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1
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Jönsson C, Ma'ayeh S, Zhang B, Kechagias S, Liljeblad M, Nasr P, Hansson SF, Ekstedt M. Vascular endothelial growth factor A, a potential non-invasive biomarker for metabolic dysfunction-associated steatotic liver disease progression. Clin Biochem 2025; 137:110920. [PMID: 40127834 DOI: 10.1016/j.clinbiochem.2025.110920] [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: 09/09/2024] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 03/26/2025]
Abstract
INTRODUCTION AND OBJECTIVES Liver fibrosis is the primary predictor of complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, there are currently no non-invasive prognostic tests to stratify patients at risk for hepatic fibrosis progression. This study aimed to explore whether plasma proteins could serve as non-invasive biomarkers for monitoring MASLD disease progression. MATERIALS AND METHODS Blood plasma protein analysis was performed on samples from a long-term follow-up study of patients with MASLD with repeated liver biopsies. Over 1100 proteins covering a broad range of biological processes were analyzed using 13 Olink® Target 96 panels. Protein level changes were compared between the different time points and between patients with or without an increase in the liver fibrosis stage between the two biopsies. RESULTS Increased vascular endothelial growth factor A (VEGFA) plasma levels were significantly associated with liver fibrosis progression in patients with a histologically assessed increase in the fibrosis stage. CONCLUSIONS These findings suggest that the plasma protein VEGFA may be an effective biomarker for monitoring fibrosis progression in patients with MASLD.
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Affiliation(s)
- Cecilia Jönsson
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden.
| | | | | | - Stergios Kechagias
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden.
| | - Mathias Liljeblad
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Göteborg, Sweden.
| | - Patrik Nasr
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden; Wallenberg Centre for Molecular Medicine, Linköping University, Sweden.
| | - Sara F Hansson
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Göteborg, Sweden.
| | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden.
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2
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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [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: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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3
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Li P, Ying S, Zou Y, Wang X, Zhang R, Huang C, Dai M, Xu K, Feng G, Li X, Jiang H, Li Z, Zhang Y, Li W, Zhou Q. NSun2-Mediated tsRNAs Alleviate Liver Fibrosis via FAK Dephosphorylation. Cell Prolif 2025:e70058. [PMID: 40355098 DOI: 10.1111/cpr.70058] [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: 02/23/2025] [Revised: 04/13/2025] [Accepted: 04/22/2025] [Indexed: 05/14/2025] Open
Abstract
Sinusoidal capillarization - key symptoms of liver fibrosis progression - represents potential therapeutic targets. tRNA modification-mediated tRNA-derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF-1-S25 and tRF-5-V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK - crucial clinical targets. Moreover, intravenous injection of tRF-1-S25 and tRF-5-V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2-mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p-FAK pathway offers an innovative approach to treat this disease.
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Affiliation(s)
- Pengcheng Li
- College of Life Science, Northeast Agricultural University of China, Harbin, China
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Sunyang Ying
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yu Zou
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xin Wang
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Runxue Zhang
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Cheng Huang
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Moyu Dai
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kai Xu
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Guihai Feng
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Xin Li
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Haiping Jiang
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Zhikun Li
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Ying Zhang
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Wei Li
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Qi Zhou
- College of Life Science, Northeast Agricultural University of China, Harbin, China
- State key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
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4
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Hernandez R, Garcia-Rodriguez NS, Arriaga MA, Perez R, Bala AA, Leandro AC, Diego VP, Almeida M, Parsons JG, Manusov EG, Galan JA. The hepatocellular model of fatty liver disease: from current imaging diagnostics to innovative proteomics technologies. Front Med (Lausanne) 2025; 12:1513598. [PMID: 40109726 PMCID: PMC11919916 DOI: 10.3389/fmed.2025.1513598] [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: 10/18/2024] [Accepted: 02/06/2025] [Indexed: 03/22/2025] Open
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition characterized by lipid accumulation and inflammation, often progressing to severe liver damage. We aim to review the pathophysiology, diagnostics, and clinical care of MASLD, and review highlights of advances in proteomic technologies. Recent advances in proteomics technologies have improved the identification of novel biomarkers and therapeutic targets, offering insight into the molecular mechanisms underlying MASLD progression. We focus on the application of mass spectrometry-based proteomics including single cell proteomics, proteogenomics, extracellular vesicle (EV-omics), and exposomics for biomarker discovery, emphasizing the potential of blood-based panels for noninvasive diagnosis and personalized medicine. Future research directions are presented to develop targeted therapies and improve clinical outcomes for MASLD patients.
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Affiliation(s)
- Renee Hernandez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Natasha S Garcia-Rodriguez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marco A Arriaga
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ricardo Perez
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Auwal A Bala
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Ana C Leandro
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Vince P Diego
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Marcio Almeida
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jason G Parsons
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Eron G Manusov
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
| | - Jacob A Galan
- Division of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
- South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, United States
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5
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Milošević N, Milanović M, Medić Stojanoska M, Tipmanee V, Smyrnioudis I, Dedoussis GV, Milić N. Triterpenoids from Chios Mastiha Resin Against MASLD-A Molecular Docking Survey. Curr Issues Mol Biol 2025; 47:51. [PMID: 39852166 PMCID: PMC11763944 DOI: 10.3390/cimb47010051] [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: 12/06/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 01/26/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease without an approved pharmacological approach for its prevention/treatment. Based on the modified Delphi process, NAFLD was redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to highlight the metabolic aspect of liver pathogenesis. Chios mastiha (Pistacia lentiscus var. Chia, Anacardiaceae) resin demonstrated promising results in MASLD treatment. In this paper, molecular docking was applied to test 16 compounds from Chios mastiha as potential ligands for the receptors GR, LXRα, LXRβ, PPARα PPARγ, MC4R, AMPK, and VEGFR2, whose up- and down-regulation interfere with MASLD development and progression. The observed compounds had moderate and high affinity for LXR, GR, MC4R, and PPARγ in comparison to proven ligands, while their affinity for PPARα, AMPK, and VEGFR was less pronounced. The combination of active compounds from Chios mastiha rather than a single molecule may have a superior ability to control the intertwined MASLD metabolic pathways.
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Affiliation(s)
- Nataša Milošević
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (N.M.); (N.M.)
| | - Maja Milanović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (N.M.); (N.M.)
| | - Milica Medić Stojanoska
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
- University Clinical Center of Vojvodina, 21000 Novi Sad, Serbia
| | - Varomyalin Tipmanee
- Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand;
| | | | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 17671 Athens, Greece;
| | - Nataša Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (N.M.); (N.M.)
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6
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He Y, Xiao F, Yi B, Lu J. Prevalence and associated factors of MAFLD in adults with type 2 diabetes. PLOS GLOBAL PUBLIC HEALTH 2024; 4:e0003572. [PMID: 39775020 PMCID: PMC11684647 DOI: 10.1371/journal.pgph.0003572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 11/03/2024] [Indexed: 01/11/2025]
Abstract
To estimate the prevalence and associated factors of hepatic steatosis and fibrosis in adults with type 2 diabetes (T2DM) in the United States.Data were retrieved from the 2017‒March 2020 prepandemic cycle of the National Health and Nutritional Examination and Survey (NHANES). The study population included patients with T2DM. The controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were used to assess hepatic steatosis and fibrosis, respectively. A total of 1,290 T2DM patients were included, 85.2% (1044 patients) of whom presented with hepatic steatosis (CAP>248 dB/m). Among the 1044 T2DM patients with metabolically associated fatty liver disease (MAFLD), 29.5% developed hepatic fibrosis (LSM>8 kPa). Non-Hispanic black individuals (adjusted OR = 0.4008), BMI (adjusted OR = 1.1627), HbA1c (adjusted OR = 1.1450), TG (adjusted OR = 1.2347), HDL (adjusted OR = 0.4981), ALT (adjusted OR = 1.0227), AST (adjusted OR = 0.9396), and albumin (adjusted OR = 1.7030) were independently associated with steatosis. Age (adjusted OR = 1.0300), female sex (adjusted OR = 0.6655), BMI (adjusted OR = 1.1324), AST (adjusted OR = 1.0483), and GGT (adjusted OR = 1.0101) were independently associated with fibrosis. Heart failure was an independent factor associated with advanced fibrosis (adjusted OR = 1.9129) and cirrhosis (adjusted OR = 2.228). In the United States, hepatic steatosis is highly prevalent among T2DM patients, with 29.5% of these patients developing hepatic fibrosis. Some components of metabolic syndrome are related to hepatic steatosis and fibrosis. Moreover, heart failure is an independent factor associated with advanced fibrosis and cirrhosis.
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Affiliation(s)
- Yifei He
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Feng Xiao
- Department of Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Bin Yi
- Department of Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
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7
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Xu S, Zhang Y, Huang Q, Xie Y, Tong X, Liu H. Bibliometric analysis of autophagy in NAFLD from 2004 to 2023. Medicine (Baltimore) 2024; 103:e40835. [PMID: 39654183 PMCID: PMC11630950 DOI: 10.1097/md.0000000000040835] [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: 06/18/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Autophagy is a cellular process in which damaged organelles or unnecessary proteins are encapsulated into double-membrane structures and transported to lysosomes for degradation. Autophagy plays a crucial role in various liver diseases, including nonalcoholic fatty liver disease. This study aims to elucidate the role of autophagy in nonalcoholic fatty liver disease through bibliometric analysis. METHODS Literature was retrieved from Web of Science CoreCollection database, and the search time was from January 01, 2004 to December 31, 2023. Data retrieval was performed using the Bibliometrix package in R software. VOSviewer and CiteSpace were utilized to visualize the research hotspots and trends related to the effect of autophagy on nonalcoholic fatty liver disease. RESULTS A total of 966 papers were obtained, published in 343 journals from 1385 institutions across 57 countries. The journals with the most publications were the "International Journal of Molecular Sciences" and "Scientific Reports." China had the highest number of published papers. The most productive authors were Yen Paul M and Jung Tae Woo, while Singh R was the most frequently co-cited author. Emerging research hotspots were associated with keywords such as insulin resistance, ferroptosis, endoplasmic reticulum stress, and mitochondrial function. CONCLUSION Research on autophagy in nonalcoholic fatty liver disease is still in its early stages, with a growing body of literature. This study is the first to provide a comprehensive bibliometric analysis, synthesizing research trends and advancements. It identifies current development trends, global cooperation models, foundational knowledge, research hotspots, and emerging frontiers in the field.
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Affiliation(s)
- Sumei Xu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yating Zhang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Qi Huang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yiwen Xie
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiaojuan Tong
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Haoge Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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Wen W, Fan H, Zhang S, Hu S, Chen C, Tang J, You Y, Wang C, Li J, Luo L, Cheng Y, Zhou M, Zhao X, Tan T, Xu F, Fu X, Chen J, Dong P, Zhang X, Wang M, Feng Y. Associations between metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Am J Med Sci 2024; 368:557-568. [PMID: 38944203 DOI: 10.1016/j.amjms.2024.06.022] [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: 07/29/2023] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/01/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely related to metabolic syndrome and remains a major global health burden. The increased prevalence of obesity and type 2 diabetes mellitus (T2DM) worldwide has contributed to the rising incidence of NAFLD. It is widely believed that atherosclerotic cardiovascular disease (ASCVD) is associated with NAFLD. In the past decade, the clinical implications of NAFLD have gone beyond liver-related morbidity and mortality, with a majority of patient deaths attributed to malignancy, coronary heart disease (CHD), and other cardiovascular (CVD) complications. To better define fatty liver disease associated with metabolic disorders, experts proposed a new term in 2020 - metabolic dysfunction associated with fatty liver disease (MAFLD). Along with this new designation, updated diagnostic criteria were introduced, resulting in some differentiation between NAFLD and MAFLD patient populations, although there is overlap. The aim of this review is to explore the relationship between MAFLD and ASCVD based on the new definitions and diagnostic criteria, while briefly discussing potential mechanisms underlying cardiovascular disease in patients with MAFLD.
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Affiliation(s)
- Wen Wen
- Department of Cardiology, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, 313000, Zhejiang, China
| | - Hua Fan
- School of Clinical Medicine, The First Affiliated Hospital of Henan University of Science and Technology, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Shenghui Zhang
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Siqi Hu
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Chen Chen
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Jiake Tang
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Yao You
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Chunyi Wang
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Jie Li
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Lin Luo
- Hangzhou Ruolin Hospital Management Co. Ltd, Hangzhou, 310007, China
| | - Yongran Cheng
- School of Public Health, Hangzhou Medical College, Hangzhou, 311300, China
| | - Mengyun Zhou
- Department of Molecular & Cellular Physiology, Shinshu University School of Medicine, 3900803, Japan
| | - Xuezhi Zhao
- Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang, China
| | - Tao Tan
- Faculty of Applied Science, Macao Polytechnic University, Macao SAR, 999078, China
| | - Fangfang Xu
- Strategy Research and Knowledge Information Center, SAIC Motor Group, 200030, Shanghai, China
| | - Xinyan Fu
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Juan Chen
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Peng Dong
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Xingwei Zhang
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China
| | - Mingwei Wang
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China.
| | - Yan Feng
- Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Institute of Cardiovascular Diseases, Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou, 310015, Hangzhou Lin'an Fourth People's Hospital, Hangzhou 311321, China.
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9
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Sharma J, Gupta P, Shalimar, Mohan P. Serum trace element alterations in Indian patients with metabolic dysfunction-associated steatotic liver disease. Indian J Gastroenterol 2024; 43:845-848. [PMID: 38703301 DOI: 10.1007/s12664-024-01587-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2024]
Affiliation(s)
- Jatin Sharma
- Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Pooja Gupta
- Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India.
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110 029, India
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Sun HJ, Jiao B, Wang Y, Zhang YH, Chen G, Wang ZX, Zhao H, Xie Q, Song XH. Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions. World J Gastroenterol 2024; 30:1968-1981. [PMID: 38681120 PMCID: PMC11045491 DOI: 10.3748/wjg.v30.i14.1968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/15/2024] [Accepted: 03/25/2024] [Indexed: 04/12/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.
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Affiliation(s)
- Hong-Ju Sun
- Department of General Medicine, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Bo Jiao
- Department of General Medicine, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Yan Wang
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Yue-Hua Zhang
- Department of Medical Administration, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Ge Chen
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
- Qingdao Medical College, Qingdao University, Qingdao 266042, Shandong Province, China
| | - Zi-Xuan Wang
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
- Qingdao Medical College, Qingdao University, Qingdao 266042, Shandong Province, China
| | - Hong Zhao
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiao-Hua Song
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
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11
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Zhang B, Li J, Zeng C, Tao C, He Q, Liu C, Zheng Z, Zhao Z, Mou S, Sun W, Wang J, Zhang Q, Wang R, Zhang Y, Ge P, Zhang D. Nonalcoholic fatty liver disease is an independent risk factor for ischemic stroke after revascularization in patients with Moyamoya disease: a prospective cohort study. Lipids Health Dis 2024; 23:80. [PMID: 38494486 PMCID: PMC10944598 DOI: 10.1186/s12944-024-02065-5] [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: 10/16/2023] [Accepted: 02/27/2024] [Indexed: 03/19/2024] Open
Abstract
BACKGROUND The study aimed to investigate the association between nonalcoholic fatty liver disease (NAFLD) and ischemic stroke events after revascularization in patients with Moyamoya disease (MMD). METHODS This study prospectively enrolled 275 MMD patients from September 2020 to December 2021. Patients with alcoholism and other liver diseases were excluded. NAFLD was confirmed by CT imaging or abdominal ultrasonography. Stroke events and modified Rankin Scale (mRS) scores at the latest follow-up were compared between the two groups. RESULTS A total of 275 patients were enrolled in the study, among which 65 were diagnosed with NAFLD. Univariate logistic regression analysis showed that NAFLD (P = 0.029) was related to stroke events. Multivariate logistic regression analysis showed that NAFLD is a predictor of postoperative stroke in MMD patients (OR = 27.145, 95% CI = 2.031-362.81, P = 0.013). Kaplan-Meier analysis showed that compared with MMD patients with NAFLD, patients in the control group had a longer stroke-free time (P = 0.004). Univariate Cox analysis showed that NAFLD (P = 0.016) was associated with ischemic stroke during follow-up in patients with MMD. Multivariate Cox analysis showed that NAFLD was an independent risk factor for stroke in patients with MMD (HR = 10.815, 95% CI = 1.259-92.881, P = 0.030). Furthermore, fewer patients in the NAFLD group had good neurologic status (mRS score ≤ 2) than the control group (P = 0.005). CONCLUSION NAFLD was an independent risk factor for stroke in patients with MMD after revascularization and worse neurological function outcomes.
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Affiliation(s)
- Bojian Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Junsheng Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chaofan Zeng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chuming Tao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Qiheng He
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chenglong Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Zhiyao Zheng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Zhikang Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Siqi Mou
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Wei Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Jia Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Qian Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Rong Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Yan Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Peicong Ge
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases, Beijing, China.
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China.
| | - Dong Zhang
- Department of Neurosurgery, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
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12
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Zuo B, Yang F, Huang L, Han J, Li T, Ma Z, Cao L, Li Y, Bai X, Jiang M, He Y, Xia L. Endothelial Slc35a1 Deficiency Causes Loss of LSEC Identity and Exacerbates Neonatal Lipid Deposition in the Liver in Mice. Cell Mol Gastroenterol Hepatol 2024; 17:1039-1061. [PMID: 38467191 PMCID: PMC11061248 DOI: 10.1016/j.jcmgh.2024.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND & AIMS The functional maturation of the liver largely occurs after birth. In the early stages of life, the liver of a newborn encounters enormous high-fat metabolic stress caused by the consumption of breast milk. It is unclear how the maturing liver adapts to high lipid metabolism. Liver sinusoidal endothelial cells (LSECs) play a fundamental role in establishing liver vasculature and are decorated with many glycoproteins on their surface. The Slc35a1 gene encodes a cytidine-5'-monophosphate (CMP)-sialic acid transporter responsible for transporting CMP-sialic acids between the cytoplasm and the Golgi apparatus for protein sialylation. This study aimed to determine whether endothelial sialylation plays a role in hepatic vasculogenesis and functional maturation. METHODS Endothelial-specific Slc35a1 knockout mice were generated. Liver tissues were collected for histologic analysis, lipidomic profiling, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. RESULTS Endothelial Slc35a1-deficient mice exhibited excessive neonatal hepatic lipid deposition, severe liver damage, and high mortality. Endothelial deletion of Slc35a1 led to sinusoidal capillarization and disrupted hepatic zonation. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) in LSECs was desialylated and VEGFR2 signaling was enhanced in Slc35a1-deficient mice. Inhibition of VEGFR2 signaling by SU5416 alleviated lipid deposition and restored hepatic vasculature in Slc35a1-deficient mice. CONCLUSIONS Our findings suggest that sialylation of LSECs is critical for maintaining hepatic vascular development and lipid homeostasis. Targeting VEGFR2 signaling may be a new strategy to prevent liver disorders associated with abnormal vasculature and lipid deposition.
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Affiliation(s)
- Bin Zuo
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Fei Yang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lulu Huang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Han
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tianyi Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenni Ma
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lijuan Cao
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yun Li
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xia Bai
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Miao Jiang
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang He
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Engineering Center of Hematological Disease of Ministry of Education, Cyrus Tang Hematology Center, Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Lijun Xia
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Key Laboratory of Thrombosis and Hemostasis of National Health Commission, The First Affiliated Hospital of Soochow University, Suzhou, China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
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13
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Ke Z, Huang Y, Xu J, Liu Y, Zhang Y, Wang Y, Zhang Y, Liu Y. Escherichia coli NF73-1 disrupts the gut-vascular barrier and aggravates high-fat diet-induced fatty liver disease via inhibiting Wnt/β-catenin signalling pathway. Liver Int 2024; 44:776-790. [PMID: 38225740 DOI: 10.1111/liv.15823] [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: 09/12/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 01/17/2024]
Abstract
BACKGROUND & AIMS Gut-vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli (E. coli) NF73-1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB. METHODS C57BL/6J mice were fed with high-fat diet (HFD) or normal diet in the presence or absence of E. coli NF73-1 for the indicated time periods. Intestinal barrier function and infiltration of immune cells were evaluated in these mice. Endothelial cells were exposed to E. coli NF73-1 for barrier integrity analysis. RESULTS HFD-induced GVB disruption preceded the damage of intestinal epithelial barrier (IEB) as well as intestinal and hepatic inflammatory changes and can be reversed by vascular endothelial growth factor A blockade. Antibiotic treatment prevented mice from HFD-induced liver steatosis by restoration of the GVB. Notably, E. coli NF73-1 caused a more conspicuous damage of GVB than that of the IEB and contributed to NAFLD development. Mechanistically, E. coli NF73-1 dismantled the GVB by inhibiting the Wnt/β-catenin signalling pathway. Activation of Wnt/β-catenin improved the GVB and impeded the translocation of E. coli NF73-1 into the liver in vitro and in vivo. CONCLUSIONS E. coli NF73-1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β-catenin signalling pathway. Targeting E. coli NF73-1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD.
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Affiliation(s)
- Ziliang Ke
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yibo Huang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Jun Xu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yun Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yu Zhang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yifan Zhang
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China
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14
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [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: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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15
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Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development. Mol Cell Pediatr 2023; 10:16. [PMID: 37957462 PMCID: PMC10643747 DOI: 10.1186/s40348-023-00170-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. MAIN TEXT Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies.
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Affiliation(s)
- Lisa Ruck
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany.
| | - Susanna Wiegand
- Abteilung Interdisziplinär, Sozial-Pädiatrisches Zentrum, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Kühnen
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Mitten EK, Portincasa P, Baffy G. Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms. J Clin Transl Hepatol 2023; 11:1201-1211. [PMID: 37577237 PMCID: PMC10412712 DOI: 10.14218/jcth.2023.00029] [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: 01/31/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 07/03/2023] Open
Abstract
Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient (PPG) between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient (HVPG), which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein. By convention, HVPG≥10 mmHg indicates clinically significant portal hypertension, which is associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) is a common disorder with a heterogeneous clinical course, which includes the development of portal hypertension. There is increasing evidence that portal hypertension in NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis in NAFLD, suggesting a bidirectional relationship between these pathological processes. Second, HVPG underestimates PPG in NAFLD, suggesting that portal hypertension is more prevalent in this condition than currently believed. Third, cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressure-fibrosis paradigm. Finally, a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease.
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Affiliation(s)
- Emilie K. Mitten
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Piero Portincasa
- Division of Internal Medicine and Department of Precision and Regenerative Medicine and Ionian Area, University ‘Aldo Moro’ Medical School, Bari, Italy
| | - György Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA
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Velliou RI, Legaki AI, Nikolakopoulou P, Vlachogiannis NI, Chatzigeorgiou A. Liver endothelial cells in NAFLD and transition to NASH and HCC. Cell Mol Life Sci 2023; 80:314. [PMID: 37798474 PMCID: PMC11072568 DOI: 10.1007/s00018-023-04966-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/04/2023] [Accepted: 09/15/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, which is characterised by obesity, insulin resistance, hypercholesterolemia and hypertension. NAFLD is the most frequent liver disease worldwide and more than 10% of NAFLD patients progress to the inflammatory and fibrotic stage of non-alcoholic steatohepatitis (NASH), which can lead to end-stage liver disease including hepatocellular carcinoma (HCC), the most frequent primary malignant liver tumor. Liver sinusoidal endothelial cells (LSEC) are strategically positioned at the interface between blood and hepatic parenchyma. LSECs are highly specialized cells, characterised by the presence of transcellular pores, called fenestrae, and exhibit anti-inflammatory and anti-fibrotic characteristics under physiological conditions. However, during NAFLD development they undergo capillarisation and acquire a phenotype similar to vascular endothelial cells, actively promoting all pathophysiological aspects of NAFLD, including steatosis, inflammation, and fibrosis. LSEC dysfunction is critical for the progression to NASH and HCC while restoring LSEC homeostasis appears to be a promising approach to prevent NAFLD progression and its complications and even reverse tissue damage. In this review we present current information on the role of LSEC throughout the progressive phases of NAFLD, summarising in vitro and in vivo experimental evidence and data from human studies.
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Affiliation(s)
- Rallia-Iliana Velliou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Polyxeni Nikolakopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Nikolaos I Vlachogiannis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece.
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
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Shi SY, Jia F, Wang MF, Zhou YF, Li JJ. Impacts of Non-alcoholic Fatty Liver Disease on Acute Coronary Syndrome: Evidence and Controversies. Curr Atheroscler Rep 2023; 25:751-768. [PMID: 37768409 PMCID: PMC10564833 DOI: 10.1007/s11883-023-01146-7] [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] [Accepted: 08/23/2023] [Indexed: 09/29/2023]
Abstract
PURPOSE OF REVIEW Acute coronary syndrome (ACS) and non-alcoholic fatty liver disease (NAFLD) are two clinically common disease entities that share numerous risk factors. This review aimed to discuss the impacts of NAFLD on ACS. RECENT FINDINGS In an era of improved control of traditional risk factors, the substantial burden of cardiometabolic abnormalities has caused widespread concern. NAFLD is considered the hepatic component of metabolic syndrome, which can exert an impact on human health beyond the liver. Accumulating studies have demonstrated that NAFLD is closely related to cardiovascular disease, especially coronary artery disease. Interestingly, although recent data have suggested an association between NAFLD and the incidence and outcomes of ACS, the results are not consistent. In this review, we comprehensively summarized evidence and controversies regarding whether NAFLD is a contributor to either the development of ACS or worse outcomes in patients with ACS. The potential pathophysiological and molecular mechanisms involved in the impacts of NAFLD on ACS were also elucidated.
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Affiliation(s)
- Shun-Yi Shi
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Fang Jia
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Meng-Fei Wang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ya-Feng Zhou
- Department of Cardiology, Suzhou Dushu Lake Hospital, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou, China
| | - Jian-Jun Li
- Cardio-Metabolism Center, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 10037, China.
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Niranjan S, Phillips BE, Giannoukakis N. Uncoupling hepatic insulin resistance - hepatic inflammation to improve insulin sensitivity and to prevent impaired metabolism-associated fatty liver disease in type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1193373. [PMID: 37396181 PMCID: PMC10313404 DOI: 10.3389/fendo.2023.1193373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/01/2023] [Indexed: 07/04/2023] Open
Abstract
Diabetes mellitus is a metabolic disease clinically-characterized as acute and chronic hyperglycemia. It is emerging as one of the common conditions associated with incident liver disease in the US. The mechanism by which diabetes drives liver disease has become an intense topic of discussion and a highly sought-after therapeutic target. Insulin resistance (IR) appears early in the progression of type 2 diabetes (T2D), particularly in obese individuals. One of the co-morbid conditions of obesity-associated diabetes that is on the rise globally is referred to as non-alcoholic fatty liver disease (NAFLD). IR is one of a number of known and suspected mechanism that underlie the progression of NAFLD which concurrently exhibits hepatic inflammation, particularly enriched in cells of the innate arm of the immune system. In this review we focus on the known mechanisms that are suspected to play a role in the cause-effect relationship between hepatic IR and hepatic inflammation and its role in the progression of T2D-associated NAFLD. Uncoupling hepatic IR/hepatic inflammation may break an intra-hepatic vicious cycle, facilitating the attenuation or prevention of NAFLD with a concurrent restoration of physiologic glycemic control. As part of this review, we therefore also assess the potential of a number of existing and emerging therapeutic interventions that can target both conditions simultaneously as treatment options to break this cycle.
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Affiliation(s)
- Sitara Niranjan
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Brett E. Phillips
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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Bulatova IA, Shevlyukova TP, Gulyaeva IL, Sobol AA, Paducheva SV. Indicators of the hemostasis system and markers of endothelial damage in patients with steatosis and liver fibrosis. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2023:106-112. [DOI: 10.21518/ms2022-039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction. According to the analysis of indicators of the hemostasis system in liver pathology, there are multidirectional data in the literature, which may be associated with the examination of patients with varying degrees of severity and etiology of the process. Aim. The aim of the study was to study the indicators of hemostasis and markers of endothelial damage in patients with non-alcoholic steatosis and liver fibrosis of viral etiology. Materials and methods. A total of 64 people were examined. The first group included 32 patients with non-alcoholic liver steatosis on the background of obesity of 1–2 degrees, with an average age of 46.3 ± 4.3 years (12 men and 20 women). The second group consisted of 22 patients with liver fibrosis on the background of chronic hepatitis C (HCV) with an average age of 36.8 ± 4.7 years (12 men and 10 women). The control group included 10 practically healthy individuals with an average age of 38.9 ± 5.3 years without liver pathology. The number of platelets, platelet aggregation with ADP inducers, collagen and ristocetin, functional activity of Willebrand factor (vWF), coagulation hemostasis and fibrinolysis system, and serum concentration of vascular endothelial growth factor (VEGF) were determined. Statistical processing of the obtained data was carried out using the program “Stat2015”. Results. Induced platelet aggregation in steatosis and liver fibrosis significantly decreased with ADP agonists and collagen against the background of a normal platelet count. In both study groups, signs of endothelial damage with a tendency to increase the functional activity of vWF and VEGF hyperproduction were found. An elongation of thrombin time was also recorded, more significantly in patients with steatosis. Conclusion. Patients with non-alcoholic liver steatosis and liver fibrosis on the background of HCV are characterized by disorders in the vascular-platelet (endothelial damage and thrombocytopathy in the form of platelet hypocoagulation) and coagulation (hypocoagulation) links of hemostasis.
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van Son KC, Verschuren L, Hanemaaijer R, Reeves H, Takkenberg RB, Drenth JPH, Tushuizen ME, Holleboom AG. Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2023; 15:1308. [PMID: 36831649 PMCID: PMC9954729 DOI: 10.3390/cancers15041308] [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: 12/23/2022] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.
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Affiliation(s)
- Koen C. van Son
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lars Verschuren
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Roeland Hanemaaijer
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Adriaan G. Holleboom
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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24
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Mitten EK, Baffy G. Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 2022; 77:1642-1656. [PMID: 36063966 DOI: 10.1016/j.jhep.2022.08.028] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/09/2022] [Accepted: 08/17/2022] [Indexed: 12/14/2022]
Abstract
Mechanobiology is a domain of interdisciplinary research that aims to explore the impact of physical force, applied externally or internally, on cell and tissue function, including development, growth, and differentiation. Mechanotransduction is a term that describes how cells sense physical forces (such as compression, stretch, and shear stress), convert them into biochemical signals, and mount adaptive responses integrated by the nucleus. There is accumulating evidence that mechanical forces extensively inform the biological behaviour of liver cells in health and disease. Recent research has elucidated many cellular and molecular mechanisms involved in this process including the pleiotropic control and diverse effects of the paralogous transcription co-activators YAP/TAZ, which play a prominent role in mechanotransduction. The liver sinusoids represent a unique microenvironment in which cells are exposed to mechanical cues originating in the cytoskeleton and at interfaces with adjacent cells, the extracellular matrix, and vascular or interstitial fluids. In non-alcoholic fatty liver disease (NAFLD), hepatocellular lipid accumulation and ballooning, activation of inflammatory responses, dysfunction of liver sinusoidal endothelial cells, and transdifferentiation of hepatic stellate cells into a pro-contractile and pro-fibrotic phenotype have been associated with aberrant cycles of mechanosensing and mechanoresponses. The downstream consequences of disrupted mechanical homeostasis likely contribute to the progression of NAFLD and promote the development of portal hypertension, cirrhosis, and hepatocellular carcinoma. Identification of molecular targets involved in pathogenic mechanotransduction will allow for the development of novel strategies to prevent the progression of liver disease in NAFLD.
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Affiliation(s)
- Emilie K Mitten
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - György Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston MA, USA.
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25
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Shen H, Yu H, Li QY, Wei YT, Fu J, Dong H, Cao D, Guo LN, Chen L, Yang Y, Xu Y, Wu MC, Wang HY, Chen Y. Hepatocyte-derived VEGFA accelerates the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via activating hepatic stellate cells. Acta Pharmacol Sin 2022; 43:2917-2928. [PMID: 35508720 PMCID: PMC9622738 DOI: 10.1038/s41401-022-00907-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/02/2022] [Indexed: 11/09/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is emerging as an epidemic risk factor for hepatocellular carcinoma (HCC). The progression of NAFLD to HCC is closely associated with paracrine communication among hepatic cells. Vascular endothelial growth factor A (VEGFA) plays a key role in NAFLD and HCC; however, the cellular communication of VEGFA in the pathological transition from NAFLD to HCC remains unclear. Here, we found that VEGFA elevation was considerably distributed in hepatocytes of clinical and murine NAFLD-HCC specimens. Notably, progression from NAFLD to HCC was attenuated in hepatocyte-specific deletion of Vegfa (VegfaΔhep) mice. Mechanistically, VEGFA activated human hepatic stellate cell (HSC) LX2 into a fibrogenic phenotype via VEGF-VEGFR signaling in fatty acid medium, and HSC activation was largely attenuated in VegfaΔhep mice during NAFLD-HCC progression. Additionally, a positive correlation between VEGFA and hepatic fibrosis was observed in the NAFLD-HCC cohort, but not in the HBV-HCC cohort. Moreover, LX2 cells could be activated by conditioned medium from NAFLD-derived organoids, but not from HBV livers, whereas this activation was blocked by a VEGFA antibody. In summary, our findings reveal that hepatocyte-derived VEGFA contributes to NAFLD-HCC development by activating HSCs and highlight the potential of precisely targeting hepatocytic VEGFA as a promising therapeutic strategy for NAFLD-HCC.
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Affiliation(s)
- Hao Shen
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Han Yu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Qian-Yu Li
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ya-Ting Wei
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Hui Dong
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Dan Cao
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Lin-Na Guo
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Yuan Yang
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Ying Xu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Meng-Chao Wu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China.
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
| | - Yao Chen
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, 200433, China.
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Ng C, Lee KL, Muthiah MD, Wu KX, Chioh FWJ, Tan K, Soon GST, Shabbir A, Loo WM, Low ZS, Chen Q, Tan NS, Ng HH, Dan YY, Cheung C. Endothelial‐immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease. EMBO Rep 2022; 23:e54271. [PMID: 35403791 PMCID: PMC9171677 DOI: 10.15252/embr.202154271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, mechanisms of NAFLD‐associated vasculopathy remain understudied. Here, we show that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. In mouse models of diet‐induced NAFLD, we confirm heightened endothelial expressions of CXCL12 in the aortas and the liver vasculatures, and increased retention of infiltrated leukocytes within the vessel walls. To elucidate endothelial‐immune crosstalk, we performed immunoprofiling by single‐cell analysis, uncovering T cell intensification in NAFLD patients. Functionally, treatment with a CXCL12‐neutralizing antibody is effective at moderating the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8+ T lymphocytes. Interference with the CXCL12‐CXCR4 axis using a CXCR4 antagonist also averts the impact of immune cell transendothelial migration and restores endothelial barrier integrity. Clinically, we detect threefold more circulating damaged endothelial cells in NAFLD patients than in healthy controls. Our work provides insight into the modulation of interactions with effector immune cells to mitigate endothelial injury in NAFLD.
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Affiliation(s)
- Chun‐Yi Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Khang Leng Lee
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Kan Xing Wu
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Konstanze Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Asim Shabbir
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Surgery University Surgical Cluster National University Health System Singapore Singapore
| | - Wai Mun Loo
- Department of Medicine National University Health System Singapore Singapore
| | - Zun Siong Low
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
| | - Huck Hui Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
- Genome Institute of Singapore Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
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Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology. Biomedicines 2022; 10:biomedicines10061315. [PMID: 35740337 PMCID: PMC9219880 DOI: 10.3390/biomedicines10061315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/24/2022] [Accepted: 06/01/2022] [Indexed: 12/10/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease; nevertheless, no definitive diagnostic method exists yet, apart from invasive liver biopsy, and nor is there a specific approved treatment. Runt-related transcription factor 1 (RUNX1) plays a major role in angiogenesis and inflammation; however, its link with NAFLD is unclear as controversial results have been reported. Thus, the objective of this work was to determine the proteins involved in the molecular mechanisms between RUNX1 and NAFLD, by means of systems biology. First, a mathematical model that simulates NAFLD pathophysiology was generated by analyzing Anaxomics databases and reviewing available scientific literature. Artificial neural networks established NAFLD pathophysiological processes functionally related to RUNX1: hepatic insulin resistance, lipotoxicity, and hepatic injury-liver fibrosis. Our study indicated that RUNX1 might have a high relationship with hepatic injury-liver fibrosis, and a medium relationship with lipotoxicity and insulin resistance motives. Additionally, we found five RUNX1-regulated proteins with a direct involvement in NAFLD motives, which were NFκB1, NFκB2, TNF, ADIPOQ, and IL-6. In conclusion, we suggested a relationship between RUNX1 and NAFLD since RUNX1 seems to regulate NAFLD molecular pathways, posing it as a potential therapeutic target of NAFLD, although more studies in this field are needed.
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Miao L, Targher G, Byrne CD, Valenti L, Qi X, Zheng M. Portal hypertension in nonalcoholic fatty liver disease: Challenges and perspectives. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:57-65. [DOI: 10.1002/poh2.8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/21/2022] [Indexed: 04/16/2025]
Abstract
AbstractNonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD‐related cirrhosis is often complicated by portal hypertension (PHT). Recent evidence showed that portal venous pressure (PVP) starts to rise in the early stages of NAFLD, even in absence of advanced fibrosis or cirrhosis. However, the precise pathological mechanisms of this process are still poorly understood. Lipid accumulation, hepatocellular ballooning, sinusoidal endothelial cell dysfunction, capillarization, microthrombosis, increased angiogenesis, and pericellular fibrosis may all be involved in the early development of increased PVP in NAFLD. Direct measurement of PHT is invasive and impractical in noncirrhotic NAFLD individuals and may also underestimate its severity. Thus, the development and validation of noninvasive and more accurate measurements, including new serum biomarkers, scoring models, and imaging techniques (such as ultrasonography, elastography, and magnetic resonance imaging), are urgently needed. Owing to the increasing morbidity, challenges in the prevention and management of PHT in NAFLD are unprecedented. This review article aims to briefly discuss these challenges and summarizes the mechanisms, diagnosis, and emerging therapies for PHT in people with NAFLD.
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Affiliation(s)
- Lei Miao
- Department of Gastroenterology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine University and Azienda Ospedaliera Universitaria Integrata of Verona Verona Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital University Hospital Southampton Southampton UK
| | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico Milano Italy
- Department of Pathophysiology and Transplantation Università degli Studi di Milano Milano Italy
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension The First Hospital of Lanzhou University Lanzhou Gansu China
| | - Ming‐Hua Zheng
- Department of Hepatology, NAFLD Research Center The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou Zhejiang China
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Angiopoietin-2 levels correlates with disease activity in children with nonalcoholic fatty liver disease. Pediatr Res 2022; 91:1781-1786. [PMID: 34331020 DOI: 10.1038/s41390-021-01666-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/25/2021] [Accepted: 07/06/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), a chronic liver disease in children, ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). We investigated the role of Angiopoietin-2 (Ang-2) as a biomarker for pediatric NAFLD-related liver damage. METHODS We assessed the plasma levels of Ang-2 and cytokeratin-18 (CK18) fragments and their association with histologic activity in 76 children with NAFLD and 28 controls. RESULTS The mean plasma levels of Ang-2 and CK18 were higher in children with NAFLD than in age-matched controls (Ang-2 155.4 ± 72.5 vs 7.5 ± 2.3 ng/mL, p < 0.001; CK18 390.4 ± 145.6 vs 193.9 ± 30.8 IU/L, p < 0.001). Ang-2 was significantly increased (p < 0.0001) in children with NASH (N = 41) while CK18 was significantly increased (p = 0.002) in children with fibrosis (N = 47). Ang-2 levels accurately predicted NASH (AUROC 0.911; 95% CI 0.844-0.979; p < 0.0001), while CK18 predicted both NASH (AUROC 0.827; 95% CI 0.735-0.919; p < 0.0001) and fibrosis (AUROC 0.724; 95% CI 0.611-0.837; p = 0.001). Ang-2 and CK18 in combination were good predictors of NASH with a sensitivity of 71.4% and a specificity of 100%. CONCLUSIONS In conclusion, our data suggested Ang-2 as a suitable biomarker of NASH in the pediatric population. However, our findings need external validation in other cohorts. IMPACT Several circulating factors have been extensively studied as potential biomarkers for NASH. Angiopoietin-2 circulating levels are increased in children with NAFLD and are associated with NASH. Angiopoietin-2 levels are more efficient than CK18 levels at assessing the most severe form of disease, and the combining of these two biomarkers reached a positive predictive value of 100% for NASH.
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Bone Marrow Mesenchymal Stem Cells and Their Derived Extracellular Vesicles Attenuate Non-Alcoholic Steatohepatitis-Induced Cardiotoxicity via Modulating Cardiac Mechanisms. Life (Basel) 2022; 12:life12030355. [PMID: 35330106 PMCID: PMC8952775 DOI: 10.3390/life12030355] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 106 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.
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Hidalgo I, Fonseca-Coronado S, Ceballos G, Meaney E, Nájera N. Dislipidemias, hígado graso y enfermedad cardiovascular. CARDIOVASCULAR AND METABOLIC SCIENCE 2022; 33:134-139. [DOI: 10.35366/107628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bhave S, Ho HK. Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease. Biomedicines 2021; 9:1776. [PMID: 34944593 PMCID: PMC8698495 DOI: 10.3390/biomedicines9121776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Recently, non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant health concern affecting approximately a quarter of the world's population. NAFLD is a spectrum of liver ailments arising from nascent lipid accumulation and leading to inflammation, fibrosis or even carcinogenesis. Despite its prevalence and severity, no targeted pharmacological intervention is approved to date. Thus, it is imperative to identify suitable drug targets critical to the development and progression of NAFLD. In this quest, a ray of hope is nestled within a group of proteins, receptor tyrosine kinases (RTKs), as targets to contain or even reverse NAFLD. RTKs control numerous vital biological processes and their selective expression and activity in specific diseases have rendered them useful as drug targets. In this review, we discuss the recent advancements in characterizing the role of RTKs in NAFLD progression and qualify their suitability as pharmacological targets. Available data suggests inhibition of Epidermal Growth Factor Receptor, AXL, Fibroblast Growth Factor Receptor 4 and Vascular Endothelial Growth Factor Receptor, and activation of cellular mesenchymal-epithelial transition factor and Fibroblast Growth Factor Receptor 1 could pave the way for novel NAFLD therapeutics. Thus, it is important to characterize these RTKs for target validation and proof-of-concept through clinical trials.
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Affiliation(s)
| | - Han Kiat Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Singapore;
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Potoupni V, Georgiadou M, Chatzigriva E, Polychronidou G, Markou E, Zapantis Gakis C, Filimidou I, Karagianni M, Anastasilakis D, Evripidou K, Ftergioti A, Togkaridou M, Tsaftaridis N, Apostolopoulos A, Polyzos SA. Circulating tumor necrosis factor-α levels in non-alcoholic fatty liver disease: A systematic review and a meta-analysis. J Gastroenterol Hepatol 2021; 36:3002-3014. [PMID: 34289181 DOI: 10.1111/jgh.15631] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/22/2021] [Accepted: 07/17/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM To synthesize data on circulating tumor necrosis factor (TNF)-α levels between patients with histologically confirmed non-alcoholic fatty liver disease (NAFLD) (simple steatosis or non-alcoholic fatty liver [NAFL] and/or non-alcoholic steatohepatitis [NASH]) and controls. METHODS We performed a systematic search in PubMed, Scopus, and Cochrane Library. Fifty-six studies, published between 2003 and 2019, were finally included, reporting data from 5848 individuals (1634 controls and 4214 NAFLD patients). RESULTS Higher circulating TNF-α levels were observed in NAFLD patients than controls (standardized mean difference [SMD] 0.84; 95% confidence interval [95% CI] 0.59-1.09), NAFL patients than controls (SMD 0.56; 95% CI 0.27-0.85), NASH patients than controls (SMD 0.93; 95% CI 0.64-1.22), and NASH than NAFL patients (SMD 0.31; 95% CI 0.16-0.46). There were only minimal changes in the comparisons between groups after excluding studies with morbidly obese populations (n = 11), or pediatric/adolescent populations (n = 6), or other than enzyme-linked immunosorbent assay method of TNF-α measurement (n = 8). There was high heterogeneity among studies in all comparisons, which was not essentially affected after sensitivity analyses. The meta-regression analysis revealed that the male ratio was positively associated with TNF-α SMD in the comparison between patients with NASH and NAFL (beta = 0.809; 95% CI 0.052-1.566) and accounted for 36% (P = 0.037) of the heterogeneity in this pair of comparison. TNF-α SMD was not associated with age, body mass index, and alanine aminotransferase in any pair of comparisons. CONCLUSIONS Circulating TNF-α levels were higher in patients with NAFLD compared with controls. Higher levels of circulating TNF-α were also associated with the severity of NAFLD.
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Affiliation(s)
- Victoria Potoupni
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Georgiadou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eftychia Chatzigriva
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgia Polychronidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Erietta Markou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos Zapantis Gakis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioanna Filimidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Myriam Karagianni
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Anastasilakis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kleo Evripidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Argyro Ftergioti
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marianthi Togkaridou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Tsaftaridis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Apostolos Apostolopoulos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Zhou T, Kundu D, Robles-Linares J, Meadows V, Sato K, Baiocchi L, Ekser B, Glaser S, Alpini G, Francis H, Kennedy L. Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease. Cells 2021; 10:2072. [PMID: 34440841 PMCID: PMC8391272 DOI: 10.3390/cells10082072] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
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Affiliation(s)
- Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Jonathan Robles-Linares
- Department of Graduate Studies, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA;
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine Bryan, Bryan, TX 77807, USA;
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
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Melo L, Bilici M, Hagar A, Klaunig JE. The effect of endurance training on non-alcoholic fatty liver disease in mice. Physiol Rep 2021; 9:e14926. [PMID: 34342164 PMCID: PMC8329433 DOI: 10.14814/phy2.14926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 11/24/2022] Open
Abstract
Chronic endurance exercise is a therapeutic strategy in the treatment of non-alcoholic fatty liver disease (NAFLD). Metabolic, cardiorespiratory, and endocrine pathways targeted by chronic endurance exercise have been identified; however, the specific cellular and molecular pathways modified by exercise in the steatotic liver remain unresolved. In this study, we show hepatic gene expression, and the structure, characteristics, and clinical differences between sedentary and exercised mice, by an endurance exercise model with wheels with a controlled velocity that allows for the quantification of a human-relevant endurance "dosage," after exposure to regular and high-fat diet. Chronic exercise modified the transcription of hepatic genes related to liver nuclear receptors, cell growth, fibrosis, inflammation, and oxidative stress, and decreased the amount of lipid accumulation in the liver. Moreover, the combination of endurance training with the change in diet differentially modified the genetic expression of the biomarkers relative to the separate interventions. Even though exercise by itself showed counteract NAFLD development, the combined intervention was sufficient to convert the structure and clinical aspects of the liver from steatotic to healthy. Given our findings, the combination of endurance exercise and change in diet should be considered a therapeutic option for NASH.
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Affiliation(s)
- Luma Melo
- Laboratory of Investigative Toxicology and PathologyDepartment of Environmental and Occupational HealthIndiana School of Public HealthIndiana UniversityBloomingtonINUSA
| | - Merve Bilici
- Laboratory of Investigative Toxicology and PathologyDepartment of Environmental and Occupational HealthIndiana School of Public HealthIndiana UniversityBloomingtonINUSA
| | - Amit Hagar
- History and Philosophy of Science and Medicine DepartmentIndiana UniversityBloomingtonINUSA
- Intelligent Systems Engineering DepartmentIndiana UniversityBloomingtonINUSA
| | - James E. Klaunig
- Laboratory of Investigative Toxicology and PathologyDepartment of Environmental and Occupational HealthIndiana School of Public HealthIndiana UniversityBloomingtonINUSA
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Jiang Q, Li Q, Liu B, Li G, Riedemann G, Gaitantzi H, Breitkopf-Heinlein K, Zeng A, Ding H, Xu K. BMP9 promotes methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in non-obese mice by enhancing NF-κB dependent macrophage polarization. Int Immunopharmacol 2021; 96:107591. [PMID: 33812253 DOI: 10.1016/j.intimp.2021.107591] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 02/22/2021] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
Our previous study confirmed that bone morphogenetic protein 9 (BMP9) participated in the development of nonalcoholic steatohepatitis (NASH) by affecting macrophage polarization. The focus of this study was to further confirm the role of macrophages in BMP9-mediated NASH and to analyze the underlying mechanism. In vivo, mice that were administered adeno-associated viral (AAV) vectors containing a null transgene (AAV-null) or the BMP9 transgene (AAV-BMP9) were divided into methionine- and choline-deficient (MCD) and control diet (CD) groups, and they were administered either control liposomes or clodronate liposomes via tail vein injection, the latter to deplete macrophages. The mice were sacrificed after 4 weeks of MCD diet feeding. In vitro, RAW264.7 cells were pretreated with or without BAY11-7085 (an NF-κB inhibitor) and stimulated with recombinant human BMP9 (rh-BMP9). To explore the underlying mechanism of action of BMP9, primary human monocyte-derived macrophages were additionally investigated and immunohistochemistry, biochemical assays, qRT-PCR, and Western blotting were used. The characteristics of NASH-related inflammation were assessed by hepatic histological analysis. Serum AST and ALT and hepatic triglyceride were examined by biochemical assays. We found that the expression of M1 macrophage genes (including CD86, IL1β, IL6, MCP-1 and TNFα) and the number of M1 macrophages (iNOS+ macrophages) in the liver were significantly elevated after BMP9 overexpression and BMP9 directly upregulated TLR4 expression in MCD-induced NASH. These effects were eliminated by macrophage depletion. In vitro, we discovered that BMP9 enhanced the nuclear translocation of NF-κB to induce macrophage M1 polarization in RAW264.7 cells and it promoted LPS-mediated activation of the NF-κB pathway in primary human macrophages. Taken together, this study demonstrates that BMP9 promotes NASH development by directly acting on macrophages.
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Affiliation(s)
- Qianqian Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qi Li
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China
| | - Beibei Liu
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guixin Li
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gabriel Riedemann
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Haristi Gaitantzi
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Katja Breitkopf-Heinlein
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Ajuan Zeng
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.
| | - Keshu Xu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Ibrahim SH. Sinusoidal endotheliopathy in nonalcoholic steatohepatitis: therapeutic implications. Am J Physiol Gastrointest Liver Physiol 2021; 321:G67-G74. [PMID: 34037463 PMCID: PMC8321796 DOI: 10.1152/ajpgi.00009.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver sinusoidal endothelial cells (LSECs) are distinct subtypes of endothelial cells lining a low flow vascular bed at the interface of the liver parenchyma and the circulating immune cells and soluble factors. Emerging literature implicates LSEC in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). During the evolution of NAFLD, LSEC dysfunction ensues. LSECs undergo morphological and functional transformation known as "capillarization," as well as a pathogenic increase in surface adhesion molecules expression, referred to in this review as "endotheliopathy." LSECs govern the composition of hepatic immune cell populations in nonalcoholic steatohepatis (NASH) by mediating leukocyte subset adhesion through specific combinations of activated adhesion molecules and secreted chemokines. Moreover, extracellular vesicles released by hepatocyte under lipotoxic stress in NASH act as a catalyst for the inflammatory response and promote immune cell chemotaxis and adhesion. In the current review, we highlight leukocyte adhesion to LSEC as an initiating event in the sterile inflammatory response in NASH. We discuss preclinical studies targeting immune cells adhesion in NASH mouse models and potential therapeutic anti-inflammatory strategies for human NASH.
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Affiliation(s)
- Samar H. Ibrahim
- 1Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota,2Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota
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Kennedy L, Meadows V, Sybenga A, Demieville J, Chen L, Hargrove L, Ekser B, Dar W, Ceci L, Kundu D, Kyritsi K, Pham L, Zhou T, Glaser S, Meng F, Alpini G, Francis H. Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet. Hepatology 2021; 74:164-182. [PMID: 33434322 PMCID: PMC9271361 DOI: 10.1002/hep.31713] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is simple steatosis but can develop into nonalcoholic steatohepatitis (NASH), characterized by liver inflammation, fibrosis, and microvesicular steatosis. Mast cells (MCs) infiltrate the liver during cholestasis and promote ductular reaction (DR), biliary senescence, and liver fibrosis. We aimed to determine the effects of MC depletion during NAFLD/NASH. APPROACH AND RESULTS Wild-type (WT) and KitW-sh (MC-deficient) mice were fed a control diet (CD) or a Western diet (WD) for 16 weeks; select WT and KitW-sh WD mice received tail vein injections of MCs 2 times per week for 2 weeks prior to sacrifice. Human samples were collected from normal, NAFLD, or NASH mice. Cholangiocytes from WT WD mice and human NASH have increased insulin-like growth factor 1 expression that promotes MC migration/activation. Enhanced MC presence was noted in WT WD mice and human NASH, along with increased DR. WT WD mice had significantly increased steatosis, DR/biliary senescence, inflammation, liver fibrosis, and angiogenesis compared to WT CD mice, which was significantly reduced in KitW-sh WD mice. Loss of MCs prominently reduced microvesicular steatosis in zone 1 hepatocytes. MC injection promoted WD-induced biliary and liver damage and specifically up-regulated microvesicular steatosis in zone 1 hepatocytes. Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) expression is reduced in WT WD mice and human NASH but increased in KitW-sh WD mice. MicroRNA 144-3 prime (miR-144-3p) expression was increased in WT WD mice and human NASH but reduced in KitW-sh WD mice and was found to target ALDH1A3. CONCLUSIONS MCs promote WD-induced biliary and liver damage and may promote microvesicular steatosis development during NAFLD progression to NASH through miR-144-3p/ALDH1A3 signaling. Inhibition of MC activation may be a therapeutic option for NAFLD/NASH treatment.
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Affiliation(s)
- Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Amelia Sybenga
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN
| | - Jennifer Demieville
- Central Texas Veterans Health Care System, Texas A&M University College of Medicine, Bryan, TX
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Laura Hargrove
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Burcin Ekser
- Department of Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Wasim Dar
- Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN
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Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach. Sci Rep 2021; 11:10485. [PMID: 34006921 PMCID: PMC8131688 DOI: 10.1038/s41598-021-89966-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/29/2021] [Indexed: 12/13/2022] Open
Abstract
NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.
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The Potential Protective Role of RUNX1 in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms22105239. [PMID: 34063472 PMCID: PMC8156882 DOI: 10.3390/ijms22105239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role.
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Network Pharmacology-Based Investigation of the Therapeutic Mechanisms of Action of Danning Tablets in Nonalcoholic Fatty Liver Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:3495360. [PMID: 33995543 PMCID: PMC8096548 DOI: 10.1155/2021/3495360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 01/30/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rising global public health concern due to its prevalence. Danning Tablets (DNt), a composite prescription of Chinese herbal medicine, shows significant curative effects on NAFLD in clinical application. This study aimed to decipher the bioactive substances and potential mechanisms of action of DNt in the treatment of NAFLD, applying an integrated network pharmacology approach. First, the bioactive compounds of DNt were screened based on their pharmacokinetic properties, and the corresponding drug targets were predicted. Then, the NAFLD-related targets were collected. The overlapping targets between the putative targets of DNt and NAFLD-related targets were identified as the potential therapeutic targets of DNt against NAFLD. Subsequently, the networks were constructed and analyzed, and the key bioactive compounds and targets were screened out depending on their importance in the networks. Functional enrichment analysis was carried out to elucidate the potential mechanisms of DNt acting on NAFLD. Finally, a molecular docking simulation was implemented to assess the potential binding affinity between the key targets and the bioactive compounds. As a result, 43 bioactive compounds of DNt and 69 putative targets were identified. Based on the network analysis, we found seven key bioactive compounds (quercetin, ß-sitosterol, luteolin, kaempferol, supraene, curcumenolactone C, and stigmasterol) of DNt might treat NAFLD via intervening IL6, MAPK8, VEGFA, CASP3, ALB, APP, MYC, PPARG, and RELA. The functional enrichment analysis revealed that DNt might affect NAFLD by modulating the signaling pathways involved in lipid metabolism, inflammation, oxidation, insulin resistance (IR), atherosclerosis, and apoptosis. Furthermore, most key bioactive compounds might bind firmly with the key targets. This study predicted the multicomponent, multitarget, and multipathway mechanisms of DNt in the treatment of NAFLD from a holistic perspective. DNt could be a promising agent for NAFLD, but further experimental verifications are still needed.
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Role of Insulin Resistance in MAFLD. Int J Mol Sci 2021; 22:ijms22084156. [PMID: 33923817 PMCID: PMC8072900 DOI: 10.3390/ijms22084156] [Citation(s) in RCA: 228] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 12/17/2022] Open
Abstract
Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.
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Wang XK, Peng ZG. Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:655557. [PMID: 33935770 PMCID: PMC8082362 DOI: 10.3389/fphar.2021.655557] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.
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Affiliation(s)
- Xue-Kai Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Biotechnology of Antibiotics, National Health and Family Planning Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Niepolski L, Drzewiecka H, Warchoł W. Circulating vascular endothelial growth factor receptor 2 levels and their association with lipid abnormalities in patients on hemodialysis. Biomed Rep 2021; 14:37. [PMID: 33692900 PMCID: PMC7938296 DOI: 10.3892/br.2021.1413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 02/08/2021] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to examine the association between the levels of circulating vascular endothelial growth factor receptor (VEGFR)2 levels, serum lipid composition and plasma receptor for advanced glycation end-products (RAGE) expression in patients undergoing hemodialysis (HD). A total of 50 patients on HD (27 men and 23 women; median age, 66 years; age range 28-88 years; HD mean time, 29.0, 3.9-157.0 months) were enrolled. Age-matched healthy subjects (n=26) were used as the control group. Plasma VEGFR2 and RAGE levels were determined using ELISA. Dyslipidemia (D) in patients on HD was diagnosed according to the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease. Circulating VEGFR2, RAGE and serum lipids were compared between dyslipidemic and non-dyslipidemic patients on HD and controls. In patients on HD, the plasma VEGFR2 levels were lower compared with those in the healthy population. D was associated with high plasma VEGFR2 levels. The triglyceride/HDL-cholesterol ratio was strongly associated with plasma VEGFR2 levels. The plasma VEGFR2 concentration was associated with circulating RAGE levels. Therefore, circulating VEGFR2 levels may be partly associated with lipid abnormalities and plasma RAGE levels in patients receiving HD.
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Affiliation(s)
- Leszek Niepolski
- Department of Physiology, Poznan University of Medical Sciences, Poznań 60-781, Poland
| | - Hanna Drzewiecka
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań 60-781, Poland
| | - Wojciech Warchoł
- Department of Ophthalmology and Optometry, Poznan University of Medical Sciences, Poznań 60-781, Poland
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Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets? Biomedicines 2021; 9:biomedicines9040365. [PMID: 33807461 PMCID: PMC8066583 DOI: 10.3390/biomedicines9040365] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.
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Role of Angiogenesis in the Pathogenesis of NAFLD. J Clin Med 2021; 10:jcm10071338. [PMID: 33804956 PMCID: PMC8037441 DOI: 10.3390/jcm10071338] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.
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Sasson A, Kristoferson E, Batista R, McClung JA, Abraham NG, Peterson SJ. The pivotal role of heme Oxygenase-1 in reversing the pathophysiology and systemic complications of NAFLD. Arch Biochem Biophys 2020; 697:108679. [PMID: 33248947 DOI: 10.1016/j.abb.2020.108679] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/03/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023]
Abstract
The pathogenesis and molecular pathways involved in non-alcoholic fatty liver disease (NAFLD) are reviewed, as well as what is known about mitochondrial dysfunction that leads to heart disease and the progression to steatohepatitis and hepatic fibrosis. We focused our discussion on the role of the antioxidant gene heme oxygenase-1 (HO-1) and its nuclear coactivator, peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α) in the regulation of mitochondrial biogenesis and function and potential therapeutic benefit for cardiac disease, NAFLD as well as the pharmacological effect they have on the chronic inflammatory state of obesity. The result is increased mitochondrial function and the conversion of white adipocyte tissue to beige adipose tissue ("browning of white adipose tissue") that leads to an improvement in signaling pathways and overall liver function. Improved mitochondrial biogenesis and function is essential to preventing the progression of hepatic steatosis to NASH and cirrhosis as well as preventing cardiovascular complications.
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Affiliation(s)
- Ariel Sasson
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Eva Kristoferson
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA
| | - Rogerio Batista
- The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John A McClung
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25701, USA
| | - Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, 11215, USA.
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Gubergrits NB, Byelyayeva NV, Mozhyna TL. Parallels between non-alcoholic fatty liver disease and non-alcoholic fatty pancreatic disease: looking for points of contact or regard through the lens of metabolic syndrome. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2020; 183:80-101. [DOI: 10.31146/1682-8658-ecg-183-11-80-101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The aim. The aim of our study was to analyze the available data from literature sources concerning the issues of etiology, pathogenesis, clinic, diagnosis and features of treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreatic disease (NAFPD).Materials and methods. We conducted a retrospective analysis of foreign literature sources that contain up-to-date information about the state of the problem of NAFLD and NAFPD.Results. NAFLD and NAFPD develop against the background of metabolic syndrome (MS), systemic insulin resistance, oxidative stress, changes in lipid metabolism. The natural course of NAFPD is associated with high risk of MS progression, occurrence of NAFLD, arterial hypertension, type 2 diabetes mellitus, exocrine pancreatic insufficiency, acute and chronic pancreatitis, pancreas cancer. Correction of the components of MS can reduce the severity of NAFLD and NAFPD; enzyme replacement therapy can improve the function of β-cells in pancreas steatosis.Conclusion. The alternatives of the pharmacological treatment of NAFLD and NAFPD continue to be actively explored. We emphasize the need of including medications containing pancreatic enzymes in the treatment of NAFLD.
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Emerging Roles of Liver Sinusoidal Endothelial Cells in Nonalcoholic Steatohepatitis. BIOLOGY 2020; 9:biology9110395. [PMID: 33198153 PMCID: PMC7697091 DOI: 10.3390/biology9110395] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 12/11/2022]
Abstract
Simple Summary Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome. With the prevalence of obesity and type 2 diabetes, NAFLD is becoming the most common liver disorder worldwide. More than 10% of NAFLD patients progress to an inflammatory and fibrotic form called nonalcoholic steatohepatitis (NASH), which can lead to end-stage liver disease. Liver sinusoidal endothelial cells (LSEC) are highly specialized cells located at the interface between the flowing blood in the liver and the other liver cells. The current review highlights the recent knowledge of the role of LSEC in the development of NASH, and how LSEC change their structure and function during NAFLD progression. Moreover, the review discusses the pathogenic role of nanometer-sized particles called extracellular vesicles that mediate intercellular communication in the NASH liver. The current manuscript has a special emphasis on the role of adhesion molecules expressed on the LSEC surface in the recruitment of circulating leukocytes to the liver, a critical step in liver inflammation in NASH. Furthermore, the review shed some lights on LSEC-targeted potential therapeutic strategies in NASH. Abstract Nonalcoholic steatohepatitis (NASH) has become a growing public health problem worldwide, yet its pathophysiology remains unclear. Liver sinusoidal endothelial cells (LSEC) have unique morphology and function, and play a critical role in liver homeostasis. Emerging literature implicates LSEC in many pathological processes in the liver, including metabolic dysregulation, inflammation, angiogenesis, and carcinogenesis. In this review, we highlight the current knowledge of the role of LSEC in each of the progressive phases of NASH pathophysiology (steatosis, inflammation, fibrosis, and the development of hepatocellular carcinoma). We discuss processes that have important roles in NASH progression including the detrimental transformation of LSEC called “capillarization”, production of inflammatory and profibrogenic mediators by LSEC as well as LSEC-mediated angiogenesis. The current review has a special emphasis on LSEC adhesion molecules, and their key role in the inflammatory response in NASH. Moreover, we discuss the pathogenic role of extracellular vesicles and their bioactive cargos in liver intercellular communication, inflammation, and fibrosis. Finally, we highlight LSEC-adhesion molecules and derived bioactive product as potential therapeutic targets for human NASH.
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Chiang CL, Huang HH, Huang TY, Shih YL, Hsieh TY, Lin HH. Nonalcoholic Fatty Liver Disease Associated With Bladder Cancer. Am J Med Sci 2020; 360:161-165. [DOI: 10.1016/j.amjms.2020.04.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 02/29/2020] [Accepted: 04/24/2020] [Indexed: 12/17/2022]
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