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Zaiou M, Joubert O. Racial and Ethnic Disparities in NAFLD: Harnessing Epigenetic and Gut Microbiota Pathways for Targeted Therapeutic Approaches. Biomolecules 2025; 15:669. [PMID: 40427561 PMCID: PMC12109303 DOI: 10.3390/biom15050669] [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: 03/31/2025] [Revised: 04/28/2025] [Accepted: 04/29/2025] [Indexed: 05/29/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern, impacting approximately 32.4% of the worldwide population. As a disease linked to metabolic dysfunction, NAFLD continues to rise alongside global increases in obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. There is considerable evidence indicating that NAFLD disproportionately affects racial, ethnic, and minority groups, although the exact reasons for these disparities remain elusive. Contributing factors to this disease may include socioeconomic status, cultural influences, stress, genetic factors, and lifestyle choices. Emerging evidence suggests that these causal factors could influence epigenetic mechanisms, particularly DNA methylation and histone modifications, as well as the composition and diversity of gut microbiota. Nevertheless, there is a scarcity of research that comprehensively examines the interplay between epigenetic changes and gut microbiome variations in relation to NAFLD disparities across different racial and ethnic populations globally. This paper intends to (i) explore the connections between NAFLD, ethnic disparities, gut microbiota composition, and epigenetic alterations, while reviewing pertinent studies that illustrate how these factors contribute to health inequities among various ethnic groups impacted by this disease; (ii) explore potential therapeutic targets and biomarkers to advance the management of NAFLD; and (iii) provide insights to enhance our understanding of the mechanisms associated with this disease, thereby promoting further research in this field. Advancements in this area are anticipated to enhance our understanding of disease susceptibilities in at-risk groups and to provide new therapeutic options for NAFLD and its associated complications.
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Affiliation(s)
- Mohamed Zaiou
- Université de Lorraine, CNRS, IJL, F-54000 Nancy, France;
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2
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Lu L, Hua W, Li F, Che Z, Tian M, Lu YY, Chi Q, Zhang J, Huang Q. Arsenic Exposure Triggers Nonalcoholic Fatty Liver Disease through Repressing S-Adenosylmethionine-Dependent Histone Methylation in Rats. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:268-278. [PMID: 39746780 DOI: 10.1021/acs.est.4c10417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Fabp1, Srebf1, and Apoc3, while downregulated Acox1 and Cpt1a in rat liver. In addition, it was found that inorganic arsenite (iAsIII) was methylated to DMA, and the S-adenosylmethionine (SAM) level was decreased, which would contribute to the repression of H3K9me1/2 in rat liver after exposure. The in vitro studies revealed that SAM supplementation attenuated lipid accumulation by restoring H3K9me1/2 in HepG2 cells, which further confirmed our animal results. Therefore, it is suggested that As methylation depleted SAM, which inhibited H3K9me1/2 and activated Fabp1, Srebf1, and Apoc3 expressions, leading to NAFLD upon inorganic As exposure. Overall, these data shed new light on the role of SAM-mediated histone methylation in As-triggered NAFLD, which could be useful for the prevention and intervention of hepatotoxicity induced by environmental As exposure.
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Affiliation(s)
- Lu Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
- College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Weizhen Hua
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Fuping Li
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Zhenbin Che
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Meiping Tian
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Yan-Yang Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Qiaoqiao Chi
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Jie Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Qingyu Huang
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
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You J, Xue H, Chao C, Zhang Z, Tan X, Wang X, Li H. Histone Methyltransferase SUV39H2 Supports Nasopharyngeal Carcinoma Cell Metastasis by Regulation of SIRT1. ENVIRONMENTAL TOXICOLOGY 2024; 39:4974-4983. [PMID: 38994737 DOI: 10.1002/tox.24370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 05/06/2024] [Accepted: 06/01/2024] [Indexed: 07/13/2024]
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor with high metastatic features originating from the nasopharynx. However, the underlying mechanism of Suppressor of variegation 3-9 homolog 2 (SUV39H2) in NPC remains poorly understood. RT-qPCR was carried out to examine SUV39H2 and SIRT1 expression in NPC tissues and cells. Kaplan-Meier method was utilized to evaluate the association between SUV39H2 level and overall survival. The function of SUV39H2 and SIRT1 in NPC cell viability, metastasis, and apoptosis was tested through CCK-8, transwell, and flow cytometry experiments. Here, it was uncovered that SUV39H2 level was augmented in NPC tissues and cells. Moreover, SUV39H2 expedited NPC cell viability, metastasis, and inhibited apoptosis, while SIRT1 addition reversed these impacts. Besides, SUV39H2 induced H3K9me3 enhancement to repress SIRT1 transcription via binding to SIRT1 promoter. Collectively, our results demonstrated upregulated SUV39H2 aggravated NPC tumorigenesis through SIRT1, which may offer a potential therapeutic target for NPC.
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Affiliation(s)
- Jianqiang You
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Haixiang Xue
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Changjiang Chao
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Zhixuan Zhang
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Xiaoye Tan
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Xiaoye Wang
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
| | - Haifeng Li
- Department of Otorhinolaryngology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China
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Du Y, He Z, Jin S, Jin G, Wang K, Yang F, Zhang J. Targeting histone methylation and demethylation for non-alcoholic fatty liver disease. Bioorg Chem 2024; 151:107698. [PMID: 39126869 DOI: 10.1016/j.bioorg.2024.107698] [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: 05/28/2024] [Revised: 07/16/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.
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Affiliation(s)
- Yuanbing Du
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Zhangxu He
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Sasa Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Gang Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Kaiyue Wang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Feifei Yang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Jingyu Zhang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
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Li D, Zhang T, Guo Y, Bi C, Liu M, Wang G. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma. Cell Death Dis 2024; 15:498. [PMID: 38997297 PMCID: PMC11245522 DOI: 10.1038/s41419-024-06888-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024]
Abstract
The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.
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Affiliation(s)
- Deming Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Ting Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ye Guo
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Cong Bi
- Department of Radiology, The First Hospital of China Medical University, Shenyang, 110001, PR China.
| | - Ming Liu
- Department of Oral Radiology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, PR China.
| | - Gang Wang
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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Wu S, Ren W, Hong J, Yang Y, Lu Y. Ablation of histone methyltransferase Suv39h2 in hepatocytes attenuates NASH in mice. Life Sci 2024; 343:122524. [PMID: 38401627 DOI: 10.1016/j.lfs.2024.122524] [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: 01/09/2024] [Revised: 02/14/2024] [Accepted: 02/21/2024] [Indexed: 02/26/2024]
Abstract
AIMS Non-alcoholic steatohepatitis (NASH) is characterized by aberrant lipid metabolism in hepatocytes. We investigated the involvement of a histone H3K9 methyltransferase Suv39h2 in the pathogenesis of NASH. METHODS AND MATERIALS NASH is induced by feeding the mice with a high-fat high-carbohydrate (HFHC) diet or a high-fat choline-deficient amino acid defined (HFD-CDAA) diet. The Suv39h2f/f mice were crossbred with the Alb-Cre mice to specifically delete Suv39h2 in hepatocytes. KEY FINDINGS Ablation of Suv39h2 in hepatocytes improved insulin sensitivity of the mice fed either the HFHC diet or the CDAA-HFD diet. Importantly, Suv39h2 deletion significantly ameliorated NAFLD as evidenced by reduced lipid accumulation, inflammation, and fibrosis in the liver. RNA-seq uncovered Vanin-1 (Vnn1) as a novel transcriptional target for Suv39h2. Mechanistically, Suv39h2 repressed Vnn1 transcription in hepatocytes exposed to free fatty acids. Consistently, Vanin-1 knockdown normalized lipid accumulation in Suv39h2-null hepatocytes. Importantly, a significant correlation between Suv39h2, Vanin-1, and hepatic triglyceride levels was identified in NASH patients. SIGNIFICANCE Our study uncovers a novel mechanism whereby Suv39h2 may contribute to NASH pathogenesis and suggests that targeting the Suv39h2-Vanin-1 axis may yield novel therapeutic solutions against NASH.
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Affiliation(s)
- Shiqiang Wu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Wenjing Ren
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Jiameng Hong
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Yuyu Yang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
| | - Yunjie Lu
- Suzhou Medical College, Soochow University, Suzhou, China; Department of Hepatobiliary and Pancreatic Surgery, the third Affiliated Hospital of Soochow University, Changzhou, China; Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, USA.
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Song Y, Zhao X, Qu H, Su Y, He R, Chen L, Fang L, Li J, Zou Z, He J, Li Z, Xu Y, Chen X, Cheng H, Xu Y, Wang Q, Lai L. Epigenetic Regulation of IL-23 by E3 Ligase FBXW7 in Dendritic Cells Is Critical for Psoriasis-like Inflammation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1701-1713. [PMID: 37843504 DOI: 10.4049/jimmunol.2300023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 08/11/2023] [Indexed: 10/17/2023]
Abstract
Dendritic cells (DCs), a driver of psoriasis pathogenesis, produce IL-23 and trigger IL-23/IL-17 cytokine axis activation. However, the mechanisms regulating IL-23 induction remain unclear. In the current study, we found that mice with E3 ligase FBXW7 deficiency in DCs show reduced skin inflammation correlated with the reduction of IL-23/IL-17 axis cytokines in the imiquimod-induced psoriasis model. Fbxw7 deficiency results in decreased production of IL-23 in DCs. FBXW7 interacts with the lysine N-methyltransferase suppressor of variegation 39 homolog 2 (SUV39H2), which catalyzes the trimethylation of histone H3 Lys9 (H3K9) during transcription regulation. FBXW7 mediates the ubiquitination and degradation of SUV39H2, thus decreasing H3K9m3 deposition on the Il23a promoter. The Suv39h2 knockout mice displayed exacerbated skin inflammation with the IL-23/IL-17 axis overactivating in the psoriasis model. Taken together, our results indicate that FBXW7 increases IL-23 expression in DCs by degrading SUV39H2, thereby aggravating psoriasis-like inflammation. Inhibition of FBXW7 or the FBXW7/SUV39H2/IL-23 axis may represent a novel therapeutic approach to psoriasis.
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Affiliation(s)
- Yinjing Song
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangtong Zhao
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Qu
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yixin Su
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Rukun He
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
| | - Luxia Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lutong Fang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiaying Li
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Ziqi Zou
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jia He
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Zilong Li
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yaohan Xu
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Hao Cheng
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Xu
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
- Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Qingqing Wang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Lihua Lai
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
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8
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Shi Y, Qi W. Histone Modifications in NAFLD: Mechanisms and Potential Therapy. Int J Mol Sci 2023; 24:14653. [PMID: 37834101 PMCID: PMC10572202 DOI: 10.3390/ijms241914653] [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: 08/10/2023] [Revised: 09/03/2023] [Accepted: 09/09/2023] [Indexed: 10/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive condition that encompasses a spectrum of liver disorders, beginning with the simple steatosis, progressing to nonalcoholic steatohepatitis (NASH), and possibly leading to more severe diseases, including liver cirrhosis and hepatocellular carcinoma (HCC). In recent years, the prevalence of NAFLD has increased due to a shift towards energy-dense dietary patterns and a sedentary lifestyle. NAFLD is also strongly associated with metabolic disorders such as obesity and hyperlipidemia. The progression of NAFLD could be influenced by a variety of factors, such as diet, genetic factors, and even epigenetic factors. In contrast to genetic factors, epigenetic factors, including histone modifications, exhibit dynamic and reversible features. Therefore, the epigenetic regulation of the initiation and progression of NAFLD is one of the directions under intensive investigation in terms of pathogenic mechanisms and possible therapeutic interventions. This review aims to discuss the possible mechanisms and the crucial role of histone modifications in the framework of epigenetic regulation in NAFLD, which may provide potential therapeutic targets and a scientific basis for the treatment of NAFLD.
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Affiliation(s)
- Yulei Shi
- Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Wei Qi
- Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
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Rajan PK, Udoh UAS, Nakafuku Y, Pierre SV, Sanabria J. Normalization of the ATP1A1 Signalosome Rescinds Epigenetic Modifications and Induces Cell Autophagy in Hepatocellular Carcinoma. Cells 2023; 12:2367. [PMID: 37830582 PMCID: PMC10572209 DOI: 10.3390/cells12192367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/23/2023] [Indexed: 10/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. In metabolic dysfunction-associated steatohepatitis (MASH)-related HCC, cellular redox imbalance from metabolic disturbances leads to dysregulation of the α1-subunit of the Na/K-ATPase (ATP1A1) signalosome. We have recently reported that the normalization of this pathway exhibited tumor suppressor activity in MASH-HCC. We hypothesized that dysregulated signaling from the ATP1A1, mediated by cellular metabolic stress, promotes aberrant epigenetic modifications including abnormal post-translational histone modifications and dysfunctional autophagic activity, leading to HCC development and progression. Increased H3K9 acetylation (H3K9ac) and H3K9 tri-methylation (H3K9me3) were observed in human HCC cell lines, HCC-xenograft and MASH-HCC mouse models, and epigenetic changes were associated with decreased cell autophagy in HCC cell lines. Inhibition of the pro-autophagic transcription factor FoxO1 was associated with elevated protein carbonylation and decreased levels of reduced glutathione (GSH). In contrast, normalization of the ATP1A1 signaling significantly decreased H3K9ac and H3K9me3, in vitro and in vivo, with concomitant nuclear localization of FoxO1, heightening cell autophagy and cancer-cell apoptotic activities in treated HCC cell lines. Our results showed the critical role of the ATP1A1 signalosome in HCC development and progression through epigenetic modifications and impaired cell autophagy activity, highlighting the importance of the ATP1A1 pathway as a potential therapeutic target for HCC.
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Affiliation(s)
- Pradeep Kumar Rajan
- Department of Surgery, Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25701, USA; (P.K.R.); (U.-A.S.U.); (Y.N.); (S.V.P.)
| | - Utibe-Abasi S. Udoh
- Department of Surgery, Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25701, USA; (P.K.R.); (U.-A.S.U.); (Y.N.); (S.V.P.)
| | - Yuto Nakafuku
- Department of Surgery, Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25701, USA; (P.K.R.); (U.-A.S.U.); (Y.N.); (S.V.P.)
| | - Sandrine V. Pierre
- Department of Surgery, Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25701, USA; (P.K.R.); (U.-A.S.U.); (Y.N.); (S.V.P.)
| | - Juan Sanabria
- Department of Surgery, Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25701, USA; (P.K.R.); (U.-A.S.U.); (Y.N.); (S.V.P.)
- Department of Nutrition and Metabolomic Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH 44100, USA
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Zaiou M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Cells 2023; 12:1205. [PMID: 37190114 PMCID: PMC10136748 DOI: 10.3390/cells12081205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean-Lamour, Université de Lorraine, UMR 7198 CNRS, 54505 Vandoeuvre-les-Nancy, France
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Li Y, Liu Y, Chen Z, Tang K, Yang L, Jiang Y, Wang J, Huang P, Wang J, Zheng P, Song H. Protopanaxadiol ameliorates NAFLD by regulating hepatocyte lipid metabolism through AMPK/SIRT1 signaling pathway. Biomed Pharmacother 2023; 160:114319. [PMID: 36724639 DOI: 10.1016/j.biopha.2023.114319] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/14/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become one of the main chronic liver diseases worldwide. Protopanaxadiol (PPD), an active compound derived from Gynostemma pentaphyllum, has been found able to improve free fatty acid-induced lipid accumulation in hepatocytes. However, the efficacy of PPD on NAFLD and the underlying mechanism remains unknown. In this study, the mice were fed with a high-fat diet for 22 weeks to induce the NAFLD model, and then were treated with PPD by gavage for 8 weeks. Moreover, AML12 and HepG2 cells induced by free fatty acids for 24 h, were treated with different doses of PPD and/or AMPK or SIRT1 inhibitor to explore the pharmacological mechanism of PPD. The results showed that mice with PPD treatment had significantly reduced liver weight and serum aminotransferase levels, less severe hepatosteatosis, and inflammatory cell infiltration in liver tissues when compared with the model mice. PPD also reversed the down-regulated activation of AMPK and SIRT1 expression as well as the change of lipid metabolism-related molecules in the mice liver tissues. Consistently, the in vitro experiments showed the effect of PPD in ameliorating lipid accumulation in hepatocytes. The inhibitor of AMPK or SIRT1 suppressed the AMPK and SIRT1 signaling and markedly diminished the anti-steatosis effect of PPD. In conclusion, our results prove the ameliorating impact of PPD on NAFLD and also reveal the involvement of regulation of AMPK/SIRT1 signaling pathway-mediated lipid metabolism in the underlying mechanism, suggesting PPD as a potential natural compound for the treatment of NAFLD.
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Affiliation(s)
- Yiping Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
| | - Yang Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Teaching Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhiwei Chen
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Kaiyue Tang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lili Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yuwei Jiang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jue Wang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ping Huang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jianyi Wang
- Department of Liver Disease, Shanghai Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1594-1605. [PMID: 36650321 DOI: 10.1007/s12094-023-03078-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/07/2023] [Indexed: 01/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy. Consequently, interventions that can prevent or restrain HCC emergence from pre-cancerous diseased liver are a desirable strategy. Histone methylation is a dynamic, reversible epigenetic modification involving the addition or removal of methyl groups from lysine, arginine or glutamine residues. Aberrant activity of histone methylation writers, erases and readers has been implicated in several cancer types, including HCC. In this review, we provide an overview of research on the role of histone methylation in pre-cancerous and cancerous HCC published over the last 5 years. In particular, we present the evidence linking environmental factors such as diet, viral infections and carcinogenic agents with dysregulation of histone methylation during liver cancer progression with the aim to highlight future therapeutic possibilities.
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13
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Liu Y, Chen M. Histone Methylation Regulation as a Potential Target for Non-alcoholic Fatty Liver Disease. Curr Protein Pept Sci 2023; 24:465-476. [PMID: 37246318 DOI: 10.2174/1389203724666230526155643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/13/2023] [Accepted: 04/20/2023] [Indexed: 05/30/2023]
Abstract
Epigenetic modulations are currently emerging as promising targets in metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), for their roles in pathogenesis and therapeutic potential. The molecular mechanisms and modulation potential of histone methylation as a histone post-transcriptional modification in NAFLD have been recently addressed. However, a detailed overview of the histone methylation regulation in NAFLD is lacking. In this review, we comprehensively summarize the mechanisms of histone methylation regulation in NAFLD. We conducted a comprehensive database search in the PubMed database with the keywords 'histone', 'histone methylation', 'NAFLD', and 'metabolism' without time restriction. Reference lists of key documents were also reviewed to include potentially omitted articles. It has been reported that these enzymes can interact with other transcription factors or receptors under pro-NAFLD conditions, such as nutritional stress, which lead to recruitment to the promoters or transcriptional regions of key genes involved in glycolipid metabolism, ultimately regulating gene transcriptional activity to influence the expression. Histone methylation regulation has been implicated in mediating metabolic crosstalk between tissues or organs in NAFLD and serves a critical role in NAFLD development and progression. Some dietary interventions or agents targeting histone methylation have been suggested to improve NAFLD; however, there is still a lack of additional research and clinical translational relevance. In conclusion, histone methylation/demethylation has demonstrated an important regulatory role in NAFLD by mediating the expression of key glycolipid metabolism-related genes, and more research is needed in the future to explore its potential as a therapeutic target.
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Affiliation(s)
- Yuanbin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, P.R. China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, P.R. China
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14
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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Liu Y, Li Y, Wang J, Yang L, Yu X, Huang P, Song H, Zheng P. Salvia-Nelumbinis naturalis improves lipid metabolism of NAFLD by regulating the SIRT1/AMPK signaling pathway. BMC Complement Med Ther 2022; 22:213. [PMID: 35945571 PMCID: PMC9361555 DOI: 10.1186/s12906-022-03697-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Salvia-Nelumbinis naturalis (SNN), the extract of Chinese herbal medicine, has shown effects on NAFLD. This study aims to explore the underlying mechanism of SNN for regulating the lipid metabolism disorder in NAFLD based on the SIRT1/AMPK signaling pathway.
Methods
Male C57BL/6J mice fed with a high-fat diet (HFD) were used to establish the NAFLD model. Dynamic changes of mice including body weight, liver weight, serological biochemical indexes, liver histopathological changes, and protein level of AMPK and SIRT1 were monitored. After18 weeks, SNN treatment was administrated to the NAFLD mice for another 4 weeks. Besides the aforementioned indices, TC and TG of liver tissues were also measured. Western blot and quantitative RT-PCR were used to detect the expression and/or activation of SIRT1 and AMPK, as well as the molecules associated with lipid synthesis and β-oxidation. Furthermore, AML12 cells with lipid accumulation induced by fatty acids were treated with LZG and EX527 (SIRT1 inhibitor) or Compound C (AMPK inhibitor ) to confirm the potential pharmacological mechanism.
Results
Dynamic observation found the mice induced by HFD with gradually increased body and liver weight, elevated serum cholesterol, hepatic lipid accumulation, and liver injury. After 16 weeks, these indicators have shown obvious changes. Additionally, the hepatic level of SIRT1 and AMPK activation was identified gradually decreased with NAFLD progress. The mice with SNN administration had lower body weight, liver weight, and serum level of LDL-c and ALT than those of the NAFLD model. Hepatosteatosis and hepatic TG content in the liver tissues of the SNN group were significantly reduced. When compared with control mice, the NAFLD mice had significantly decreased hepatic expression of SIRT1, p-AMPK, p-ACC, ACOX1, and increased total Acetylated-lysine, SUV39H2, and SREBP-1c. The administration of SNN reversed the expression of these molecules. In vitro experiments showed the effect of SNN in ameliorating hepatosteatosis and regulating the expression of lipid metabolism-related genes in AML12 cells, which were diminished by EX527 or Compound C co-incubation.
Conclusions
Taken together, the SIRT1/AMPK signaling pathway, involved in hepatic lipid synthesis and degradation, plays a pivotal role in the pathogenesis of NAFLD development. The regulation of SIRT1/AMPK signaling greatly contributes to the underlying therapeutic mechanism of SNN for NAFLD.
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16
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Wang Q, Zhou H, Bu Q, Wei S, Li L, Zhou J, Zhou S, Su W, Liu M, Liu Z, Wang M, Lu L. Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis. J Hepatol 2022; 77:312-325. [PMID: 35292349 DOI: 10.1016/j.jhep.2022.02.031] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH. METHODS Human liver tissues obtained from patients with NASH and controls were used to assess XBP1 expression. NASH models were developed in hepatocyte-specific Xbp1 knockout (Xbp1ΔHep), macrophage-specific Xbp1 knockout (Xbp1ΔMf), macrophage-specific Nlrp3 knockout, and wild-type (Xbp1FL/FL or Nlrp3FL/FL) mice fed with a high-fat diet for 26 weeks or a methionine/choline-deficient diet for 6 weeks. RESULTS The expression of XBP1 was significantly upregulated in liver samples from patients with NASH. Hepatocyte-specific Xbp1 deficiency inhibited the development of steatohepatitis in mice fed the high-fat or methionine/choline-deficient diets. Meanwhile, macrophage-specific Xbp1 knockout mice developed less severe steatohepatitis and fibrosis than wild-type Xbp1FL/FL mice in response to the high-fat or methionine/choline-deficient diets. Macrophage-specific Xbp1 knockout mice showed M2 anti-inflammatory polarization. Xbp1-deleted macrophages reduced steatohepatitis by decreasing the expression of NLRP3 and secretion of pro-inflammatory cytokines, which mediate M2 macrophage polarization in macrophage-specific Xbp1 knockout mice. Steatohepatitis was less severe in macrophage-specific Nlrp3 knockout mice than in wild-type Nlrp3FL/FL mice. Xbp1-deleted macrophages prevented hepatic stellate cell activation by decreasing expression of TGF-β1. Less fibrotic changes were observed in macrophage-specific Xbp1 knockout mice than in wild-type Xbp1FL/FL mice. Inhibition of XBP1 suppressed the development of NASH. CONCLUSION XBP1 regulates the development of NASH. XBP1 inhibitors protect against steatohepatitis. Thus, XBP1 is a potential target for the treatment of NASH. LAY SUMMARY XBP1 is a transcription factor that is upregulated in liver tissues of patients with non-alcoholic steatohepatitis (NASH). Conditional knockout of Xbp1 in hepatocytes resulted in decreased lipid accumulation in mice, while genetic deletion of Xbp1 in macrophages ameliorated nutritional steatohepatitis and fibrosis in mice. Pharmacological inhibition of XBP1 protects against steatohepatitis and fibrosis, highlighting a promising therapeutic strategy for NASH.
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Affiliation(s)
- Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qingfa Bu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Song Wei
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China
| | - Lei Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Jinren Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Shun Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wantong Su
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Mu Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Zheng Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Mingming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
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Feoli A, Viviano M, Cipriano A, Milite C, Castellano S, Sbardella G. Lysine methyltransferase inhibitors: where we are now. RSC Chem Biol 2022; 3:359-406. [PMID: 35441141 PMCID: PMC8985178 DOI: 10.1039/d1cb00196e] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/10/2021] [Indexed: 12/14/2022] Open
Abstract
Protein lysine methyltransferases constitute a large family of epigenetic writers that catalyse the transfer of a methyl group from the cofactor S-adenosyl-l-methionine to histone- and non-histone-specific substrates. Alterations in the expression and activity of these proteins have been linked to the genesis and progress of several diseases, including cancer, neurological disorders, and growing defects, hence they represent interesting targets for new therapeutic approaches. Over the past two decades, the identification of modulators of lysine methyltransferases has increased tremendously, clarifying the role of these proteins in different physio-pathological states. The aim of this review is to furnish an updated outlook about the protein lysine methyltransferases disclosed modulators, reporting their potency, their mechanism of action and their eventual use in clinical and preclinical studies.
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Affiliation(s)
- Alessandra Feoli
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Monica Viviano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Alessandra Cipriano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Ciro Milite
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Sabrina Castellano
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
| | - Gianluca Sbardella
- Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno via Giovanni Paolo II 132 I-84084 Fisciano SA Italy +39-089-96-9602 +39-089-96-9770
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18
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Huang HM, Fan SJ, Zhou XR, Liu YJ, Li X, Liao LP, Huang J, Shi CC, Yu L, Fu R, Fan JG, Zhang YY, Luo C, Li GM. Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis. Acta Pharmacol Sin 2022; 43:941-953. [PMID: 34341511 PMCID: PMC8975805 DOI: 10.1038/s41401-021-00725-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 06/22/2021] [Indexed: 12/15/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg-1·d-1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.
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Affiliation(s)
- He-Ming Huang
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Shi-Jie Fan
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao-Ru Zhou
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yan-Jun Liu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiao Li
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Li-Ping Liao
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jing Huang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cui-Cui Shi
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Liang Yu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Rong Fu
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China
| | - Yuan-Yuan Zhang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Cheng Luo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Guang-Ming Li
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
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Dam TV, Toft NI, Grøntved L. Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD. Cells 2022; 11:870. [PMID: 35269495 PMCID: PMC8909044 DOI: 10.3390/cells11050870] [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: 01/27/2022] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 11/20/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver.
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Affiliation(s)
| | | | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark; (T.V.D.); (N.I.T.)
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20
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Rodríguez-Sanabria JS, Escutia-Gutiérrez R, Rosas-Campos R, Armendáriz-Borunda JS, Sandoval-Rodríguez A. An Update in Epigenetics in Metabolic-Associated Fatty Liver Disease. Front Med (Lausanne) 2022; 8:770504. [PMID: 35087844 PMCID: PMC8787199 DOI: 10.3389/fmed.2021.770504] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis accompanied by one of three features: overweight or obesity, T2DM, or lean or normal weight with evidence of metabolic dysregulation. It is distinguished by excessive fat accumulation in hepatocytes, and a decrease in the liver's ability to oxidize fats, the accumulation of ectopic fat, and the activation of proinflammatory pathways. Chronic damage will keep this pathophysiologic cycle active causing progression from hepatic steatosis to cirrhosis and eventually, hepatocarcinoma. Epigenetics affecting gene expression without altering DNA sequence allows us to study MAFLD pathophysiology from a different perspective, in which DNA methylation processes, histone modifications, and miRNAs expression have been closely associated with MAFLD progression. However, these considerations also faced us with the circumstance that modifying those epigenetics patterns might lead to MAFLD regression. Currently, epigenetics is an area of great interest because it could provide new insights in therapeutic targets and non-invasive biomarkers. This review comprises an update on the role of epigenetic patterns, as well as innovative therapeutic targets and biomarkers in MAFLD.
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Affiliation(s)
- J Samael Rodríguez-Sanabria
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Rebeca Escutia-Gutiérrez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Rebeca Rosas-Campos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
| | - Juan S Armendáriz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico.,School of Medicine and Health Sciences, Tecnologico de Monterrey, Campus Guadalajara, Zapopan, Mexico
| | - Ana Sandoval-Rodríguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Mexico
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21
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Wang C, Ma C, Gong L, Guo Y, Fu K, Zhang Y, Zhou H, Li Y. Macrophage Polarization and Its Role in Liver Disease. Front Immunol 2022; 12:803037. [PMID: 34970275 PMCID: PMC8712501 DOI: 10.3389/fimmu.2021.803037] [Citation(s) in RCA: 335] [Impact Index Per Article: 111.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.
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Affiliation(s)
- Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihong Gong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuqin Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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22
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Das D, Karthik N, Taneja R. Crosstalk Between Inflammatory Signaling and Methylation in Cancer. Front Cell Dev Biol 2021; 9:756458. [PMID: 34901003 PMCID: PMC8652226 DOI: 10.3389/fcell.2021.756458] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/11/2021] [Indexed: 01/08/2023] Open
Abstract
Inflammation is an intricate immune response against infection and tissue damage. While the initial immune response is important for preventing tumorigenesis, chronic inflammation is implicated in cancer pathogenesis. It has been linked to various stages of tumor development including transformation, proliferation, angiogenesis, and metastasis. Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules contribute to the survival, growth, and progression of the tumor in its microenvironment. The aberrant expression and secretion of pro-inflammatory and growth factors by the tumor cells result in the recruitment of immune cells, thus creating a mutual crosstalk. The reciprocal signaling between the tumor cells and the immune cells creates and maintains a successful tumor niche. Many inflammatory factors are regulated by epigenetic mechanisms including DNA methylation and histone modifications. In particular, DNA and histone methylation are crucial forms of transcriptional regulation and aberrant methylation has been associated with deregulated gene expression in oncogenesis. Such deregulations have been reported in both solid tumors and hematological malignancies. With technological advancements to study genome-wide epigenetic landscapes, it is now possible to identify molecular mechanisms underlying altered inflammatory profiles in cancer. In this review, we discuss the role of DNA and histone methylation in regulation of inflammatory pathways in human cancers and review the merits and challenges of targeting inflammatory mediators as well as epigenetic regulators in cancer.
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Affiliation(s)
- Dipanwita Das
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nandini Karthik
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reshma Taneja
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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23
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Zaiou M, Amrani R, Rihn B, Hajri T. Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Biomedicines 2021; 9:1256. [PMID: 34572442 PMCID: PMC8468830 DOI: 10.3390/biomedicines9091256] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to the pathologic buildup of extra fat in the form of triglycerides in liver cells without excessive alcohol intake. NAFLD became the most common cause of chronic liver disease that is tightly associated with key aspects of metabolic disorders, including insulin resistance, obesity, diabetes, and metabolic syndrome. It is generally accepted that multiple mechanisms and pathways are involved in the pathogenesis of NAFLD. Heredity, sedentary lifestyle, westernized high sugar saturated fat diet, metabolic derangements, and gut microbiota, all may interact on a on genetically susceptible individual to cause the disease initiation and progression. While there is an unquestionable role for gene-diet interaction in the etiopathogenesis of NAFLD, it is increasingly apparent that epigenetic processes can orchestrate many aspects of this interaction and provide additional mechanistic insight. Exciting research demonstrated that epigenetic alterations in chromatin can influence gene expression chiefly at the transcriptional level in response to unbalanced diet, and therefore predispose an individual to NAFLD. Thus, further discoveries into molecular epigenetic mechanisms underlying the link between nutrition and aberrant hepatic gene expression can yield new insights into the pathogenesis of NAFLD, and allow innovative epigenetic-based strategies for its early prevention and targeted therapies. Herein, we outline the current knowledge of the interactive role of a high-fat high-calories diet and gene expression through DNA methylation and histone modifications on the pathogenesis of NAFLD. We also provide perspectives on the advancement of the epigenomics in the field and possible shortcomings and limitations ahead.
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Affiliation(s)
- Mohamed Zaiou
- The Jean-Lamour Institute, UMR 7198 CNRS, University of Lorraine, F-54000 Nancy, France;
| | - Rim Amrani
- Department of Neonatology, University Mohammed First, Oujda 60000, Morocco;
| | - Bertrand Rihn
- The Jean-Lamour Institute, UMR 7198 CNRS, University of Lorraine, F-54000 Nancy, France;
| | - Tahar Hajri
- Department of Human Ecology, Delaware State University, Dover, DE 1191, USA;
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24
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Zhou D, Luan J, Huang C, Li J. Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe? Gut Liver 2021; 15:500-516. [PMID: 33087588 PMCID: PMC8283292 DOI: 10.5009/gnl20223] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.
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Affiliation(s)
- Dexi Zhou
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, China.,School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China
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25
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Shi CX, Wang Y, Jiao FZ, Chen Q, Cao P, Pei MH, Zhang LY, Guo J, Deng W, Wang LW, Gong ZJ. Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation. Front Physiol 2021; 12:683526. [PMID: 34276405 PMCID: PMC8281248 DOI: 10.3389/fphys.2021.683526] [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: 03/31/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Chronic liver inflammation is a complex pathological process under different stress conditions, and the roles of stellate cells and macrophages in chronic liver inflammation have been widely reported. Moderate liver inflammation can protect the liver from damage and facilitate the recovery of liver injury. However, an inflammatory response that is too intense can result in massive death of hepatocytes, which leads to irreversible damage to the liver parenchyma. Epigenetic regulation plays a key part in liver inflammation. This study reviews the regulation of epigenetics on stellate cells and macrophages to explore the new mechanisms of epigenetics on liver inflammation and provide new ideas for the treatment of liver disease.
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Affiliation(s)
- Chun-Xia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang-Zhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pan Cao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mao-Hua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Yi Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jin Guo
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Deng
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Wen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
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26
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Zhao S, Song T, Gu Y, Zhang Y, Cao S, Miao Q, Zhang X, Chen H, Gao Y, Zhang L, Han Y, Wang H, Pu J, Xie L, Ji Y. Hydrogen Sulfide Alleviates Liver Injury Through the S-Sulfhydrated-Kelch-Like ECH-Associated Protein 1/Nuclear Erythroid 2-Related Factor 2/Low-Density Lipoprotein Receptor-Related Protein 1 Pathway. Hepatology 2021; 73:282-302. [PMID: 32219872 DOI: 10.1002/hep.31247] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/02/2020] [Accepted: 03/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Protein S-sulfhydration mediated by H2 S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear. APPROACH AND RESULTS We showed that in streptozotocin (STZ)-treated and high-fat diet (HFD)-treated low-density lipoprotein receptor-negative (LDLr-/- ) mice, the H2 S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S-sulfhydration of Kelch-like ECH-associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD-treated LDLr-/- mice and in high glucose-treated and oxidized low-density lipoprotein (ox-LDL)-treated primary mouse hepatocytes, the GYY4137-mediated increase in Keap1 S-sulfhydration induced nuclear erythroid 2-related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S-sulfhydration and abolished the hepatoprotective effects of H2 S both in vivo and in vitro. Nrf2 deficiency inhibited the H2 S-induced beneficial impacts in Nrf2-/- mice. Similarly, in CCl4 -stimulated mice, GYY4137 increased Keap1 S-sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H2 S increased the binding of Nrf2 to the promoter region of LDLr-related protein 1 (Lrp1) and consequently up-regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation. CONCLUSIONS H2 S-mediated Keap1 S-sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H2 S in the form of the H2 S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia-induced or CCl4 -stimulated liver dysfunction.
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Affiliation(s)
- Shuang Zhao
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Tianyu Song
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Yue Gu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.,Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yihua Zhang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Siyi Cao
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Qing Miao
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Xiyue Zhang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Hongshan Chen
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Yuanqing Gao
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Zhang
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Military Preventive Medicine, Air Force Military Medical University, Xi'an, China
| | - Yi Han
- Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hong Wang
- Centers for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA
| | - Jun Pu
- State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, School of Medicine, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Liping Xie
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China.,Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
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27
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Xu F, Guo W. The progress of epigenetics in the development and progression of non-alcoholic fatty liver disease. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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28
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The role of histone methylation in the development of digestive cancers: a potential direction for cancer management. Signal Transduct Target Ther 2020; 5:143. [PMID: 32747629 PMCID: PMC7398912 DOI: 10.1038/s41392-020-00252-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/22/2020] [Accepted: 07/15/2020] [Indexed: 02/08/2023] Open
Abstract
Digestive cancers are the leading cause of cancer-related death worldwide and have high risks of morbidity and mortality. Histone methylation, which is mediated mainly by lysine methyltransferases, lysine demethylases, and protein arginine methyltransferases, has emerged as an essential mechanism regulating pathological processes in digestive cancers. Under certain conditions, aberrant expression of these modifiers leads to abnormal histone methylation or demethylation in the corresponding cancer-related genes, which contributes to different processes and phenotypes, such as carcinogenesis, proliferation, metabolic reprogramming, epithelial–mesenchymal transition, invasion, and migration, during digestive cancer development. In this review, we focus on the association between histone methylation regulation and the development of digestive cancers, including gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer, as well as on its clinical application prospects, aiming to provide a new perspective on the management of digestive cancers.
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29
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Alharthi J, Latchoumanin O, George J, Eslam M. Macrophages in metabolic associated fatty liver disease. World J Gastroenterol 2020; 26:1861-1878. [PMID: 32390698 PMCID: PMC7201150 DOI: 10.3748/wjg.v26.i16.1861] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/10/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries. The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis, hepatocellular carcinoma, liver transplantation, and death, but also to extrahepatic complications including cardiovascular disease, diabetes and chronic kidney disease. The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development. This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis, inflammation, fibrosis, and hepatocellular carcinoma, as well as for the extra-hepatic manifestations of MAFLD. We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes, hepatic stellate cells, and adipose tissue. We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
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Affiliation(s)
- Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney 2145, NSW, Australia
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30
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Wang J, Deng M, Wu H, Wang M, Gong J, Bai H, Wu Y, Pan J, Chen Y, Li S. Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation‑induced hepatic ischemia‑reperfusion injury by regulating the AKT/GSK3β/NF‑κB and AKT/mTOR pathways in rat Kupffer cells. Int J Mol Med 2020; 45:1875-1887. [PMID: 32236599 PMCID: PMC7169828 DOI: 10.3892/ijmm.2020.4551] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 03/06/2020] [Indexed: 12/26/2022] Open
Abstract
Multiple mechanisms are involved in regulating hepatic ischemia-reperfusion injury (IRI), in which Kupffer cells (KCs), which are liver-resident macrophages, play critical roles by regulating inflammation and the immune response. Suberoylanilide hydroxamic acid (SAHA), a pan-histone deacetylase inhibitor, has anti-inflammatory effects and induces autophagy. To investigate whether SAHA ameliorates IRI and the mechanisms by which SAHA exerts its effects, an orthotopic liver transplantation (OLT) rat model was established after treatment with SAHA. The results showed that SAHA effectively ameliorated OLT-induced IRI by reducing M1 polarization of KCs through inhibition of the AKT/glycogen synthase kinase (GSK)3β/NF-κB signaling pathway. Furthermore, the present study found that SAHA upregulates autophagy 5 protein (ATG5)/LC3B in KCs through the AKT/mTOR signaling pathway and inhibition of autophagy by knockdown of ATG5 in KCs partly impaired the protective effect of SAHA on IR-injured liver. Therefore, the current study demonstrated that SAHA reduces M1 polarization of KCs by inhibiting the AKT/GSK3β/NF-κB pathway and upregulates autophagy in KCs through the AKT/mTOR signaling pathway, which both alleviate OLT-induced IRI. The present study revealed that SAHA may be a novel treatment for the amelioration of OLT-induced IRI.
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Affiliation(s)
- Jingyuan Wang
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Minghua Deng
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Menghao Wang
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - He Bai
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yakun Wu
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan 629000, P.R. China
| | - Junjiang Pan
- Department of General Surgery, Second People's Hospital of Yibin City, Yibin, Sichuan 644000, P.R. China
| | - Yong Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, P.R. China
| | - Shengwei Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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31
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Roderburg C, Wree A, Demir M, Schmelzle M, Tacke F. The role of the innate immune system in the development and treatment of hepatocellular carcinoma. Hepat Oncol 2020; 7:HEP17. [PMID: 32273975 PMCID: PMC7137177 DOI: 10.2217/hep-2019-0007] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Most patients present with advanced or metastatic HCC at diagnosis and face a dismal prognosis. Tyrosine kinases are the gold standard treatment for this disease but yield limited survival benefits. Immune checkpoint inhibitors that augment adaptive immunity have been tested in HCC. Complex interactions between tumor cells, lymphocytes and the tumor environment determine the efficacy of such immunotherapies. Innate immune mechanisms – known drivers of liver disease progression in pre-HCC conditions such as fibrosis or cirrhosis – may either support or counteract tumor-related immune activation. In this review, we will highlight current concepts of the role of the innate immune system in hepatocarcinogenesis and discuss their relevance for translation into clinics.
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Affiliation(s)
- Christoph Roderburg
- Department of Hepatology & Gastroenterology, Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin Institute of Health, Augustenburger, Platz 1 13353, Berlin
| | - Alexander Wree
- Department of Hepatology & Gastroenterology, Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin Institute of Health, Augustenburger, Platz 1 13353, Berlin
| | - Münevver Demir
- Department of Hepatology & Gastroenterology, Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin Institute of Health, Augustenburger, Platz 1 13353, Berlin
| | - Moritz Schmelzle
- Department of Surgery, Charité, Universitätsmedizin Berlin,Humboldt-Universität zu Berlin, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin Institute of Health, Augustenburger, Platz 1 13353, Berlin
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin Institute of Health, Augustenburger, Platz 1 13353, Berlin
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32
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Sun P, Zhang SJ, Maksim S, Yao YF, Liu HM, Du J. Epigenetic Modification in Macrophages: A Promising Target for Tumor and Inflammation-associated Disease Therapy. Curr Top Med Chem 2019; 19:1350-1362. [PMID: 31215380 DOI: 10.2174/1568026619666190619143706] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 04/25/2019] [Accepted: 05/09/2019] [Indexed: 01/13/2023]
Abstract
Macrophages are essential for supporting tissue homeostasis, regulating immune response, and promoting tumor progression. Due to its heterogeneity, macrophages have different phenotypes and functions in various tissues and diseases. It is becoming clear that epigenetic modification playing an essential role in determining the biological behavior of cells. In particular, changes of DNA methylation, histone methylation and acetylation regulated by the corresponding epigenetic enzymes, can directly control macrophages differentiation and change their functions under different conditions. In addition, epigenetic enzymes also have become anti-tumor targets, such as HDAC, LSD1, DNMT, and so on. In this review, we presented an overview of the latest progress in the study of macrophages phenotype and function regulated by epigenetic modifications, including DNA methylation and histone modifications, to better understand how epigenetic modification controls macrophages phenotype and function in inflammation-associated diseases, and the application prospect in anti-tumor.
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Affiliation(s)
- Pei Sun
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, China
| | - Shu-Jing Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, China
| | - Semenov Maksim
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, China
| | - Yong-Fang Yao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, China
| | - Juan Du
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
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Kong M, Chen X, Lv F, Ren H, Fan Z, Qin H, Yu L, Shi X, Xu Y. Serum response factor (SRF) promotes ROS generation and hepatic stellate cell activation by epigenetically stimulating NCF1/2 transcription. Redox Biol 2019; 26:101302. [PMID: 31442911 PMCID: PMC6831835 DOI: 10.1016/j.redox.2019.101302] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/25/2022] Open
Abstract
Activation of hepatic stellate cells (HSC) is a hallmark event in liver fibrosis. Accumulation of reactive oxygen species (ROS) serves as a driving force for HSC activation. The regulatory subunits of the NOX complex, NCF1 (p47phox) and NCF2 (p67phox), are up-regulated during HSC activation contributing to ROS production and liver fibrosis. The transcriptional mechanism underlying NCF1/2 up-regulation is not clear. In the present study we investigated the role of serum response factor (SRF) in HSC activation focusing on the transcriptional regulation of NCF1/2. We report that compared to wild type littermates HSC-conditional SRF knockout (CKO) mice exhibited a mortified phenotype of liver fibrosis induced by thioacetamide (TAA) injection or feeding with a methionine-and-choline deficient diet (MCD). More importantly, SRF deletion attenuated ROS levels in HSCs in vivo. Similarly, SRF knockdown in cultured HSCs suppressed ROS production in vitro. Further analysis revealed that SRF deficiency resulted in repression of NCF1/NCF2 expression. Mechanistically, SRF regulated epigenetic transcriptional activation of NCF1/NCF2 by interacting with and recruiting the histone acetyltransferase KAT8 during HSC activation. In conclusion, we propose that SRF integrates transcriptional activation of NCF1/NCF2 and ROS production to promote liver fibrosis.
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Affiliation(s)
- Ming Kong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xuyang Chen
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Fangqiao Lv
- Department of Cell Biology and the Municipal Laboratory of Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Haozhen Ren
- Department of Hepato-biliary Surgery and Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhiwen Fan
- Department of Hepato-biliary Surgery and Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Hao Qin
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Liming Yu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiaolei Shi
- Department of Hepato-biliary Surgery and Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
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Li B, Zheng Y, Yang L. The Oncogenic Potential of SUV39H2: A Comprehensive and Perspective View. J Cancer 2019; 10:721-729. [PMID: 30719171 PMCID: PMC6360419 DOI: 10.7150/jca.28254] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 11/09/2018] [Indexed: 02/07/2023] Open
Abstract
Epigenetic modifications at the histone level have attracted significant attention because of their roles in tumorigenesis. Suppressor of variegation 3-9 homolog 2 (SUV39H2, also known as KMT1B) is a member of the SUV39 subfamily of lysine methyltransferases (KMTs) that plays a significant role in histone H3-K9 di-/tri-methylation, transcriptional regulation and cell cycle. Overexpressions of SUV39H2 at gene, mRNA and protein levels are known to be associated with a range of cancers: leukemia, lymphomas, lung cancer, breast cancer, colorectal cancer, gastric cancer, hepatocellular cancer and so on. Accumulating evidence indicates that SUV39H2 acts as an oncogene and contributes to the initiation and progression of cancers. It could, therefore, be a promising target for anti-cancer treatment. In this review, we focus on the dysregulation of SUV39H2 in cancers, including its clinical prognostic predictor role, molecular mechanism involved in cancer occurrence and development, relevant inhibitors against cancer, and its epigenetic modification interaction with immunotherapy. A better understanding of the SUV39H2 will be beneficial to the development of molecular-targeted therapies in cancer.
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Affiliation(s)
- Baihui Li
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Yu Zheng
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Lili Yang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
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35
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Zheng Y, Li B, Wang J, Xiong Y, Wang K, Qi Y, Sun H, Wu L, Yang L. Identification of SUV39H2 as a potential oncogene in lung adenocarcinoma. Clin Epigenetics 2018; 10:129. [PMID: 30348215 PMCID: PMC6198372 DOI: 10.1186/s13148-018-0562-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 10/09/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND SUV39H2 (suppressor of variegation 3-9 homolog 2), which introduces H3K9me3 to induce transcriptional repression, has been reported to play critical roles in heterochromatin maintenance, DNA repair, and recently, carcinogenesis. Dysregulation of SUV39H2 expression has been observed in several types of cancers. However, neither the genomic landscape nor the clinical significance of SUV39H2 in lung adenocarcinoma has been probed comprehensively. METHODS In this research, we conducted bioinformatics analysis to primarily sort out potential genes with dysregulated expressions. After we identified SUV39H2, RNA-seq was performed for a high-throughput evaluation of altered gene expression and dysregulated pathways, followed by a series of validations via RT-qPCR and bioinformatics analyses. Finally, to assess the potential oncogenic role of SUV39H2, we employed the invasion assay and clone formation assay in vitro and tumorigenesis assays in mouse models in vivo. RESULTS Through bioinformatics analyses, we found that SUV39H2 underwent a severe upregulation in the tumor tissue, which was also confirmed in the surgically removed tissues. Overexpression of SUV39H2 was mainly associated with its amplification and with shorter patient overall survival. Then, the RNA-seq demonstrated that TPM4, STOM, and OPTN might be affected by the loss of function of SUV39H2. Finally, in vitro and in vivo experiments with SUV39H2 knockdown all suggested a potential role of SUV39H2 in both carcinogenesis and metastasis. CONCLUSIONS SUV39H2 expression was elevated in lung adenocarcinoma. TPM4, OPTN, and STOM were potentially regulated by SUV39H2. SUV39H2 might be a potential oncogene in lung adenocarcinoma, mediating tumorigenesis and metastasis.
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Affiliation(s)
- Yu Zheng
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Baihui Li
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Jian Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Yanjuan Xiong
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Kaiyuan Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Ying Qi
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Houfang Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Lei Wu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Lili Yang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. .,National Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. .,Tianjin's Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
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36
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Li Z, Zhang X, Liu S, Zeng S, Yu L, Yang G, Guo J, Xu Y. BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3477-3486. [DOI: 10.1016/j.bbadis.2018.08.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 07/14/2018] [Accepted: 08/01/2018] [Indexed: 12/24/2022]
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37
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Liu W, Ye C, Cheng Q, Zhang X, Yao L, Li Q, Huang J, Liu Y, Zou Z, Wang H, Yan J, Zhu Y, Wang C, Ai D. Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol 2018; 7:211-231. [PMID: 30539788 PMCID: PMC6282883 DOI: 10.1016/j.jcmgh.2018.09.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 09/11/2018] [Accepted: 09/11/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown. METHODS mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH. RESULTS We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter's phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency-mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1-dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13. CONCLUSIONS Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs.
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Affiliation(s)
- Wenli Liu
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Chenji Ye
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Qian Cheng
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Xuejiao Zhang
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Liu Yao
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Qi Li
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jing Huang
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Yajin Liu
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Zhengsheng Zou
- The Center for Non-infectious Liver Diseases, Beijing 302 Military Hospital, Beijing, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Yan
- Department of Pathology, Tianjin First Center Hospital, Tianjin, China
| | - Yi Zhu
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Chunjiong Wang
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
| | - Ding Ai
- Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
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38
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Li N, Kong M, Zeng S, Xu Z, Li M, Hong W, Chu X, Sun X, Zhu M, Xu Y. The chromatin remodeling protein BRG1 regulates APAP-induced liver injury by modulating CYP3A11 transcription in hepatocyte. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3487-3495. [PMID: 30293568 DOI: 10.1016/j.bbadis.2018.08.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 07/12/2018] [Accepted: 08/01/2018] [Indexed: 12/22/2022]
Abstract
Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure. The underlying epigenetic mechanism is not fully understood. In the present study we investigated the mechanism whereby the chromatin remodeling protein brahma related gene 1 (Brg1) regulates APAP induced liver injury in mice. We report that hepatocyte-specific deletion of Brg1 attenuated APAP induced liver injury in mice as evidenced by reduced plasma ALT and AST levels, decreased liver necrosis, amelioration of GSH depletion, and prolonged survival. Brg1 regulated APAP-induced liver injury likely by stimulating the transcription of Cyp3a11, a key cytochrome enzyme involved in APAP metabolism. Immunoprecipitation coupled with DNA affinity microarray identified hepatocyte nuclear factor 4 (HNF4) as a novel binding partner for Brg1. HNF4 recruited Brg1 to the Cyp3a11 promoter and formed a complex with Brg1 to trans-activate Cyp3a11. In contrast, BRG1 deficiency attenuated HNF4 binding to the Cyp3a11 promoter and dampened Cyp3a11 transcription. Therefore, our data suggest that Brg1 might play an essential role mediating APAP induced liver injury in vivo.
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Affiliation(s)
- Nan Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Ming Kong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Sheng Zeng
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Zheng Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Min Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Wenxuan Hong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Xuehui Chu
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Xitai Sun
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China
| | - Min Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Anatomy, Nanjing Medical University, Nanjing, China.
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
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Zhang X, Liu S, Weng X, Zeng S, Yu L, Guo J, Xu Y. Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice. Int J Cardiol 2018; 269:250-258. [PMID: 30049497 DOI: 10.1016/j.ijcard.2018.07.105] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 07/14/2018] [Accepted: 07/20/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Increased neutrophil infiltration and the ensuing inflammatory response represent a hallmark event in cardiac ischemia-reperfusion injury (IRI). It remains poorly defined how the epigenetic machinery contributes to this process. METHODS AND RESULTS Here we report that mice with endothelial specific deletion of brahma related gene 1 (BRG1), a chromatin remodeling protein, exhibited amelioration when subjected to cardiac ischemia-reperfusion as evidenced by a reduction in infarct size as well as better recovery of heart function. Endothelial BRG1 deficiency also attenuated cardiac fibrosis following IRI when compared to wild type littermates. Interestingly, ablation of BRG1 in the endothelium suppressed neutrophil infiltration and down-regulated the levels of pro-inflammatory mediators in the heart following IRI. Further studies revealed that BRG1 activated the transcription of PODOCALYXIN (PODXL), an L-SELECTIN ligand crucial for neutrophil adhesion, in vascular endothelial cells in response to hypoxia-reoxygenation (HR). BRG1 knockdown by small interfering RNA abrogated HR-induced PODXL expression and blocked the adhesion of neutrophils to endothelial cells. Mechanistically, BRG1 alters the chromatin structure surrounding the PODXL promoter by interacting with JMJD2B, a histone H3K9 demethylase. Depletion of JMJD2B abrogated PODXL induction by HR and inhibited the adhesion of neutrophils to endothelial cells. CONCLUSION Our data suggest that trans-activation of PODXL by the BRG1-JMJD2B complex in endothelial cells may promote neutrophil infiltration and consequently the pathogenesis of cardiac ischemia-reperfusion injury.
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Affiliation(s)
- Xinjian Zhang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Shuai Liu
- Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, China
| | - Xinyu Weng
- Institute of Biomedical Science, Fudan University, Shanghai, China
| | - Sheng Zeng
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Liming Yu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Junli Guo
- Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, China.
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
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40
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Li N, Kong M, Zeng S, Hao C, Li M, Li L, Xu Z, Zhu M, Xu Y. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β-catenin pathway in mice. FASEB J 2018; 33:327-338. [PMID: 30001167 DOI: 10.1096/fj.201800197r] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver regeneration is a complicated pathophysiologic process that is regulated by a myriad of signaling pathways and transcription factors. The interaction among these pathways and factors, either cooperatively or antagonistically, may ultimately lead to recovery and restoration of liver function or permanent loss of liver function and liver failure. In the present study, we investigated the mechanism whereby the chromatin remodeling protein brahma related gene 1 (Brg1) regulates liver regeneration in mice. The Smarca4-Flox strain of mice was crossbred with the Alb-Cre strain to generate hepatocyte-specific Brg1 knockout mice. Liver injury was induced by partial hepatectomy (PHx). We report that Brg1 deletion in hepatocyte compromised liver regeneration and dampened survival after PHx in mice. Brg1 interacted with β-catenin to potentiate Wnt signaling and promote hepatocyte proliferation. Mechanistically, Brg1 recruited lysine demethylase 4 (KDM4) to activate β-catenin target genes. Our data suggest that Brg1 might play an essential role maintaining hepatic homeostasis and contributing to liver repair.-Li, N., Kong, M., Zeng, S., Hao, C., Li, M., Li, L., Xu, Z., Zhu, M., Xu, Y. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β-catenin pathway in mice.
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Affiliation(s)
- Nan Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Ming Kong
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Sheng Zeng
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Chenzhi Hao
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Min Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Luyang Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Zheng Xu
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Min Zhu
- Department of Anatomy, Nanjing Medical University, Nanjing, China
| | - Yong Xu
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
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41
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Hepatocyte-specific deletion of Brg1 alleviates methionine-and-choline-deficient diet (MCD) induced non-alcoholic steatohepatitis in mice. Biochem Biophys Res Commun 2018; 503:344-351. [PMID: 29890136 DOI: 10.1016/j.bbrc.2018.06.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 06/07/2018] [Indexed: 12/22/2022]
Abstract
Uncontrolled inflammatory response and augmented lipid accumulation represent two key pathophysiological events in the pathogenesis of non-alcoholic steatohepatitis (NASH). NF-κB and SREBP1c program transcriptional regulation of cellular inflammatory response and lipid metabolism, respectively. The epigenetic mechanism underlying NF-κB-dependent pro-inflammatory transcription and SREBP1c-dependent pro-lipogenic transcription remains incompletely understood. In the present study we investigated the involvement of Brg1, a chromatin remodeling protein, in NASH pathogenesis in a methionine-and-choline deficient diet (MCD) induced mouse model. Brg1 expression was up-regulated in the liver in mice fed on the MCD diet and in primary hepatocytes exposed to free fatty acids. Liver injury and hepatic inflammation attenuated in hepatocyte-specific Brg1 knockout (CKO) mice fed on the MCD diet compared to the wild type (WT) littermates. Likewise, synthesis of pro-inflammatory mediators was down-regulated in primary hepatocytes isolated from CKO mice compared to WT mice, which resulted in reduced macrophage chemotaxis. Brg1 contributed to the transcription of pro-inflammatory mediators possibly by regulating the interaction between NF-κB and its co-factor MRTF-A. On the other hand, accumulation of triglyceride and cholesterol was ameliorated in MCD-fed CKO mice with a concomitant reduction of SREBP1c target genes. Brg1 interacted with SREBP1c and modulated the transcription of SREB1c target genes in the liver in response to MCD feeding by influencing active histone modifications. In conclusion, targeting Brg1 may yield novel anti-NASH therapeutics by simultaneously normalizing hepatic inflammatory status and metabolic profile in NASH patients.
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Animal models of NAFLD from the pathologist's point of view. Biochim Biophys Acta Mol Basis Dis 2018; 1865:929-942. [PMID: 29746920 DOI: 10.1016/j.bbadis.2018.04.024] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 04/25/2018] [Accepted: 04/30/2018] [Indexed: 01/18/2023]
Abstract
Fatty liver disease is a multifactorial world-wide health problem resulting from a complex interplay between liver, adipose tissue and intestine and initiated by alcohol abuse, overeating, various types of intoxication, adverse drug reactions and genetic or acquired metabolic defects. Depending on etiology fatty liver disease is commonly categorized as alcoholic or non-alcoholic. Both types may progress from simple steatosis to the necro-inflammatory lesion of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH), respectively, and finally to cirrhosis and hepatocellular carcinoma. Animal models are helpful to clarify aspects of pathogenesis and progression. Generally, they are classified as nutritional (dietary), toxin-induced and genetic, respectively, or represent a combination of these factors. Numerous reviews are dealing with NASH animal models designed to imitate as closely as possible the metabolic situation associated with human disease. This review focuses on currently used mouse models of NASH with particular emphasis on liver morphology. Despite metabolic similarities most models (except those with chemically or genetically induced porphyria or keratin 18-deficiency) fail to develop the morphologic key features of NASH, namely hepatocyte ballooning and formation of histologically and immunohistochemically well-defined Mallory-Denk-Bodies (MDBs). Although MDBs are not universally detectable in ballooned hepatocytes in NASH their experimental reproduction and analysis may, however, significantly contribute to our understanding of important pathogenic aspects of NASH despite the obvious differences in etiology.
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SUV39H2 promotes colorectal cancer proliferation and metastasis via tri-methylation of the SLIT1 promoter. Cancer Lett 2018; 422:56-69. [PMID: 29458143 DOI: 10.1016/j.canlet.2018.02.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/30/2018] [Accepted: 02/12/2018] [Indexed: 01/01/2023]
Abstract
Suppressor of variegation 3-9 homolog 2 (SUV39H2) is a member of the SUV39H subfamily of lysine methyltransferases. Its role in colorectal cancer (CRC) proliferation and metastasis has remained unexplored. Here, we determined that SUV39H2 was upregulated in CRC tissues compared with that in adjacent non-neoplastic tissues. Further statistical analysis revealed that high SUV39H2 expression was strongly associated with distant metastasis (P = 0.016) and TNM stage (P = 0.038) and predicted a shorter overall survival (OS; P = 0.018) and progression-free survival (PFS; P = 0.018) time for CRC patients. Both in vitro and in vivo assays demonstrated that ectopically expressed SUV39H2 enhanced CRC proliferation and metastasis, while SUV39H2 knockdown inhibited CRC proliferation and metastasis. A molecular screen of SUV39H2 targets found that SUV39H2 negatively regulated the expression of SLIT guidance ligand 1 (SLIT1). Moreover, rescue assays suggested that SLIT1 could antagonize the function of SUV39H2 in CRC. Mechanistic studies indicated that SUV39H2 can directly bind to the SLIT1 promoter, suppressing SLIT1 transcription by catalyzing histone H3 lysine 9 (H3K9) tri-methylation. In summary, we propose that SUV39H2 can predict CRC patient prognosis and stimulate CRC malignant phenotypes via SLIT1 promoter tri-methylation.
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Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol 2018; 19:222-232. [PMID: 29379119 DOI: 10.1038/s41590-018-0044-z] [Citation(s) in RCA: 721] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023]
Abstract
In contrast to most other malignancies, hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancers, arises almost exclusively in the setting of chronic inflammation. Irrespective of etiology, a typical sequence of chronic necroinflammation, compensatory liver regeneration, induction of liver fibrosis and subsequent cirrhosis often precedes hepatocarcinogenesis. The liver is a central immunomodulator that ensures organ and systemic protection while maintaining immunotolerance. Deregulation of this tightly controlled liver immunological network is a hallmark of chronic liver disease and HCC. Notably, immunotherapies have raised hope for the successful treatment of advanced HCC. Here we summarize the roles of specific immune cell subsets in chronic liver disease, with a focus on non-alcoholic steatohepatitis and HCC. We review new advances in immunotherapeutic approaches for the treatment of HCC and discuss the challenges posed by the immunotolerant hepatic environment and the dual roles of adaptive and innate immune cells in HCC.
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Affiliation(s)
- Marc Ringelhan
- Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany.,Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich, Munich, Germany.,German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Tracy O'Connor
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munich, Munich, Germany.,Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany
| | - Eli Pikarsky
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada and Department of Pathology, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany. .,Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
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45
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Liu L, Chen J, Sun L, Xu Y. RhoJ promotes hypoxia induced endothelial‐to‐mesenchymal transition by activating WDR5 expression. J Cell Biochem 2018; 119:3384-3393. [DOI: 10.1002/jcb.26505] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 11/07/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Li Liu
- Key Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine,Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Junliang Chen
- Key Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine,Department of PathophysiologyNanjing Medical UniversityNanjingChina
- Department of Pathophysiology, Wuxi College of MedicineJiangnan UniversityJiangsuChina
| | - Lina Sun
- Key Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine,Department of PathophysiologyNanjing Medical UniversityNanjingChina
- Department of Pathology and PathophysiologySoochow UniversityJiangsuChina
| | - Yong Xu
- Key Laboratory of Targeted Invention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine,Department of PathophysiologyNanjing Medical UniversityNanjingChina
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46
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Hepatic stellate cell-specific deletion of SIRT1 exacerbates liver fibrosis in mice. Biochim Biophys Acta Mol Basis Dis 2017; 1863:3202-3211. [DOI: 10.1016/j.bbadis.2017.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 08/23/2017] [Accepted: 09/08/2017] [Indexed: 01/15/2023]
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47
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Zhang X, Chen J, Sun L, Xu Y. SIRT1 deacetylates KLF4 to activate Claudin-5 transcription in ovarian cancer cells. J Cell Biochem 2017; 119:2418-2426. [PMID: 28888043 DOI: 10.1002/jcb.26404] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 08/30/2017] [Indexed: 12/23/2022]
Abstract
Malignant cancers are distinguished from more benign forms of cancers by enhanced ability to disseminate. A number of factors aid the migration and invasion of malignant cancer cells. Epithelial-to-mesenchymal transition (EMT), which greatly facilitates the dissemination of cancer cells, is characterized by the loss of epithelial markers and the acquisition of mesenchymal markers thereby rendering the cells more migratory and invasive. We have previously shown that the class III lysine deacetylase SIRT1 plays a critical role curbing the metastasis of ovarian cancer cells partly by blocking EMT. Here we investigated the mechanism by which SIRT1 regulates the transcription of Claudin 5 (CLDN5), an epithelial marker gene, in ovarian cancer cells. SIRT1 activation or over-expression up-regulated CLDN5 expression while SIRT1 inhibition or depletion down-regulated CLDN5 expression. SIRT1 interacted with and deacetylated Kruppel-like factor 4 (KLF4), a known transcriptional activator for CLDN5. Deacetylation by SIRT1 promoted nuclear accumulation of KLF4 and enhanced the binding of KLF4 to the CLDN5 promoter in the nucleus. SIRT1-mediated up-regulation of CLDN5 was abrogated in the absence of KLF4. In accordance, KLF4 depletion by siRNA rendered ovarian cancer cells more migratory and invasive despite of SIRT1 activation or over-expression. In conclusion, our data suggest that SIRT1 activates CLDN5 transcription by deacetylating and potentiating KLF4.
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Affiliation(s)
- Xinjian Zhang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Junliang Chen
- Department of Pathophysiology, Wuxi College of Medicine, Jiangnan University, Nanjing, Jiangsu, China
| | - Lina Sun
- Department of Pathology and Pathophysiology, Soochow University, Suzhou, Jiangsu, China
| | - Yong Xu
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
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48
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Li M, Hong W, Hao C, Li L, Wu D, Shen A, Lu J, Zheng Y, Li P, Xu Y. SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice. FASEB J 2017; 32:500-511. [PMID: 28970250 DOI: 10.1096/fj.201700612r] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/11/2017] [Indexed: 01/10/2023]
Abstract
Hepatic stellate cells (HSCs) are a major source of fibrogenesis in the liver, contributing to cirrhosis. When activated, HSCs transdifferentiate into myofibroblasts and undergo profound functional alterations paralleling an overhaul of the transcriptome, the mechanism of which remains largely undefined. We investigated the involvement of the class III deacetylase sirtuin [silent information regulator 1 (SIRT1)] in HSC activation and liver fibrosis. SIRT1 levels were down-regulated in the livers in mouse models of liver fibrosis, in patients with cirrhosis, and in activated HSCs as opposed to quiescent HSCs. SIRT1 activation halted, whereas SIRT1 inhibition promoted, HSC transdifferentiation into myofibroblasts. Liver fibrosis was exacerbated in mice with HSC-specific deletion of SIRT1 [conditional knockout (cKO)], receiving CCl4 (1 mg/kg) injection or subjected to bile duct ligation, compared to wild-type littermates. SIRT1 regulated peroxisome proliferator activated receptor γ (PPARγ) transcription by deacetylating enhancer of zeste homolog 2 (EZH2) in quiescent HSCs. Finally, EZH2 inhibition or PPARγ activation ameliorated fibrogenesis in cKO mice. In summary, our data suggest that SIRT1 plays an essential role guiding the transition of HSC phenotypes.-Li, M., Hong, W., Hao, C., Li, L., Wu, D., Shen, A., Lu, J., Zheng, Y., Li, P., Xu, Y. SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice.
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Affiliation(s)
- Min Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Wenxuan Hong
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Chenzhi Hao
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Luyang Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Dongmei Wu
- Key Laboratory of Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - Aiguo Shen
- Key Laboratory of Inflammation and Molecular Targets, Nantong University College of Medicine, Nantong, China
| | - Jun Lu
- Key Laboratory of Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China;
| | - Yuanlin Zheng
- Key Laboratory of Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China
| | - Ping Li
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China
| | - Yong Xu
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China;
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