID: PMC11866219 DOI: 10.4251/wjgo.v17.i3.102424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 02/14/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), a critical global health concern, continues to challenge medical researchers with limited treatment options. This letter examines on the study by Luo et al, demonstrating that vitamin D 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] improves hepatic steatosis in NAFLD by inhibiting M1 macrophage polarization via the vitamin D receptor-peroxisome proliferator-activated receptor gamma signaling pathway. This letter critically appraises these findings, comparing them to similar studies, and discusses their potential implications for treating NAFLD. Furthermore, we highlight future directions, including dose optimization and mechanistic studies.
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Affiliation(s)
- Jin-Wei Zhang
- State Key Laboratory of Chemical Biology, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
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Wang Z, Xie X, Xue Y, Chen Y. Tryptophan-2,3-Dioxygenase as a Therapeutic Target in Digestive System Diseases. BIOLOGY 2025; 14:295. [PMID: 40136551 PMCID: PMC11939885 DOI: 10.3390/biology14030295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/06/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
Tryptophan (Trp) is an essential amino acid that must be acquired exclusively through dietary intake. The metabolism of tryptophan plays a critical role in maintaining immune homeostasis and tolerance, as well as in preventing excessive inflammatory responses. Tryptophan-2,3-dioxygenase (TDO2) is a tetrameric heme protein and serves as one of the pivotal rate-limiting enzymes in the first step of tryptophan metabolism. Dysregulation of TDO2 expression has been observed in various digestive system diseases, encompassing those related to the oral cavity, esophagus, liver, stomach, pancreas, and colon and rectum. Digestive system diseases are the most common clinical diseases, with complex clinical manifestations and interrelated symptoms, and have become a research hotspot in the field of medicine. Studies have demonstrated that aberrant TDO2 expression is closely associated with various clinical manifestations and disease outcomes in patients with digestive system disorders. Consequently, TDO2 has garnered increasing recognition as a promising therapeutic target for digestive system diseases in recent years, attracting growing attention. This article provides a brief overview of the role of TDO2 in the tryptophan pathway, emphasizing its significant involvement in diseases of the digestive system. Strategies targeting TDO2 through specific inhibitors suggest considerable promise in enhancing therapeutic outcomes for digestive diseases. Thus, this review concludes by discussing recent advancements in the development of TDO2 inhibitors. We believe that targeted inhibition of TDO2 combined with immunotherapy, the screening of a large number of natural products, and the assistance of artificial intelligence in drug design will be important directions for developing more effective TDO2 inhibitors and improving treatment outcomes in the future.
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Affiliation(s)
| | | | | | - Yixuan Chen
- The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China
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Liang X, Lai K, Li X, Li Y, Xing Z, Gui S. Non-linear relationship between triglyceride glucose index and new-onset diabetes among individuals with non-alcoholic fatty liver disease: a cohort study. Lipids Health Dis 2025; 24:94. [PMID: 40089802 PMCID: PMC11910846 DOI: 10.1186/s12944-025-02518-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/10/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND The relationship between the triglyceride glucose (TyG) values and the development of diabetes in non-alcoholic fatty liver disease (NAFLD) patients is not yet well researched. This study aims to examine how the baseline TyG levels correlate with the incidence of new-onset diabetes in this specific cohort. METHODS This cohort included 2,506 normoglycemic Japanese adults with NAFLD who underwent routine health check-ups at Murakami Memorial Hospital between 2004 and 2015. Several statistical approaches, including restricted cubic splines and two-piecewise linear regression, were utilized to assess the relation between the TyG levels and diabetes risk. RESULTS Among the 2,506 participants (mean age: 44.78 ± 8.32 years; 81.09% male), 203 individuals (8.10%) developed diabetes over the course of the 11-year follow-up period. A U-shaped relationship was observed between the levels of TyG and the onset of diabetes, with an inflection point identified at a TyG value of 7.82 (95% CI: 7.72-8.00). Below this threshold, each one-unit elevation in TyG values reduced the probability of diabetes by 93% (HR = 0.07, 95% CI: 0.01-0.32, P = 0.001). Conversely, above this threshold, each one-unit elevation increased the probability of diabetes by 70% (HR = 1.70, 95% CI: 1.19-2.44, P = 0.004). CONCLUSIONS The findings validate a U-shaped association between TyG levels and new-onset diabetes in adults with NAFLD. Both low and high TyG levels increase diabetes probability in such a group.
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Affiliation(s)
- Xiaomin Liang
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Kai Lai
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xiaohong Li
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ying Li
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China.
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Zemao Xing
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China.
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Shuiqing Gui
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, Shenzhen, China.
- Department of Critical Care Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
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Donghia R, Bonfiglio C, Giannelli G, Tatoli R. Impact of Education on Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Southern Italy Cohort-Based Study. J Clin Med 2025; 14:1950. [PMID: 40142757 PMCID: PMC11943323 DOI: 10.3390/jcm14061950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/07/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Background: An association between education levels and liver disease has been confirmed, but not yet with metabolic dysfunction-associated steatotic liver disease (MASLD). The aim is to investigate the relationship between education and MASLD in two cohorts in southern Italy. Methods: The study cohort included 2909 participants assessed during the third recall of the MICOL study and the second of NUTRIHEP, subdivided into four groups based on education levels. Results: A strong protective association was found between MASLD and higher education levels. Participants had an OR = 0.50 (p < 0.001, 0.36 to 0.69 95% C.I.), OR = 0.29 (p < 0.001, 0.21 to 0.41), and OR = 0.24 (p < 0.001, 0.16 to 0.37 95% C.I.) for middle, high school, and graduate education, respectively. Conclusions: This study's findings indicate that there is an association linking MASLD with education level, i.e., having a lower education level increases the risk of liver disease, and a proper policy to regulate education may also mitigate the ever-increasing problem of this disease.
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Affiliation(s)
- Rossella Donghia
- Data Science Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy; (C.B.); (R.T.)
| | - Caterina Bonfiglio
- Data Science Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy; (C.B.); (R.T.)
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy;
| | - Rossella Tatoli
- Data Science Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy; (C.B.); (R.T.)
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Nakazawa S, Fukai K, Sano K, Furuya Y, Hoshi K, Kojimahara N, Toyota A, Korenaga M, Tatemichi M. Association of occupational physical activity and sedentary behaviour with the risk of hepatocellular carcinoma: a case-control study based on the Inpatient Clinico-Occupational Database of Rosai Hospital Group. BMJ Open 2025; 15:e092020. [PMID: 40074261 PMCID: PMC11904348 DOI: 10.1136/bmjopen-2024-092020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVES While there is growing evidence that physical activity reduces the risk of hepatocellular carcinoma (HCC), the impact of occupational physical activity and sedentary behaviour remains unclear. This study aimed to investigate the associations between occupational physical activity and sedentary behaviour and HCC risk. DESIGN Matched case-control study. SETTING Nationwide multicentre, hospital-inpatient data set in Japan, from 2005 to 2021. PARTICIPANTS The study included 5625 inpatients diagnosed with HCC and 27 792 matched controls without liver disease or neoplasms. Participants were matched based on sex, age, admission date, and hospital. PRIMARY MEASURES The association between levels of occupational physical activity (low, medium, high) and sedentary time (short, medium, long) with the risk of HCC. SECONDARY MEASURES Stratification of HCC risk by viral infection status (hepatitis B/C virus), alcohol consumption levels and the presence of metabolic diseases (hypertension, diabetes, dyslipidaemia, obesity). RESULTS High occupational physical activity was not associated with HCC caused by hepatitis B/C virus infection in men. In women, high occupational physical activity was associated with a reduced risk of non-viral HCC, with ORs (95% CIs) of 0.65 (0.45-0.93). Among patients with non-viral HCC, medium occupational physical activity combined with medium alcohol intake further decreased the HCC risk in men with an OR of 0.70 (0.50-0.97), while high occupational physical activity combined with lowest alcohol intake decreased the HCC risk in women with an OR of 0.69 (0.48-0.99). Men and women with medium sedentary time had a lower HCC risk compared with those with long sedentary time, with ORs of 0.88 (0.79-0.98) in men and 0.77 (0.62-0.97) in women, respectively. In patients without viral infection or alcohol use, medium sedentary time reduced the HCC risk associated with fatty liver disease without comorbid metabolic diseases in women. CONCLUSIONS High levels of occupational physical activity and/or medium periods of sedentary time are associated with a reduced risk of HCC, particularly non-alcoholic steatohepatitis.
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Affiliation(s)
- Shoko Nakazawa
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kei Sano
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuko Furuya
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Keika Hoshi
- Center for Health Informatics Policy, National Institute of Public Health, Wako, Japan
- Department of Hygiene, Kitasato University School of Medicine, Sagamihara, Japan
| | - Noriko Kojimahara
- Department of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Akihiro Toyota
- Chugoku Rosai Hospital Research Center for the Promotion of Health and Employment Support, Japan Organization of Occupational Health and Safety, Hiroshima, Japan
| | - Masaaki Korenaga
- Hepatitis Information Centre, Research Centre for Hepatitis and Immunology, National Centre for Global Health and Medicine, Ichikawa, Japan
| | - Masayuki Tatemichi
- Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Japan
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Li J, Su WW, Wang ZL, Ji XF, Wang JW, Wang K. Identification and verification of biomarkers associated with arachidonic acid metabolism in non-alcoholic fatty liver disease. Sci Rep 2025; 15:8521. [PMID: 40074804 PMCID: PMC11903885 DOI: 10.1038/s41598-025-92972-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Elevated arachidonic acid metabolism (AAM) has been linked to the progression of non-alcoholic fatty liver disease (NAFLD). However, the specific role of AAM-related genes (AAMRGs) in NAFLD remains poorly understood. To investigate the involvement of AAMRGs in NAFLD, this study analyzed datasets GSE89632 and GSE135251 from the Gene Expression Omnibus (GEO) and Molecular Signatures Database (MSigDB). Differential expression analysis revealed 2256 differentially expressed genes (DEGs) between NAFLD and control liver tissues. Cross-referencing these DEGs with AAMRGs identified nine differentially expressed AAMRGs (DE-AAMRGs). Least absolute shrinkage and selection operator (LASSO) and univariate logistic regression analyses pinpointed five biomarkers-CYP2U1, GGT1, PLA2G1B, GPX2, and PTGS1-demonstrating significant diagnostic potential for NAFLD, as validated by receiver operating characteristic (ROC) analysis. These biomarkers were implicated in pathways related to AAM and arachidonate transport. An upstream regulatory network, involving transcription factors (TFs) and MicroRNAs (miRNAs), was constructed to explore the regulatory mechanisms of these biomarkers. In vivo validation using a NAFLD mouse model revealed liver histopathological changes, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) analyses confirmed the upregulation of biomarker expression, particularly PTGS1, in NAFLD. The bioinformatic analysis identified five AAM-related biomarkers, enhancing the understanding of NAFLD pathogenesis and offering potential diagnostic targets.
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Affiliation(s)
- Jia Li
- Qilu Hospital (Qingdao), Department of Hepatology, Shandong University, Qingdao, 266035, China
| | - Wei-Wei Su
- Qilu Hospital (Qingdao), Department of Hepatology, Shandong University, Qingdao, 266035, China
| | - Zhen-Li Wang
- Qilu Hospital (Qingdao), Department of Hepatology, Shandong University, Qingdao, 266035, China
| | - Xiang-Fen Ji
- Qilu Hospital (Qingdao), Department of Hepatology, Shandong University, Qingdao, 266035, China
| | - Jing-Wei Wang
- Qilu Hospital (Qingdao), Department of Hepatology, Shandong University, Qingdao, 266035, China
| | - Kai Wang
- Qilu Hospital, Department of Hepatology, Shandong University, Jinan, 250012, China.
- Hepatology Institute of Shandong University, Jinan, 250012, China.
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Zheng C, Qi Z, Chen R, Liao Z, Xie L, Zhang F. The association between the dietary index for gut microbiota and non-alcoholic fatty liver disease and liver fibrosis: evidence from NHANES 2017-2020. BMC Gastroenterol 2025; 25:163. [PMID: 40075346 PMCID: PMC11899059 DOI: 10.1186/s12876-025-03756-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Imbalance in the gut microbiota is a key factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. The Dietary Index for Gut Microbiota (DI-GM) integrates the potential relationship between diet and gut microbiota diversity. This study aims to investigate the association between DI-GM and the risk of NAFLD and liver fibrosis, providing theoretical support for dietary intervention strategies. METHODS This study utilized data from NHANES 2017-2020, including 6,181 eligible adult participants. The relationship between DI-GM and the risk of NAFLD and liver fibrosis was assessed using DI-GM quartiles, multivariate logistic regression, and restricted cubic spline (RCS) analysis. Subgroup analysis was performed to explore the predictive role of DI-GM in different populations. All analyses were weighted to ensure the representativeness of the results. RESULTS DI-GM was negatively associated with the risks of NAFLD and liver fibrosis. As DI-GM scores increased, the risk of NAFLD and liver fibrosis significantly decreased (52.81%, 43.16%, 40.40%, and 31.98%, p < 0.05; 17.52%, 9.04%, 7.21%, and 6.78%, p < 0.05). Multivariate logistic regression analysis revealed that, in the unadjusted model (Model 1), for each unit increase in DI-GM, the risk of NAFLD decreased by 6.9% (OR = 0.931, 95% CI: 0.886-0.979, p < 0.001), while the risk of liver fibrosis decreased by 15.6% (OR = 0.844, 95% CI: 0.757-0.941, p < 0.05). In the quartile analysis, individuals in the highest DI-GM quartile (Q4) had a 58% lower risk of NAFLD compared to those in the lowest quartile (Q1) (OR = 0.42, 95% CI: 0.219-0.806, p < 0.001). The results remained significant even after adjusting for covariates. RCS analysis showed that DI-GM had a nonlinear relationship with the risks of NAFLD and liver fibrosis, with inflection points at scores of 2 and 5, indicating enhanced protective effects. CONCLUSION This study reveals a negative association between DI-GM and the risk of NAFLD and liver fibrosis, highlighting the potential role of healthy dietary patterns in the prevention and management of NAFLD and liver fibrosis through gut microbiota modulation, providing a theoretical basis for dietary interventions.
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Affiliation(s)
- Ce Zheng
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zeming Qi
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Rui Chen
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zhixiong Liao
- Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Lanfeng Xie
- Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Fumang Zhang
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
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Chowdhury K, Das D, Huang M. Advancing the Metabolic Dysfunction-Associated Steatotic Liver Disease Proteome: A Post-Translational Outlook. Genes (Basel) 2025; 16:334. [PMID: 40149485 PMCID: PMC11941888 DOI: 10.3390/genes16030334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.
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Affiliation(s)
- Kushan Chowdhury
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA; (K.C.); (D.D.)
| | - Debajyoti Das
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA; (K.C.); (D.D.)
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University, Indianapolis, IN 46202, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Melvin & Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Li S, Zhu H, Zhai Q, Hou Y, Yang Y, Lan H, Jiang M, Xuan J. Exploring Mechanisms of Lang Qing Ata in Non-Alcoholic Steatohepatitis Based on Metabolomics, Network Pharmacological Analysis, and Experimental Validation. Drug Des Devel Ther 2025; 19:1681-1701. [PMID: 40098906 PMCID: PMC11911237 DOI: 10.2147/dddt.s503757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 02/28/2025] [Indexed: 03/19/2025] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH), as a progressive form of Non-alcoholic fatty liver disease (NAFLD), poses a significant threat to human health as a prevalent and common condition, with a lack of safe and effective therapeutic options. However, the therapeutic effects and potential mechanisms of Lang Qing Ata (LQAtta) against NASH remain elusive. Materials and Methods The components of LQAtta were identified using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). Subsequently, we employed network construction and analysis approaches within the field of network pharmacology. By integrating known databases and target prediction algorithms, which encompassed database-based target prediction, protein-protein interaction networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we unveiled the potential key targets and signaling pathways that these bioactive components might engage with. These discoveries were further validated in subsequent mouse models. An HFHC-induced NASH mouse model was used to validate the therapeutic effects and potential mechanisms of LQAtta on NASH. Results From the UHPLC-MS/MS analysis of LQAtta, a total of 1518 chemical components were identified, with 106 of them being absorbed into the bloodstream. Additionally, based on the acquisition of targets from both LQAtta and the NASH database, a total of 160 common targets were screened. KEGG enrichment analysis indicated that LQAtta may alleviate NASH by modulating pathways such as the Toll-like receptor signaling pathway, the NF-κB signaling pathway, and inflammation-related pathways. In vivo experimental results demonstrated that LQAtta could alleviate liver injury, steatosis, and inflammation induced by NASH, thereby slowing down the disease process. Additionally, LQAtta inhibited the expression and phosphorylation of NF-κB protein, playing a role in preventing NASH. Conclusion In this study, the combination of mass spectrometry analysis, network pharmacology, and animal experiments preliminarily elucidated the potential of LQAtta to treat NASH through NF-κB pathways.
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Affiliation(s)
- Shupei Li
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Hanlong Zhu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Qi Zhai
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Yu Hou
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ya Yang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Haifeng Lan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Mingzuo Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ji Xuan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
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Wang J, Bao S, An Q, Li C, Feng J. Roles of extracellular vesicles from different origins in metabolic-associated fatty liver disease: progress and perspectives. Front Immunol 2025; 16:1544012. [PMID: 40129979 PMCID: PMC11930831 DOI: 10.3389/fimmu.2025.1544012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/19/2025] [Indexed: 03/26/2025] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Metabolic-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There is a critical lack of reliable non-invasive diagnostic methods and effective pharmaceutical treatments for MAFLD/MASH, emphasizing the need for further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there is a significant gap in literature regarding the roles of EVs from hosts, plants, and microbiota in MAFLD. This review explores the potential of EVs from various sources-host, plants, and microbiota-as biomarkers, therapeutic agents, drug carriers, and treatment targets for MAFLD. Firstly, the roles of host-derived extracellular vesicles (EVs) in MAFLD, with a focus on cell-type specific EVs and their components-proteins, miRNAs, and lipids-for disease diagnosis and monitoring were discussed. Moreover, it highlighted the therapeutic potential of mesenchymal stem cell (MSC)-derived EVs in reducing lipid accumulation and liver injury, and immune cell-derived EVs in mitigating inflammation and fibrosis. The review also discussed the use of host-derived EVs as drug carriers and therapeutic targets due to their ability to deliver bioactive molecules that impact disease mechanisms. Additionally, it summarized research on plant-derived EVs, which help reduce liver lipid accumulation, inflammation, and enhance gut barrier function in MAFLD. Also, the review explored microbial-derived EVs as novel therapeutic targets, particularly in relation to insulin resistance, liver inflammation, and dysfunction in MAFLD. Overall, by exploring the diverse roles of EVs from host, plant, and microbiota sources in MAFLD, this review offers valuable insights into their potential as non-invasive biomarkers and novel therapeutic strategies, which could pave the way for more effective diagnostic and treatment options for this increasingly prevalent liver disease. Notably, the challenges of translating EVs into clinical practice were also thoroughly discussed, aiming to provide possible directions and strategies for future research.
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Affiliation(s)
- Jing Wang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Shuoqiang Bao
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qi An
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Caihong Li
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Juan Feng
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, China
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Xu M, Xu H, Ling YW, Liu JJ, Song P, Fang ZQ, Yue ZS, Duan JL, He F, Wang L. Neutrophil extracellular traps-triggered hepatocellular senescence exacerbates lipotoxicity in non-alcoholic steatohepatitis. J Adv Res 2025:S2090-1232(25)00175-4. [PMID: 40068761 DOI: 10.1016/j.jare.2025.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/19/2025] [Accepted: 03/08/2025] [Indexed: 03/17/2025] Open
Abstract
INTRODUCTION Neutrophils are initial responders in inflammation and contribute to non-alcoholic fatty liver disease (NAFLD) progression to steatohepatitis (NASH). Neutrophil extracellular traps (NETs) are implicated in liver injury, yet their precise mechanisms in NASH progression remains unclear. OBJECTIVES This study investigates how NETs drive NASH progression by exacerbating hepatocyte lipotoxicity and explore the regulatory mechanism of NETs formation and its downstream effects on liver pathology. METHODS Clinical samples from NASH patients and diet-induced NASH mice were analyzed for NET levels. NETs were pharmacologically inhibited, and senescent cells were selectively eliminated in mice. Myeloid-specific RBP-J knockout mice were generated to disrupt Notch signaling, with subsequent evaluation of NET formation, senescence markers, steatosis, fibrosis, and inflammation. RESULTS NETs were elevated in NASH patients and mice, correlating with hepatocyte senescence and lipotoxicity. Pharmacological NET disruption reduced hepatocyte senescence, accompanied by attenuated steatosis and fibrosis. Senescent cell clearance replicated these improvements, confirming liver senescence emerges is a vital step for NETs to promote the progression of NASH. Myeloid-specific Notch signaling ablation suppressed NET generation, concurrently decreasing lipid deposition and liver inflammation. CONCLUSION Our findings elucidate a novel mechanism by which neutrophil-derived Notch driven NETs exacerbate NASH by promoting cell senescence, thereby contributing to hepatic steatosis and fibrosis. This insight may provide potential intervention strategies and therapeutic targets for NASH treatment.
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Affiliation(s)
- Ming Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Hao Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yu-Wei Ling
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jing-Jing Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ping Song
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Zhi-Qiang Fang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Zhen-Sheng Yue
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Juan-Li Duan
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
| | - Fei He
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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Zeng J, Way G, Wu N, Jiang X, Tai YL, Zhao D, Su L, Yan Q, Wang X, Gurley EC, Hylemon PB, Aseem SO, Sanyal AJ, Fan J, Zhou H. Transcriptomics, lipidomics, and single-nucleus RNA sequencing integration: exploring sphingolipids in MASH-HCC progression. Cell Biosci 2025; 15:34. [PMID: 40057751 PMCID: PMC11890728 DOI: 10.1186/s13578-025-01362-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 02/03/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses various conditions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MASLD is a significant risk factor for hepatocellular carcinoma (HCC) and is rapidly becoming the primary cause of liver transplantation. Dysregulated sphingolipid metabolism has been linked to the development of MASH-HCC. However, detailed insight into the sphingolipid profiles and cell type-specific changes in key genes involved in sphingolipid metabolism remains limited and forms the primary focus of this study. APPROACHES & RESULTS This study used the well-characterized diet-induced MASH-HCC mouse model (DIAMOND). Total RNA sequencing data, NanoString nCounter® Gene profiling, and single-nucleus RNA sequencing (snRNA-seq) GEO data (GSE225381) were used in characterizing gene regulation in MASH-HCC progression. Sphingolipids in the serum and liver were profiled using targeted lipidomics. RNA data analysis showed dysregulation of key genes involved in sphingolipid metabolism, including ceramide synthase 6 (Cers6), serine palmitoyltransferase long chain base subunit 2 (Sptlc2), sphingosine kinase 2 (SphK2), and sphingosine-1-phosphate receptor 1-3 (S1pr1-3) which paralleled significant changes in sphingolipid composition and levels in both serum and liver. Furthermore, TCGA-LIHC patient data were analyzed and potential prognostic genes for MASH-HCC were identified using univariate and multivariate Cox analysis. The multivariate Cox analysis underscored the prognostic significance of several genes related to sphingolipid metabolism, including CERS6, SPTLC2, and S1PR1. CONCLUSION Our findings provided valuable insights into the role of sphingolipids in the progression of MASH to HCC. Specific serum and liver sphingolipid profiles may serve as valuable biomarkers for diagnosis and prognosis in MASH-HCC.
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Affiliation(s)
- Jing Zeng
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Grayson Way
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Nan Wu
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Xixian Jiang
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Yun-Ling Tai
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Derrick Zhao
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Lianyong Su
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Qianhua Yan
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Xuan Wang
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Emily C Gurley
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
| | - Phillip B Hylemon
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
| | - Sayed Obaidullah Aseem
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Huiping Zhou
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, 1220 East Broad Street, Richmond, VA, MMRB-5044, 23298-0678, USA.
- Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA.
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Zhang W, Guo J, Miao G, Chen J, Xu Y, Lai P, Zhang L, Han Y, Lam SM, Shui G, Wang Y, Huang W, Xian X. Fat-1 Ameliorates Metabolic Dysfunction-Associated Fatty Liver Disease and Atherosclerosis through Promoting the Nuclear Localization of PPARα in Hamsters. RESEARCH (WASHINGTON, D.C.) 2025; 8:0577. [PMID: 40052160 PMCID: PMC11884683 DOI: 10.34133/research.0577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 03/09/2025]
Abstract
Fat-1, an enzyme encoded by the fat-1 gene, is responsible for the conversion of endogenous omega-6 polyunsaturated fatty acids into omega-3 polyunsaturated fatty acids in Caenorhabditis elegans. To better investigate whether the expression of Fat-1 will exert a beneficial function in dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), we established an adeno-associated virus 9 expressing Fat-1. We found that adeno-associated-virus-mediated expression of Fat-1 markedly reduced the levels of plasma triglycerides and total cholesterol but increased high-density lipoprotein levels in male wild-type hamsters on both chow diet and high-fat diet as well as in chow-diet-fed male LDLR-/- hamsters. Fat-1 ameliorated diet-induced MAFLD in wild-type hamsters by enhancing fatty acid oxidation through the hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent pathway. Mechanistically, Fat-1 increased the levels of multiple lipid derivatives as ligands for PPARα and simultaneously facilitated the nuclear localization of PPARα. Our results provide new insights into the multiple therapeutic potentials of Fat-1 to treat dyslipidemia, MAFLD, and atherosclerosis.
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Affiliation(s)
- Wenxi Zhang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Jiabao Guo
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Guolin Miao
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Jingxuan Chen
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Yitong Xu
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Pingping Lai
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Lianxin Zhang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Yufei Han
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- LipidALL Technologies Company Limited, Changzhou 213022, Jiangsu Province, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuhui Wang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Wei Huang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Xunde Xian
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
- Beijing Key Laboratory of Cardiovascular Receptors Research,
Peking University Third Hospital, Beijing 100191, China
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Du X, Li DL, Xu X, Wu Y, Du Z, Liang G, Li YZ, Zheng YJ, Qin Y, Qian K, Xu J, Gao L, Tao G, Pan CW, Zheng W. Effects of mixed exposure to PFAS on adolescent non-alcoholic fatty liver disease: Integrating evidence from human cohorts, toxicogenomics, and animal models to uncover mechanisms and potential target sites. JOURNAL OF HAZARDOUS MATERIALS 2025; 485:136854. [PMID: 39706014 DOI: 10.1016/j.jhazmat.2024.136854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/25/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024]
Abstract
Extensive evidence suggests a correlation between environmental pollutants, specifically perfluoroalkyl and polyfluoroalkyl substances (PFAS) and non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the association and underlying mechanisms of PFAS-induced NAFLD in adolescents by employing a comprehensive approach of population-based studies, toxicogenomics, and animal models. A total of 2014 freshmen from Dali University were recruited for this study, with 1694 participants undergoing serum testing for PFAS exposure. Additionally, Comparative Toxicogenomics Database analysis and PFAS exposure experiments were conducted by orally administering PFAS to 8-week-old adult C57/6 J mice for 28 days. Epidemiological analysis of the adolescent cohort revealed that perfluorohexanesulfonic acid and perfluorooctanoic acid are significant risk factors for NAFLD in adolescents. Toxicogenomic analysis revealed that the negative regulation of gap junction assembly and glutathione derivative biosynthesis contributes to NAFLD development. Animal model studies further demonstrated that combined PFAS exposure led to pathological changes in hepatocytes, including inflammation and steatosis, elevated liver enzymes, cholestasis, and bile canalicular blockage. This study reveals that PFAS exposure serves as a significant risk factor for hepatic steatosis/NAFLD in adolescents. The activation of cytochrome P4502E1 and glutathione S-transferase A1 signaling highlights new molecular targets for PFAS-induced disruptions in hepatic lipid metabolism.
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Affiliation(s)
- Xiushuai Du
- Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China; Key Laboratory of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, Shanghai 200032, China
| | - Dan-Lin Li
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Xueming Xu
- Clinical Medical Research Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yitian Wu
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China
| | - Zhiyuan Du
- Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China; Key Laboratory of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, Shanghai 200032, China
| | - Gang Liang
- Department of Ophthalmology, the Affiliated Hospital of Yunnan University, Kunming, China; Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Yue-Zu Li
- Department of Ophthalmology, the Affiliated Hospital of Yunnan University, Kunming, China; Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Ya-Jie Zheng
- Department of Ophthalmology, the Affiliated Hospital of Yunnan University, Kunming, China; Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Yu Qin
- Department of Ophthalmology, the Affiliated Hospital of Yunnan University, Kunming, China; Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Kelei Qian
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China
| | - Jing Xu
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China
| | - Liping Gao
- Department of Laboratory Medicine, Huangpu Branch, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Gonghua Tao
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China.
| | - Chen-Wei Pan
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China.
| | - Weiwei Zheng
- Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, China; Key Laboratory of Health Technology Assessment, National Health Commission of the People's Republic of China, Fudan University, Shanghai 200032, China; Center for Water and Health, School of Public Health, Fudan University, Shanghai 200032, China.
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50
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Hu Z, Yue H, Jiang N, Qiao L. Diet, oxidative stress and MAFLD: a mini review. Front Nutr 2025; 12:1539578. [PMID: 40104813 PMCID: PMC11913703 DOI: 10.3389/fnut.2025.1539578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
Globally, metabolic dysfunction-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), is a common chronic liver disease. The progression of MAFLD leads to a vicious cycle in which oxidative stress results from the disease that is augmenting de-novo lipid levels and increases steatosis. Most non-enzymatic antioxidants are present in food. Therefore, the present review summarizes the findings of studies on food-derived antioxidants and presents an oxidative stress-related regulatory network in MAFLD, offering new ideas for MAFLD prevention and treatment.
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Affiliation(s)
- Zenan Hu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hanxun Yue
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Na Jiang
- School of Public Health, Lanzhou University, Lanzhou, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, NSW, Australia
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