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1
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Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
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Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
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2
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Cao D, Liu H. Dysregulated cholesterol regulatory genes in hepatocellular carcinoma. Eur J Med Res 2023; 28:580. [PMID: 38071335 PMCID: PMC10710719 DOI: 10.1186/s40001-023-01547-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Cholesterol is an indispensable component in mammalian cells, and cholesterol metabolism performs important roles in various biological activities. In addition to the Warburg effect, dysregulated cholesterol metabolism is one of the metabolic hallmarks of several cancers. It has reported that reprogrammed cholesterol metabolism facilitates carcinogenesis, metastasis, and drug-resistant in various tumors, including hepatocellular carcinoma (HCC). Some literatures have reported that increased cholesterol level leads to lipotoxicity, inflammation, and fibrosis, ultimately promoting the development and progression of HCC. Contrarily, other clinical investigations have demonstrated a link between higher cholesterol level and lower risk of HCC. These incongruent findings suggest that the connection between cholesterol and HCC is much complicated. In this report, we summarize the roles of key cholesterol regulatory genes including cholesterol biosynthesis, uptake, efflux, trafficking and esterification in HCC. In addition, we discuss promising related therapeutic targets for HCC.
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Affiliation(s)
- Dan Cao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, No. 1 the South of Maoyuan Road, Nanchong, 637000, Sichuan, People's Republic of China
| | - Huan Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
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3
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Han N, Yuan M, Yan L, Tang H. Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers. Biomolecules 2023; 13:1184. [PMID: 37627249 PMCID: PMC10452869 DOI: 10.3390/biom13081184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.
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Affiliation(s)
- Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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4
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Gong Z, Yan Z, Liu W, Luo B. Oncogenic viruses and host lipid metabolism: a new perspective. J Gen Virol 2023; 104. [PMID: 37279154 DOI: 10.1099/jgv.0.001861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.
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Affiliation(s)
- Zhiyuan Gong
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Zhiyong Yan
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
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5
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Li Y, Wu S, Zhao X, Hao S, Li F, Wang Y, Liu B, Zhang D, Wang Y, Zhou H. Key events in cancer: Dysregulation of SREBPs. Front Pharmacol 2023; 14:1130747. [PMID: 36969840 PMCID: PMC10030587 DOI: 10.3389/fphar.2023.1130747] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.
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Affiliation(s)
- Yunkuo Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shouwang Wu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Xiaodong Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shiming Hao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yuxiong Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Difei Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
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6
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Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece,*Correspondence: Stelios F. Assimakopoulos,
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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Diaz O, Vidalain PO, Ramière C, Lotteau V, Perrin-Cocon L. What role for cellular metabolism in the control of hepatitis viruses? Front Immunol 2022; 13:1033314. [PMID: 36466918 PMCID: PMC9713817 DOI: 10.3389/fimmu.2022.1033314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.
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Affiliation(s)
- Olivier Diaz
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Christophe Ramière
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
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8
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Zou X, Yang Y, Lin F, Chen J, Zhang H, Li L, Ouyang H, Pang D, Ren L, Tang X. Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis. iScience 2022; 25:105353. [PMID: 36339254 PMCID: PMC9626675 DOI: 10.1016/j.isci.2022.105353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 11/29/2022] Open
Abstract
An emerging topic in virology is that viral replication is closely linked with the metabolic reprogramming of host cells. Understanding the effects of reprogramming host cell metabolism due to classical swine fever virus (CSFV) infection and the underling mechanisms would facilitate controlling the spread of classical swine fever (CSF). In the current study, we found that CSFV infection enhanced aerobic glycolysis in PK-15 cells. Blocking glycolysis with 2-deoxy-d-glycose or disrupting the enzymes PFKL and LDHA decreased CSFV replication. Lactate was identified as an important molecule in CSFV replication, independent of the pentose phosphate pathway and tricarboxylic acid cycle. Further analysis demonstrated that the accumulated lactate in cells promoted cholesterol biosynthesis, which facilitated CSFV replication and disrupted the type I interferon response during CSFV replication, and the disruption of cholesterol synthesis abolished the lactate effects on CSFV replication. The results provided more insights into the complex pathological mechanisms of CSFV.
Aerobic glycolysis plays an important role in CSFV replication Intracellular lactate maintains CSFV replication as an effector of glycolysis Lactate promotes cholesterol biosynthesis to maintain CSFV replication Enhanced cholesterol biosynthesis inhibited the response of IFNs during CSFV replication
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Affiliation(s)
- Xiaodong Zou
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yang Yang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Feng Lin
- College of Animal Sciences, Jilin University, Changchun, China
| | - Jiahuan Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Huanyu Zhang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Linquan Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Hongsheng Ouyang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Daxin Pang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
| | - Linzhu Ren
- College of Animal Sciences, Jilin University, Changchun, China
- Corresponding author
| | - Xiaochun Tang
- College of Animal Sciences, Jilin University, Changchun, China
- Chongqing Research Institute of Jilin University, Chongqing, China
- Corresponding author
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9
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Farías MA, Diethelm-Varela B, Navarro AJ, Kalergis AM, González PA. Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections. Cells 2022; 11:2224. [PMID: 35883666 PMCID: PMC9324743 DOI: 10.3390/cells11142224] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 12/10/2022] Open
Abstract
Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections.
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Affiliation(s)
- Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Areli J. Navarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
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10
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Boulahtouf Z, Virzì A, Baumert TF, Verrier ER, Lupberger J. Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences. Int J Mol Sci 2022; 23:ijms23052787. [PMID: 35269929 PMCID: PMC8911453 DOI: 10.3390/ijms23052787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein-host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.
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Affiliation(s)
- Zakaria Boulahtouf
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Alessia Virzì
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Thomas F. Baumert
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Service d’Hépato-Gastroentérologie, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
- Institut Universitaire de France (IUF), F-75005 Paris, France
| | - Eloi R. Verrier
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Joachim Lupberger
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Correspondence:
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11
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The interplay between non-alcoholic fatty liver disease and innate immunity in hepatitis B virus patients. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00084-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most epidemic liver disorder worldwide as a result of rapid lifestyle transformation over the past few decades and is expected to elevate in the next few years as well as it is ranging from plain hepatic steatosis via non-alcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC).
Main text
NAFLD can also stimulate the diseases progression as diabetes and cardiovascular. Therefore, understanding the NAFLD pathogenesis is of vital clinical interest additionally is a crucial for disease treatment and prevention. After analyzing NAFLD and liver diseases prevalence, it has been a belief regarding the interaction between NAFLD and chronic hepatitis B (CHB).
Conclusion
The liver is an essential innate immune organ with large numbers of innate immune cells that contribute in NAFLD pathogenesis, additionally play the influential role that control NAFLD progression in the hepatitis B patients. Here, we summarized the recent advances in understanding and managing the NAFLD patients with chronic hepatitis B infection and interplay with innate immunity.
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12
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Hu Y, He W, Huang Y, Xiang H, Guo J, Che Y, Cheng X, Hu F, Hu M, Ma T, Yu J, Tian H, Tian S, Ji YX, Zhang P, She ZG, Zhang XJ, Huang Z, Yang J, Li H. Fatty Acid Synthase-Suppressor Screening Identifies Sorting Nexin 8 as a Therapeutic Target for NAFLD. Hepatology 2021; 74:2508-2525. [PMID: 34231239 DOI: 10.1002/hep.32045] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. METHODS AND RESULTS Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocyte-specific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression. CONCLUSIONS These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment.
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Affiliation(s)
- Yufeng Hu
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China
| | - Wenzhi He
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, China
| | - Yongping Huang
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, China
| | - Hui Xiang
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Juan Guo
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, China
| | - Yan Che
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Cheng
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fengjiao Hu
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China
| | - Manli Hu
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China
| | - Tengfei Ma
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jie Yu
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Han Tian
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Song Tian
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan-Xiao Ji
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China.,Basic Medical School, Wuhan University, Wuhan, China
| | - Zhi-Gang She
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China.,Basic Medical School, Wuhan University, Wuhan, China
| | - Zan Huang
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, China
| | - Juan Yang
- Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongliang Li
- College of Life Sciences, Medical Science Research Center, Zhongnan Hospital, Wuhan University, Wuhan, China.,Institute of Model Animal, Wuhan University, Wuhan, China.,Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Basic Medical School, Wuhan University, Wuhan, China
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13
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Wang X, Wei Z, Jiang Y, Meng Z, Lu M. mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication. Virol Sin 2021; 36:1303-1314. [PMID: 34580816 PMCID: PMC8692646 DOI: 10.1007/s12250-021-00450-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/24/2021] [Indexed: 01/05/2023] Open
Abstract
Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that includes mTOR complex (mTORC) 1 and mTORC2. The mTOR pathway is activated in viral hepatitis, including hepatitis B virus (HBV) infection-induced hepatitis. Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the mTOR pathway, indicating that HBV utilizes or hijacks the mTOR pathway to benefit its own replication. Therefore, the mTOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the mTOR signaling pathway and HBV replication.
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Affiliation(s)
- Xueyu Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany
| | - Zhiqiang Wei
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China. .,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany.
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14
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Aykutlu U, Argon A, Orman M, Ulukaya S, Zeytunlu M, Karasu Z, Günşar F, Nart D, Akarca U, Yilmaz F. Steatotic and Steatohepatitic Hepatocellular Carcinomas: Features in a Series With Predominantly Viral Etiology. Am J Surg Pathol 2021; 45:1252-1263. [PMID: 33826548 DOI: 10.1097/pas.0000000000001714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying definitions and clinicopathologic features. We aimed to search the attributes of steatohepatitic hepatocellular carcinoma (SH-HCC) and steatotic-HCC in our series. A retrospective clinicopathologic analyses of 150 HCCs and immunostaining for C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Tumors were reclassified as all SH-HCC, limited SH-HCC, typical SH-HCC (steatohepatitic features in >5%, 5% to 50%, and ≥50% of the tumor, respectively), steatotic-HCC, and classic HCC (C-HCC). Group comparisons were made using Kruskal-Wallis and Kaplan-Meier tests. The background etiology in all SH-HCCs was pure viral in 51.4%, nonalcoholic steatohepatitis (NASH)/alcoholic liver disease (ALD) alone/mixed in 34.3%, and unidentified in normal liver in 14.3%. All SH-HCCS (n=35, 23.3%) and typical SH-HCCs (n=13, 8.6%) had higher NASH/ALD. Limited SH-HCCs (n=22, 14.6%) had higher ALD (all P<0.05). Typical SH-HCCs tended to have more NASH (P=0.054). Steatotic-HCCs (n=13, 9%) and C-HCCs (n=102, 68%) had higher pure viral etiology and serum CRP (all P<0.05). CRP and SAA were positive in 69% and 27% of the tumors, respectively. SAA positivity correlated with ALD (P=0.026). In the overall group disease-free survival rates at 1, 5, 10, and 20 years were 97.0%, 82.3%, 79.6%, and 77.2%, respectively. Demographics, tumor characteristics, CRP and SAA positivity, and survival were similar between the groups (P>0.05). SH-HCC is heterogenous in terms of underlying etiologies, and can be seen in NASH/ALD, pure viral and noncirrhotic/normal background. The ≥50% cutoff for the definition of SH-HCC can lead to overlook ALD-related SH-HCC. Steatotic-HCC seems more similar to C-HCC rather than SH-HCC, but none of them feature as a different prognostic group.
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Affiliation(s)
| | - Asuman Argon
- Department of Pathology, University of Health Sciences, Bozyaka Training and Research Hospital
| | - Mehmet Orman
- Departments of Biostatistics and Medical Informatics
| | | | | | | | | | - Deniz Nart
- Pathology, Ege University Faculty of Medicine, Ege University Application and Research Center of Organ Transplantation, Izmir, Turkey
| | | | - Funda Yilmaz
- Pathology, Ege University Faculty of Medicine, Ege University Application and Research Center of Organ Transplantation, Izmir, Turkey
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15
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Zhuang Z, Qu H, Yang W, Liu J, Wang F, Liu Y, Ding J, Shi J. Comparing hepatic steatosis distribution patterns between non-alcoholic fatty liver disease and fatty liver disease with chronic hepatitis B by second-harmonic generation/two-photon excited fluorescence method. Ann Hepatol 2021; 19:313-319. [PMID: 31870745 DOI: 10.1016/j.aohep.2019.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 11/16/2019] [Accepted: 11/20/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatitis B virus (HBV) might be an etiological factor modulating fat distribution in steatotic livers. We aim to compare hepatic steatosis distribution patterns between NAFLD and FL&CHB patients with second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) method. PATIENTS AND METHODS 42 patients with NAFLD, 46 with FL&CHB and 55 without steatosis were enrolled in the study. Overall and regional steatosis in liver sections were quantified by SHG/TPEF method. The accuracy of which was validated by pathologist evaluation and magnetic resonance spectroscopy (MRS). Difference in degree of overall and regional steatosis between NAFLD and FL&CHB groups was analyzed by Mann-Whitney U test. Multivariable linear regression analysis was used to model factors contributing to steatosis distribution. RESULTS The hepatic steatosis measured by SHG/TPEF method was highly correlated with pathologist grading (r=0.83, p<0.001) and MRS measurement (r=0.82, p<0.001). The level of overall steatosis in FL&CHB group is significantly lower than that in NAFLD group (p<0.001). In NAFLD group, periportal region has significantly lower steatosis percentage than lobule region and overall region (p<0.001); while in FL&CHB group there is no difference among regions. The ratio of steatosis at periportal region to lobule region is significantly higher in FL&CHB group than that in NAFLD group (p<0.05). Multivariable linear regression analysis shows that HBV infection is the major contributing factor (β=0.322, p<0.01). CONCLUSIONS SHG/TPEF method is an accurate and objective method in hepatic steatosis quantification. By quantifying steatosis in different histological regions, we found steatosis distribution patterns are different between FL&CHB and NAFLD patients.
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Affiliation(s)
- Zhenjie Zhuang
- Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 18, Floor 5, Hangzhou 310015, Zhejiang Province, China
| | - Huanjia Qu
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 6, Floor 6, Hangzhou 310015, Zhejiang Province, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 18, Floor 3, Hangzhou 310015, Zhejiang Province, China
| | - Juan Liu
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 18, Floor 3, Hangzhou 310015, Zhejiang Province, China
| | - Fuyan Wang
- Department of Medical Imaging, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 1, Floor 3, Hangzhou 310015, Zhejiang Province, China
| | - Yinlan Liu
- Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 18, Floor 5, Hangzhou 310015, Zhejiang Province, China
| | - Jianping Ding
- Department of Medical Imaging, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 1, Floor 3, Hangzhou 310015, Zhejiang Province, China
| | - Junping Shi
- Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 18, Floor 5, Hangzhou 310015, Zhejiang Province, China; Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Building 6, Floor 6, Hangzhou 310015, Zhejiang Province, China.
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16
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Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22105297. [PMID: 34069902 PMCID: PMC8157577 DOI: 10.3390/ijms22105297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/04/2021] [Accepted: 05/15/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.
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17
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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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18
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Churin Y, Irungbam K, Imiela CS, Schwarz D, Mollenkopf HJ, Drebber U, Odenthal M, Pak O, Huber M, Glebe D, Roderfeld M, Roeb E. Lipid Storage and Interferon Response Determine the Phenotype of Ground Glass Hepatocytes in Mice and Humans. Cell Mol Gastroenterol Hepatol 2021; 12:383-394. [PMID: 33766783 PMCID: PMC8255940 DOI: 10.1016/j.jcmgh.2021.03.009] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS A histopathological hallmark of chronic hepatitis B virus (HBV) infection is the presence of ground glass hepatocytes (GGHs). GGHs are liver cells that exhibit eosinophilic, granular, glassy cytoplasm in light microscopy and are characterized by accumulation of HBV surface (HBs) proteins in the endoplasmic reticulum (ER). More important, GGHs have been accepted as a precursor of HCC and may represent preneoplastic lesions of the liver. METHODS Here we show that the reason for ground glass phenotype of hepatocytes in patients with chronic hepatitis B (CHB) and in HBs transgenic mice is a complex formation between HBs proteins and lipid droplets (LDs) within the ER. RESULTS As fat is a main component of LDs their presence reduces the protein density of HBs aggregates. Therefore, they adsorb less amount of eosin during hematoxylin-eosin staining and appear dull in light microscopy. However, after induction of interferon response in the liver LDs were not only co-localized with HBs but also distributed throughout the cytoplasm of hepatocytes. The uniform distribution of LDs weakens the contrast between HBs aggregates and the rest of the cytoplasm and complicates the identification of GGHs. Suppression of interferon response restored the ground glass phenotype of hepatocytes. CONCLUSIONS Complex formation between HBs and LDs represents a very important feature of CHB that could affect LDs functions in hepatocytes. The strain specific activation of the interferon response in the liver of HBs/c mice prevented the development of GGHs. Thus, manipulation of LDs could provide a new treatment strategy in the prevention of liver cancer.
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Affiliation(s)
- Yuri Churin
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany; Institute for Veterinary Food Science, Faculty of Veterinary Medicine, Justus Liebig University, Giessen, Germany
| | - Karuna Irungbam
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Christoph S Imiela
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - David Schwarz
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | | | - Uta Drebber
- Institute for Pathology, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Margarete Odenthal
- Institute for Pathology, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Oleg Pak
- Excellence Cluster Cardiopulmonary System, University of Giessen and Marburg Lung Center, Justus Liebig University, Giessen, Germany
| | - Magdalena Huber
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University Giessen, Giessen, Germany
| | - Martin Roderfeld
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany
| | - Elke Roeb
- Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
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19
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Zhang J, Ling N, Lei Y, Peng M, Hu P, Chen M. Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B. Front Microbiol 2021; 12:636897. [PMID: 33776969 PMCID: PMC7991784 DOI: 10.3389/fmicb.2021.636897] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) is considered a “metabolic virus” and affects many hepatic metabolic pathways. However, how HBV affects lipid metabolism in hepatocytes remains uncertain yet. Accumulating clinical studies suggested that compared to non-HBV-infected controls, chronic HBV infection was associated with lower levels of serum total cholesterol and triglycerides and a lower prevalence of hepatic steatosis. In patients with chronic HBV infection, high ALT level, high body mass index, male gender, or old age was found to be positively correlated with hepatic steatosis. Furthermore, mechanisms of how HBV infection affected hepatic lipid metabolism had also been explored in a number of studies based on cell lines and mouse models. These results demonstrated that HBV replication or expression induced extensive and diverse changes in hepatic lipid metabolism, by not only activating expression of some critical lipogenesis and cholesterolgenesis-related proteins but also upregulating fatty acid oxidation and bile acid synthesis. Moreover, increasing studies found some potential targets to inhibit HBV replication or expression by decreasing or enhancing certain lipid metabolism-related proteins or metabolites. Therefore, in this article, we comprehensively reviewed these publications and revealed the connections between clinical observations and experimental findings to better understand the interaction between hepatic lipid metabolism and HBV infection. However, the available data are far from conclusive, and there is still a long way to go before clarifying the complex interaction between HBV infection and hepatic lipid metabolism.
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Affiliation(s)
- Jiaxuan Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Lei
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Fowl Adenovirus Serotype 4 Induces Hepatic Steatosis via Activation of Liver X Receptor-α. J Virol 2021; 95:JVI.01938-20. [PMID: 33361420 DOI: 10.1128/jvi.01938-20] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/09/2020] [Indexed: 12/24/2022] Open
Abstract
Fowl adenovirus serotype 4 (FAdV-4) is a hepatotropic virus that causes severe hepatic damage characterized by basophilic intranuclear inclusion bodies, vacuolar degeneration, and multifocal necrosis in hepatocytes. Many aspects of FAdV-4 infection and pathogenesis, however, remain unknown. Here, we found that FAdV-4-induced hepatic injury is accompanied by the accumulation of oil droplets (triglycerides) in the cytoplasm of hepatocytes, a typical indicator of steatosis, in FAdV-4-infected chickens. Significant upregulation of adipose synthesis-related genes, such as liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), and sterol regulatory element-binding protein-1c (SREBP-1c), and significant downregulation of low-density lipoprotein secretion-related genes and lipid oxidation- and lipid decomposition-related genes were observed in the infected chickens. FAdV-4 infection in cultured leghorn male hepatoma (LMH) cells caused similar signs of steatosis, with alterations in various lipogenesis-related genes. We eliminated the effect of LXR-α activation on FAdV-4-induced steatosis and found that treatment with an LXR-α antagonist (SR9243) and RNA interference (small interfering RNA targeting LXR-α [Si-LXR-α]) decreased the number of oil droplets and the accumulation of lipogenic genes, but treatment with an LXR-α agonist (T0901317) increased the number of oil droplets and the accumulation of lipogenic genes in the cells. Additionally, SR9243 treatment or Si-LXR-α transfection led to significant reductions in viral DNA level, protein expression, and virus production, whereas T0901317 treatment caused significant increases in viral DNA level, protein expression, and virus production. However, inhibition of SREBP-1c activity had no significant effect on virus production. Collectively, these results indicated that FAdV-4-induced steatosis involves activation of the LXR-α signaling pathway, which might be a molecular mechanism underlying the hepatic injury associated with FAdV-4 infection.IMPORTANCE Fowl adenovirus serotype 4 (FAdV-4) is an important hepatotropic adenovirus in chicken, but the underlying mechanism of FAdV-4-induced hepatic injury remains unclear. We report here that infection with FAdV-4 induced the accumulation of oil droplets (triglycerides) in the cytoplasm of hepatocytes, a typical indicator of steatosis, in the livers of chickens. FAdV-4-induced steatosis might be caused by a disrupted balance of fat metabolism, as evidenced by differential regulation of various lipase genes. The significant upregulation of liver X receptor-α (LXR-α) prompted us to investigate the interplay between LXR-α activation and FAdV-4-induced steatosis. Treatment with an agonist, an antagonist, or RNA interference targeting LXR-α in cultured leghorn male hepatoma (LMH) cells indicated that FAdV-4-induced steatosis was dependent upon LXR-α activation, which contributed to virus replication. These results provide important mechanistic insights, revealing that FAdV-4 induces hepatic steatosis by activating the LXR-α signaling pathway and highlighting the therapeutic potential of strategies targeting the LXR-α pathway for the treatment of FAdV-4 infection.
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21
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Wang L, Liu J, Miao Z, Pan Q, Cao W. Lipid droplets and their interactions with other organelles in liver diseases. Int J Biochem Cell Biol 2021; 133:105937. [PMID: 33529713 DOI: 10.1016/j.biocel.2021.105937] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/07/2020] [Accepted: 01/06/2021] [Indexed: 02/01/2023]
Abstract
Lipid droplets are cellular organelles used for lipid storage with a hydrophobic core of neutral lipids enclosed by a phospholipid monolayer. Besides presenting as giant single organelles in fat tissue, lipid droplets are also widely present as a multitude of small structures in hepatocytes, where they play key roles in health and disease of the liver. In addition to lipid storage, lipid droplets are also directly involved in lipid metabolism, membrane biosynthesis, cell signaling, inflammation, pathogen-host interaction and cancer development. In addition, they interact with other cellular organelles to regulate cellular biology. It is fair to say that the exact functions of lipid droplets in cellular physiology remain largely obscure. Thus prompted, here we aim to analyze the corpus of contemporary biomedical literature to create a framework as to how the role of lipid droplets in hepatocyte physiology and pathophysiology should be understood. The resulting framework should help understanding the interaction of lipid droplets with other organelles in important liver diseases, including fatty liver disease, viral hepatitis and liver cancer and direct further research directions.
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Affiliation(s)
- Ling Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Jiaye Liu
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Zhijiang Miao
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
| | - Wanlu Cao
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
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22
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Guo R, Yang B. Hypoxia-Induced LXRα Contributes to the Migration and Invasion of Gastric Cancer Cells. Folia Biol (Praha) 2021; 67:91-101. [PMID: 35151242 DOI: 10.14712/fb2021067030091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Gastric cancer is characterized by the presence of high invasion ability, hypoxia and chemoresistance. Previous studies reported that liver X receptor α (LXRα) was involved in epithelial-mesenchymal transition (EMT) of gastric cancer cells. However, hypoxia-mediated EMT and the role of LXRα in gastric cancer remained elusive. In this study, we demonstrated that LXRa mRNA and protein levels were up-regulated by hypoxia treatment and LXRα played an important role in HIF-1 dimer induced-EMT. The putative HIF-1α binding site was identified in the LXRa promoter. Expression of LXRα and HIF-1α was significantly up-regulated in gastric cancer tissues compared to that in normal tissues. More importantly, we noticed that the expression of LXRα and HIF-1α was significantly correlated. Taken together, these data suggested that LXRα is regulated by the activity and accumulation of HIF-1α and contributes to EMT of gastric cancer cells. This suggests that targeting LXRα might be a potential approach for improving survival of gastric cancer patients.
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Affiliation(s)
- R Guo
- Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - B Yang
- Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
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23
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Zeng J, Wu D, Hu H, Young JAT, Yan Z, Gao L. Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes. Hepatology 2020; 72:1935-1948. [PMID: 32145089 DOI: 10.1002/hep.31217] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 12/19/2019] [Accepted: 02/19/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. APPROACH AND RESULTS In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSIONS We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.
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Affiliation(s)
- Jing Zeng
- Roche Innovation Center Shanghai, Shanghai, China
| | - Daitze Wu
- Roche Innovation Center Shanghai, Shanghai, China
| | - Hui Hu
- Roche Innovation Center Shanghai, Shanghai, China
| | | | - Zhipeng Yan
- Roche Innovation Center Shanghai, Shanghai, China
| | - Lu Gao
- Roche Innovation Center Shanghai, Shanghai, China
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24
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Jia W, Wei M, Rajani C, Zheng X. Targeting the alternative bile acid synthetic pathway for metabolic diseases. Protein Cell 2020; 12:411-425. [PMID: 33252713 PMCID: PMC8106556 DOI: 10.1007/s13238-020-00804-9] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/21/2020] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.
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Affiliation(s)
- Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. .,School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
| | - Meilin Wei
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Cynthia Rajani
- University of Hawaii Cancer Center, Honolulu, HI, 96813, USA
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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25
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Gao L, Li B, Wang J, Shen D, Yang M, Sun R, Tung H, Xu M, Ren S, Zhang M, Yang D, Lu B, Wang H, Liu Y, Xie W. Activation of Liver X Receptor α Sensitizes Mice to T-Cell Mediated Hepatitis. Hepatol Commun 2020; 4:1664-1679. [PMID: 33163836 PMCID: PMC7603537 DOI: 10.1002/hep4.1584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/14/2020] [Accepted: 07/06/2020] [Indexed: 12/27/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the α and β isoforms, are previously known for their anti-inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXRα gain-of-function and loss-of-function mouse models were used, in conjunction with the concanavalin A (ConA) model of T-cell mediated hepatitis. We first showed that the hepatic expression of LXRα was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXRα in the constitutively activated VP-LXRα whole-body knock-in (LXRα-KI) mice exacerbated ConA-induced AIH, whereas the LXRα-/- mice showed attenuated ConA-induced AIH. Interestingly, hepatocyte-specific activation of LXRα in the fatty acid binding protein-VP-LXRα transgenic mice did not exacerbate ConA-induced hepatitis. Mechanistically, the sensitizing effect of the LXRα-KI allele was invariant natural killer T (iNKT)-cell dependent, because the sensitizing effect was abolished when the LXRα-KI allele was bred into the NKT-deficient CD1d-/- background. In addition, LXRα-enhanced ConA-induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated from LXRα-KI mice was sufficient to sensitize CD1d-/- mice to ConA-induced AIH. Conclusion: Activation of LXRα sensitizes mice to ConA-induced AIH in iNKT and interferon gamma-dependent manner. Our results suggest that LXRα plays an important role in the development of AIH.
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Affiliation(s)
- Li Gao
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of GastroenterologyPeking University People's HospitalBeijingChina
| | - Bin Li
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Orthopedic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Department of PharmacologyBasic Medical School of Wuhan UniversityWuhanChina
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Danhua Shen
- Department of PathologyPeking University People’s HospitalBeijingChina
| | - Min Yang
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Runzi Sun
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Hung‐Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Min Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Binfeng Lu
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Hui Wang
- Department of PharmacologyBasic Medical School of Wuhan UniversityWuhanChina
| | - Yulan Liu
- Department of GastroenterologyPeking University People's HospitalBeijingChina
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Pharmacology & Chemical BiologyUniversity of PittsburghPittsburghPAUSA
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26
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Zhong D, Lyu X, Fu X, Xie P, Liu M, He F, Huang G. Upregulation of miR-124-3p by Liver X Receptor Inhibits the Growth of Hepatocellular Carcinoma Cells Via Suppressing Cyclin D1 and CDK6. Technol Cancer Res Treat 2020; 19:1533033820967473. [PMID: 33073697 PMCID: PMC7592319 DOI: 10.1177/1533033820967473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
MiR-124-3p has been identified as a novel tumor suppressor and a potential therapeutic target in hepatocellular carcinoma (HCC) through regulating its target genes. However, the upstream regulatory mechanisms of mir-124-3p in HCC has not been fully understood. The transcription factor liver X receptor (LXR) plays a critical role in suppressing the proliferation of HCC cells, but it is unclear whether LXR is involved in the regulation of mir-124-3p. In the present study, we demonstrated that the expression of mir-124-3p was positively correlated with that of LXR in HCC, and the cell growth of HCC was significantly inhibited by LXR agonists. Moreover, activation of LXR with the agonists up-regulated the expression of mir-124-3p, and in turn down-regulated cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression, which are the target genes of mir-124-3p. Mechanistically, miR-124-3p mediates LXR induced inhibition of HCC cell growth and down-regulation of cyclin D1 and CDK6 expression. In vivo experiments also confirmed that LXR induced miR-124-3p expression inhibited the growth of HCC xenograft tumors, as well as cyclin D1 and CDK6 expression. Our findings revealed that miR-124-3p is a novel target gene of LXR, and regulation of the miR-124-3p-cyclin D1/CDK6 pathway by LXR plays a crucial role in the proliferation of HCC cells. LXR-miR-124-3p-cyclin D1/CDK6 pathway may be a novel potential therapeutic target for HCC treatment.
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Affiliation(s)
- Dan Zhong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Xilin Lyu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaohong Fu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Peng Xie
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Menggang Liu
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Gang Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
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27
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Nguyen TN, Nguyen HQ, Le DH. Unveiling prognostics biomarkers of tyrosine metabolism reprogramming in liver cancer by cross-platform gene expression analyses. PLoS One 2020; 15:e0229276. [PMID: 32542016 PMCID: PMC7295234 DOI: 10.1371/journal.pone.0229276] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022] Open
Abstract
Tyrosine is mainly degraded in the liver by a series of enzymatic reactions. Abnormal expression of the tyrosine catabolic enzyme tyrosine aminotransferase (TAT) has been reported in patients with hepatocellular carcinoma (HCC). Despite this, aberration in tyrosine metabolism has not been investigated in cancer development. In this work, we conduct comprehensive cross-platform study to obtain foundation for discoveries of potential therapeutics and preventative biomarkers of HCC. We explore data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Oncomine and Kaplan Meier plotter (KM plotter) and performed integrated analyses to evaluate the clinical significance and prognostic values of the tyrosine catabolic genes in HCC. We find that five tyrosine catabolic enzymes are downregulated in HCC compared to normal liver at mRNA and protein level. Moreover, low expression of these enzymes correlates with poorer survival in patients with HCC. Notably, we identify pathways and upstream regulators that might involve in tyrosine catabolic reprogramming and further drive HCC development. In total, our results underscore tyrosine metabolism alteration in HCC and lay foundation for incorporating these pathway components in therapeutics and preventative strategies.
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Affiliation(s)
- Tran N. Nguyen
- Department of Computational Biomedicine, Vingroup Big Data Institute, Hanoi, Vietnam
- * E-mail:
| | - Ha Q. Nguyen
- Department of Computer Vision, Vingroup Big Data Institute, Hanoi, Vietnam
| | - Duc-Hau Le
- Department of Computational Biomedicine, Vingroup Big Data Institute, Hanoi, Vietnam
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28
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Hwang KB, Kyaw YY, Kang HR, Seong MS, Cheong J. Mitochondrial dysfunction stimulates HBV gene expression through lipogenic transcription factor activation. Virus Res 2019; 277:197842. [PMID: 31874211 DOI: 10.1016/j.virusres.2019.197842] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 12/12/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022]
Abstract
In previous studies, we showed two consistent findings regarding the functional relationship between hepatitis B virus (HBV) gene expression and hepatic lipid accumulation. One is that HBV X (HBx) protein expression induces hepatic lipid accumulation via specific transcriptional activation. The other is that hepatic rich lipids increase HBV gene expression. A variety of transcription factors, including nuclear receptors have been defined as regulators of HBV promoters and enhancers. However, the association between these metabolic events and HBV gene expression remains to be clearly elucidated. Here, we showed that lipid accumulation due to mitochondrial dysfunction is associated with an increase in HBV gene expression. Saturated fatty acids increase the expression of lipogenic factors cooperated with C/EBPα and LXRα. In addition, activation of PPARγ and SREBP-1 by fatty acids derived from hepatic lipid accumulation was found to increase HBV gene expression through mitochondrial dysfunction. These results provide that metabolic changes in the hepatic cells play a critical role in the HBV gene induction.
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Affiliation(s)
- Keum Bit Hwang
- Advanced Molecular Research Centre, Department of Medical Research, Yangon, Myanmar
| | - Yi Yi Kyaw
- Advanced Molecular Research Centre, Department of Medical Research, Yangon, Myanmar; Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Hyo Rin Kang
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
| | - Mi So Seong
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea
| | - JaeHun Cheong
- Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea.
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29
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Chen YY, Lin Y, Han PY, Jiang S, Che L, He CY, Lin YC, Lin ZN. HBx combined with AFB1 triggers hepatic steatosis via COX-2-mediated necrosome formation and mitochondrial dynamics disorder. J Cell Mol Med 2019; 23:5920-5933. [PMID: 31282064 PMCID: PMC6714226 DOI: 10.1111/jcmm.14388] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 04/04/2019] [Accepted: 04/18/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure have been recognized as independent risk factors for the occurrence and exacerbation of hepatic steatosis but their combined impacts and the potential mechanisms remain to be further elucidated. Here, we showed that exposure to AFB1 impaired mitochondrial dynamics and increased intracellular lipid droplets (LDs) in the liver of HBV-transgenic mice in vivo and the hepatitis B virus X protein (HBx)-expressing human hepatocytes both ex vivo and in vitro. HBx combined with AFB1 exposure also up-regulated receptor interaction protein 1 (RIP1), receptor interaction protein 3 (RIP3) and activated mixed lineage kinase domain like protein (MLKL), providing evidence of necrosome formation in the hepatocytes. The shift of the mitochondrial dynamics towards imbalance of fission and fusion was rescued when MLKL was inhibited in the HBx and AFB1 co-treated hepatocytes. Most importantly, based on siRNA or CRISPR/Cas9 system, we found that the combination of HBx and AFB1 exposure increased cyclooxygenase-2 (COX-2) to mediate up-regulation of RIP3 and dynamin-related protein 1 (Drp1), which in turn promoted location of RIP3-MLKL necrosome on mitochondria, subsequently exacerbated steatosis in hepatocytes. Taken together, these findings advance the understanding of mechanism associated with HBx and AFB1-induced hepatic necrosome formation, mitochondrial dysfunction and steatosis and make COX-2 a good candidate for treatment.
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Affiliation(s)
- Yuan-Yuan Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yi Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Pei-Yu Han
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.,Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Shan Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Lin Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Cheng-Yong He
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yu-Chun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Zhong-Ning Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
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30
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Mesquita I, Estaquier J. Viral Manipulation of the Host Metabolic Network. EXPERIENTIA. SUPPLEMENTUM 2019; 109:377-401. [PMID: 30535606 DOI: 10.1007/978-3-319-74932-7_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Viruses are intracellular parasites that rely on host machinery to replicate and achieve a successful infection. Viruses have evolved to retain a broad range of strategies to manipulate host cell metabolism and metabolic resources, channeling them toward the production of virion components leading to viral production. Although several viruses share similar strategies for manipulating host cell metabolism, these processes depend on several factors, namely, the viral life cycle and the metabolic and energetic status of the infected cell. Based on this knowledge, the development of new therapeutic approaches that circumvent viral spread through the target of altered metabolic pathways is an opportunity to tackle the infection. However, finding effective broad-spectrum strategies that aim at restoring to homeostasis the metabolic alterations induced upon virus infection is still a Holy Grail quest for antiviral therapies. Here, we review the strategies by which viruses manipulate host metabolism for their own benefit, with a particular emphasis on carbohydrate, glutamine, and lipid metabolism.
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Affiliation(s)
- Inês Mesquita
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Jérôme Estaquier
- Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada. .,CNRS FR 3636, Université Paris Descartes, Paris, France.
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31
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Kim W. Can hepatic steatosis really promote hepatitis B viral hepatocarcinogenesis? The jury is out on. Clin Mol Hepatol 2019; 25:40-41. [PMID: 30599476 PMCID: PMC6435973 DOI: 10.3350/cmh.2018.0101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/05/2018] [Indexed: 12/23/2022] Open
Affiliation(s)
- Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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32
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Gao Y, Chen Z, Wang R, Tan X, Huang C, Chen G, Chen Z. LXRα Promotes the Differentiation of Human Gastric Cancer Cells through Inactivation of Wnt/β-catenin Signaling. J Cancer 2019; 10:156-167. [PMID: 30662536 PMCID: PMC6329868 DOI: 10.7150/jca.28600] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 11/02/2018] [Indexed: 12/18/2022] Open
Abstract
LXRα is a subtype of the liver X receptors (LXRs). There is accumulating evidence to support the involvement of LXRα in a variety of malignancies. However, the function and specific mechanism of LXRα in gastric cancer (GC) remain unclear. In this study, the expression of LXRα was significantly lower in poorly differentiated and undifferentiated GC tissues compared with well- and moderately differentiated GC tissues by immunohistochemistry analysis. The activation of LXRα leads to the decreased expression of β-catenin, CD44, and Cyclin D1, whereas the inhibition of LXRα has opposite effect. The same results were obtained in animal experiments. Furthermore, results showed that CD44 and Cyclin D1 expression significantly decreased when Wnt/β-catenin signaling was blocked in LXRα silent GC cells, whereas it was significantly increased when Wnt/β-catenin signaling was activated in LXRα over-expressed GC cells. CD44 and Cyclin D1, downstream targets of Wnt/β-catenin signaling, are specific markers for cell differentiation. Therefore, we conclude that LXRα may promote the differentiation of human GC cells through inactivation of Wnt/β-catenin signaling.
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Affiliation(s)
- Yu Gao
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Zihua Chen
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Ran Wang
- Department of Colorectal and Anus Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Xiangzhou Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Changhao Huang
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Guanyang Chen
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
| | - Zhikang Chen
- Department of Colorectal and Anus Surgery, Xiangya Hospital of Central South University, Hunan key laboratory of precise diagnosis and treatment of gastrointestinal tumor, Changsha, Hunan, P.R. China
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33
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Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, Shi X. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:324. [PMID: 30591064 PMCID: PMC6307162 DOI: 10.1186/s13046-018-0965-2] [Citation(s) in RCA: 332] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/16/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains a global challenge due to its high morbidity and mortality rates as well as poor response to treatment. The communication between tumor-derived elements and stroma plays a critical role in facilitating cancer progression of HCC. Exosomes are small extracellular vesicles (EVs) that are released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is emerging evidence indicating that exosomes play a central role in cell-to-cell communication. Much attention has been paid to exosomes since they are found to transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) that can be transferred in active form to adjacent cells or to distant organs. However, the mechanisms underlying such cancer progression remain largely unexplored. METHODS Exosomes were isolated by differential ultracentrifugation from conditioned medium of HCC cells and identified by electron microscopy and Western blotting analysis. Hepatic stellate cells (HSCs) were treated with different concentrations of exosomes, and the activation of HSCs was analyzed by Western blotting analysis, wound healing, migration assay, Edu assay, CCK-8 assay and flow cytometry. Moreover, the different miRNA levels of exosomes were tested by real-time quantitative PCR (RT-PCR). The angiogenic ability of activated HSCs was analyzed by qRT-PCR, CCK-8 assay and tube formation assay. In addition, the abnormal lipid metabolism of activated HSCs was analyzed by Western blotting analysis and Oil Red staining. Finally, the relationship between serum exosomal miRNA-21 and prognosis of HCC patients was evaluated. RESULTS We showed that HCC cells exhibited a great capacity to convert normal HSCs to cancer-associated fibroblasts (CAFs). Moreover, our data revealed that HCC cells secreted exosomal miRNA-21 that directly targeted PTEN, leading to activation of PDK1/AKT signaling in HSCs. Activated CAFs further promoted cancer progression by secreting angiogenic cytokines, including VEGF, MMP2, MMP9, bFGF and TGF-β. Clinical data indicated that high level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients. CONCLUSIONS Intercellular crosstalk between tumor cells and HSCs was mediated by tumor-derived exosomes that controlled progression of HCC. Our findings provided potential targets for prevention and treatment of live cancer.
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Affiliation(s)
- Yuan Zhou
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
| | - Haozhen Ren
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
| | - Bo Dai
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
| | - Jun Li
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
| | - Longcheng Shang
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
| | - Jianfei Huang
- 0000 0000 9530 8833grid.260483.bDepartment of Clinical Biobank, Nantong University Affiliated Hospital, 20, Xisi Road, Nantong, 226001 Jiangsu Province China
| | - Xiaolei Shi
- 0000 0004 1800 1685grid.428392.6Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, Nanjing, 210008 Jiangsu Province China
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Wang L, Xie W, Zhang L, Li D, Yu H, Xiong J, Peng J, Qiu J, Sheng H, He X, Zhang K. CVB3 Nonstructural 2A Protein Modulates SREBP1a Signaling via the MEK/ERK Pathway. J Virol 2018; 92:e01060-18. [PMID: 30258014 PMCID: PMC6258932 DOI: 10.1128/jvi.01060-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/10/2018] [Indexed: 01/11/2023] Open
Abstract
Coxsackievirus B3 (CVB3) is the predominant pathogen of viral myocarditis. In our previous study, we found that CVB3 caused abnormal lipid accumulation in host cells. However, the underlying mechanisms by which CVB3 disrupts and exploits the host lipid metabolism are not well understood. Sterol regulatory element binding protein 1 (SREBP1) is the major transcriptional factor in lipogenic genes expression. In this study, we demonstrated that CVB3 infection and nonstructural 2A protein upregulated and activated SREBP1a at the transcriptional level. Deletion analysis of SREBP1a promoter revealed that two regions, -1821/-1490 and -312/+217, in this promoter were both required for its activation by 2A. These promoter regions possessed several binding motifs for transcription factor SP1. Next, we used SP1-specific small interfering RNAs (siRNAs) to confirm that SP1 might be the essential factor in SREBP1a upregulation by 2A. Furthermore, we showed that MEK/ERK pathway was involved in the activation of SREBP1a by 2A and that blocking this signaling pathway with the specific inhibitor U0126 attenuated SREBP1a activation and lipid accumulation by 2A. Finally, we showed that inhibition of SREBP1 with siRNAs attenuated lipid accumulation induced by CVB3 infection and reduced virus replication. Moreover, inhibition of the MEK/ERK pathway also led to reduction of SREBP1a activation, lipid accumulation, and virus replication during CVB3 infection. Taken together, these data demonstrate that CVB3 nonstructural 2A protein activates SREBP1a at the transcription level through a mechanism involving MEK/ERK signaling pathway and SP1 transcription factor, which promotes cellular lipid accumulation and benefits virus replication.IMPORTANCE Coxsackievirus B3 (CVB3) infection is the leading cause of viral myocarditis, but effective vaccines and antiviral therapies against CVB3 infection are still lacking. It is important to understand the precise interactions between host and virus for the rational design of effective therapies. During infection, CVB3 disrupts and exploits host lipid metabolism to promote excessive lipid accumulation, which benefits virus replication. SREBP1 is the master regulator of cellular lipid metabolism. Here, we report that one of the viral nonstructural proteins, 2A, upregulates and activates SREBP1a. Furthermore, we find that inhibition of SREBP1 decreases CVB3 virus replication. These results reveal the regulation of SREBP1a expression by 2A and the roles of SREBP1 in lipid accumulation and viral replication during CVB3 infection. Our findings provide a new insight into CVB3 host interactions and inform a potential novel therapeutic target for this important pathogen.
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Affiliation(s)
- Lei Wang
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Xie
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Le Zhang
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Defeng Li
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hua Yu
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Junzhi Xiong
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jin Peng
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jing Qiu
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Halei Sheng
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaomei He
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Kebin Zhang
- Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:7512159. [PMID: 30524660 PMCID: PMC6247426 DOI: 10.1155/2018/7512159] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches.
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Wang B, Li W, Fang H, Zhou H. Hepatitis B virus infection is not associated with fatty liver disease: Evidence from a cohort study and functional analysis. Mol Med Rep 2018; 19:320-326. [PMID: 30387826 PMCID: PMC6297757 DOI: 10.3892/mmr.2018.9619] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 10/01/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection has been reported to be associated with the prevalence of non-alcoholic fatty liver disease (NAFLD). However, the present study demonstrated that the incidence of fatty liver disease in HBV-infected subjects (16/152, 10.5%) was not significantly different from in non-HBV-infected subjects (292/1,714, 17%), following adjustment for age (odds ratio=0.656; 95% confidence interval=0.379–1.134; P=0.131). Hepatitis B protein X (HBx) is considered a key regulator in HBV infection and several studies have confirmed that HBx serves a pivotal role in the process of fatty liver disease. In the present study, it was demonstrated that HBx-expressing cells exhibited increased mitochondrial membrane potential, ATP generation, and endogenous mitochondrial respiration. In addition, higher levels of mitochondrial reactive oxygen species (ROS) were detected in HBx-expressing cells compared with in control cells. Increased ROS production may contribute to increased lipid droplet formation in HBx-expressing cells, whereas the removal of ROS with N-acetylcysteine may decrease the accumulation of lipid droplets in a time-dependent manner. In conclusion, the present findings indicated that HBV, and perhaps more specifically HBx, was not a protective factor against NAFLD. HBx may function as a risk factor for fatty liver disease, based on the findings of the present functional study; however, further studies are required to clarify the effects of HBx on hepatic steatosis.
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Affiliation(s)
- Bingqian Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Wenna Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Hezhi Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
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Dropping in on lipid droplets: insights into cellular stress and cancer. Biosci Rep 2018; 38:BSR20180764. [PMID: 30111611 PMCID: PMC6146295 DOI: 10.1042/bsr20180764] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/01/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023] Open
Abstract
Lipid droplets (LD) have increasingly become a major topic of research in recent years following its establishment as a highly dynamic organelle. Contrary to the initial view of LDs being passive cytoplasmic structures for lipid storage, studies have provided support on how they act in concert with different organelles to exert functions in various cellular processes. Although lipid dysregulation resulting from aberrant LD homeostasis has been well characterised, how this translates and contributes to cancer progression is poorly understood. This review summarises the different paradigms on how LDs function in the regulation of cellular stress as a contributing factor to cancer progression. Mechanisms employed by a broad range of cancer cell types in differentially utilising LDs for tumourigenesis will also be highlighted. Finally, we discuss the potential of targeting LDs in the context of cancer therapeutics.
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Tarakhovsky A, Prinjha RK. Drawing on disorder: How viruses use histone mimicry to their advantage. J Exp Med 2018; 215:1777-1787. [PMID: 29934321 PMCID: PMC6028506 DOI: 10.1084/jem.20180099] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/24/2018] [Accepted: 06/07/2018] [Indexed: 12/16/2022] Open
Abstract
Humans carry trillions of viruses that thrive because of their ability to exploit the host. In this exploitation, viruses promote their own replication by suppressing the host antiviral response and by inducing changes in host biosynthetic processes, often with extremely small genomes of their own. In the review, we discuss the phenomenon of histone mimicry by viral proteins and how this mimicry allows the virus to dial in to the cell's transcriptional processes and establish a cell state that promotes infection. We suggest that histone mimicry is part of a broader viral strategy to use intrinsic protein disorder as a means to overcome the size limitations of its own genome and to maximize its impact on host protein networks. In particular, we discuss how intrinsic protein disorder may enable viral proteins to interfere with phase-separated host protein condensates, including those that contribute to chromatin-mediated control of gene expression.
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Affiliation(s)
- Alexander Tarakhovsky
- Laboratory of the Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY
| | - Rab K Prinjha
- Epigenetics DPU, Oncology and Immuno-inflammation TA Units, GlaxoSmithKline Medicines Research Centre, Stevenage, England, UK
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Glingston RS, Deb R, Kumar S, Nagotu S. Organelle dynamics and viral infections: at cross roads. Microbes Infect 2018; 21:20-32. [PMID: 29953921 PMCID: PMC7110583 DOI: 10.1016/j.micinf.2018.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/14/2018] [Accepted: 06/15/2018] [Indexed: 01/12/2023]
Abstract
Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.
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Affiliation(s)
- R Sahaya Glingston
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Rachayeeta Deb
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sachin Kumar
- Viral Immunology Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
| | - Shirisha Nagotu
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
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Wu Q, Li Z, Liu Q. An important role of SREBP-1 in HBV and HCV co-replication inhibition by PTEN. Virology 2018; 520:94-102. [PMID: 29803738 DOI: 10.1016/j.virol.2018.05.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 02/07/2023]
Abstract
HBV HCV co-infection leads to more severe liver diseases including liver cancer than mono-infections. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, inhibits sterol regulatory element binding protein-1 (SREBP-1). In this study, we characterized the effect of the PTEN - SREBP-1 pathway on HBV HCV co-replication in a cellular model. We found that HBV and HCV can co-replicate in Huh-7 cells with no interference. Overexpression of PTEN inhibits, whereas PTEN knockdown enhances, HBV replication as well as HBV and HCV co-replication. Knocking down SREBP-1 decreases HBV replication in an HBx-dependent manner. SREBP-1 knockdown also decreases HCV replication. PTEN knockdown is concomitant with increased nuclear SREBP-1 levels. PTEN and SREBP-1 double knockdown results in intermediate levels of HBV and HCV replication in mono- and co-replication scenarios. Taken together, we demonstrated, for the first time, that the PTEN - SREBP-1 pathway can regulate HBV HCV co-replication.
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Affiliation(s)
- Qi Wu
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; Department of Veterinary Microbiology, University of Saskatchewan, Canada
| | - Zhubing Li
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; Department of Veterinary Microbiology, University of Saskatchewan, Canada; School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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Lin M, Lv D, Zheng Y, Wu M, Xu C, Zhang Q, Wu L. Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther 2018; 11:3101-3110. [PMID: 29872321 PMCID: PMC5975610 DOI: 10.2147/ott.s163266] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background Cancer cells often have characteristic changes in metabolism. Besides Warburg effect, abnormal lipid metabolism is also considered as one of the most typical metabolic symbols of cancer. Thus, understanding the mechanisms of cell metabolic reprogramming may provide a potential avenue for cancer treatment. Materials and methods In total, 41 pairs of matched samples of primary hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues were collected. Afterward, we performed quantitative reverse transcriptase polymerase chain reaction to investigate carnitine palmitoyltransferase-2 (CPT2) expression and then systematically analyzed its relationship with clinicopathologic features. We further performed proliferation, colony formation, migration and invasion, drug resistance, and lipogenesis assays to determine the function of CPT2 in HCC. Results In this study, we have identified CPT2 which is the rate-limiting enzyme of fatty acid oxidation, downregulated in HCC and was significantly associated with tumor histological differentiation and venous invasion. In vitro studies demonstrated that knockdown of CPT2 remarkably enhanced the tumorigenic activity and metastatic potential of hepatoma cells. In addition, CPT2 silencing induced chemoresistance to cisplatin. Mechanistically, low expression of CPT2 promoted cancer cell lipogenesis via upregulation of stearoyl-CoA desaturase-1, the key enzyme involved in the synthesis of monounsaturated fatty acids, at both mRNA and protein levels in hepatoma cell line. Conclusion Altogether, our findings demonstrate that CPT2 has a critical role in HCC progression and chemoresistance and may potentially serve as a novel prognostic marker and therapeutic target for HCC treatment.
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Affiliation(s)
- Meihua Lin
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Duo Lv
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yunliang Zheng
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Minglan Wu
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Chang Xu
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Qiao Zhang
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Lihua Wu
- Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Guo W, Tan HY, Wang N, Wang X, Feng Y. Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation. Cancer Manag Res 2018; 10:715-734. [PMID: 29692630 PMCID: PMC5903488 DOI: 10.2147/cmar.s156837] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer, with increasing prevalence worldwide. The mortality rate of HCC is similar to its incidence rate, which reflects its poor prognosis. At present, the diagnosis of HCC is still mostly dependent on invasive biopsy, imaging methods, and serum α-fetoprotein (AFP) testing. Because of the asymptomatic nature of early HCC, biopsy and imaging methods usually detect HCC at the middle–late stages. AFP has limited sensitivity and specificity, as many other nonmalignant liver diseases can also result in a very high serum level of AFP. Therefore, better biomarkers with higher sensitivity and specificity at earlier stages are greatly needed. Since metabolic reprogramming is an essential hallmark of cancer and the liver is the metabolic hub of living systems, it is useful to investigate HCC from a metabolic perspective. As a noninvasive and nondestructive approach, metabolomics provides holistic information on dynamically metabolic responses of living systems to both endogenous and exogenous factors. Therefore, it would be conducive to apply metabolomics in investigating HCC. In this review, we summarize recent metabolomic studies on HCC cellular, animal, and clinicopathologic models with attention to metabolomics as a biomarker in cancer diagnosis. Recent applications of metabolomics with respect to therapeutic and prognostic evaluation of HCC are also covered, with emphasis on the potential of treatment by drugs from natural products. In the last section, the current challenges and trends of future development of metabolomics on HCC are discussed. Overall, metabolomics provides us with novel insight into the diagnosis, prognosis, and therapeutic evaluation of HCC.
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Affiliation(s)
- Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.,Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
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Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis. Oncotarget 2018; 8:3895-3932. [PMID: 27965466 PMCID: PMC5354803 DOI: 10.18632/oncotarget.13904] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/05/2016] [Indexed: 12/11/2022] Open
Abstract
Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.
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Lin HJ, Ku KL, Lin IH, Yeh CC. Naringenin attenuates hepatitis B virus X protein-induced hepatic steatosis. Altern Ther Health Med 2017; 17:505. [PMID: 29183361 PMCID: PMC5706293 DOI: 10.1186/s12906-017-2019-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/20/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Naringenin (Nar), a common dietary flavonoid abundantly present in fruits, vegetables, and Chinese herbs, is believed to possess strong anti-inflammatory properties and to modulate hepatic apolipoprotein and lipid synthesis. However, there are no reports describing Nar's effects on the hepatitis B virus protein X (HBx) -induced hepatic steatosis, and the detailed molecular mechanisms of the compound's effects are still unclear. METHODS Nar was administered by oral gavage to HBx-transgenic mice from 4 to 6 weeks of age. Mice were sacrificed after 14 days of once-daily naringenin administration. Liver tissues and sera were collected for histopathology and biochemical analysis. RESULTS Nar counteracted hepatic lipid accumulation and liver dysfunction in HBx-transgenic mice. In addition, Nar significantly decreased expression of adipogenic and lipogenic genes in mice, suggesting that the compound may have therapeutic effects in the early stages of HBx-mediated hepatic steatosis. These results indicated that naringenin inhibits HBx-induced expression of hepatic adipogenic and lipogenic genes through suppression of HBx-induced gene expression, including decreases in the transcriptional activity of SREBP1c, LXRα, and PPARγ in HBx-trangenic mice and HBx-transfected HepG2 cells. CONCLUSIONS Results from this study suggested that Nar may serve as a therapeutic agent for preventing HBx-infected hepatic steatosis in humans.
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Bai P, Xia N, Sun H, Kong Y. Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. J Cell Mol Med 2017; 21:3023-3043. [PMID: 28557334 PMCID: PMC5661149 DOI: 10.1111/jcmm.13213] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/29/2017] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up-regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N-syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection.
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Affiliation(s)
- Pei‐song Bai
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Nan Xia
- Institute of Cancer Prevention and ControlPeking University Cancer HospitalBei'jingChina
| | - Hong Sun
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Ying Kong
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
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Masson JJ, Billings HW, Palmer CS. Metabolic reprogramming during hepatitis B disease progression offers novel diagnostic and therapeutic opportunities. Antivir Chem Chemother 2017; 25:53-57. [PMID: 28768434 PMCID: PMC5890528 DOI: 10.1177/2040206617701372] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Metabolic remodeling occurs in immune cells during an infection. Host cells must upregulate energy production for growth, proliferation, and effector functions to limit the damage imposed by pathogens. One example, the hepatitis B virus, induces hepatic injury in human hepatocytes through dysregulation of aerobic glycolysis and lipid metabolism. Increased glycolytic metabolism mediated by elevated expression of Glut1, glucose influx, and lactate secretion is associated with this Warburg phenotype, a classic metabolic signature also observed in cancer cells. This article brings into focus the tight interaction between HBV infection and metabolic dysfunction and how these processes facilitate the progression of end-stage liver diseases, such as hepatocellular carcinoma. We also provide evidence and models by which other viruses such as HIV and Zika disrupt their host metabolic machinery. The emergence of the immunometabolism field provides novel opportunities to take advantage of intermediary metabolites and key metabolic pathways for diagnostic and therapeutic purposes.
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Affiliation(s)
- Jesse Jr Masson
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
| | - Hugh Ww Billings
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
| | - Clovis S Palmer
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.,2 Department of Infectious Diseases, Monash University, Melbourne, Australia.,3 Department of Microbiology and Immunology, University of, Melbourne, Melbourne, Australia
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Wang M, Han J, Xing H, Zhang H, Li Z, Liang L, Li C, Dai S, Wu M, Shen F, Yang T. Dysregulated fatty acid metabolism in hepatocellular carcinoma. Hepat Oncol 2017; 3:241-251. [PMID: 30191046 DOI: 10.2217/hep-2016-0012] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/17/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent and deadly malignancies worldwide. Studies are urgently needed on its molecular pathogenesis and biological characteristics. Dysregulation of fatty acid (FA) metabolism, in which aberrant activation of oncogenic signaling pathways alters the expression and activity of lipid-metabolizing enzymes, is an emerging hallmark of cancer cells, and it may be involved in HCC development and progression. The current review summarizes what is known about dysregulated FA metabolism in HCC and pathways through which this dysregulation may regulate HCC survival and growth. Our understanding of dysregulated FA metabolism and associated signaling pathways may contribute to the development of novel and efficient antitumor approaches for patients with HCC.
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Affiliation(s)
- Mingda Wang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Jun Han
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Hao Xing
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Han Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Zhenli Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Lei Liang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China
| | - Chao Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Shuyang Dai
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Mengchao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
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Li N, Zhou ZS, Shen Y, Xu J, Miao HH, Xiong Y, Xu F, Li BL, Luo J, Song BL. Inhibition of the sterol regulatory element-binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice. Hepatology 2017; 65:1936-1947. [PMID: 28027595 DOI: 10.1002/hep.29018] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 12/20/2016] [Indexed: 12/25/2022]
Abstract
UNLABELLED Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78-kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down-regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1β. CONCLUSION Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936-1947).
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Affiliation(s)
- Na Li
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Zhang-Sen Zhou
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China
| | - Yang Shen
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jie Xu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hong-Hua Miao
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ying Xiong
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feng Xu
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Bo-Liang Li
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jie Luo
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China
| | - Bao-Liang Song
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China
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49
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Tumor LXR Expression is a Prognostic Marker for Patients with Hepatocellular Carcinoma. Pathol Oncol Res 2017; 24:339-344. [PMID: 28508927 DOI: 10.1007/s12253-017-0249-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 04/27/2017] [Indexed: 10/19/2022]
Abstract
Liver X receptor (LXR) activation exerts an anti-tumor effect. However, whether the tumor LXR expression has prognostic significance in hepatocellular carcinoma (HCC) patient has not been addressed yet. Primary HCC and the adjacent non-tumor tissues were obtained from 169 patients who underwent routine curative surgical treatment. All patients were followed for prognosis analyses. Tumor LXR was detected by immunohistochemical analysis. In in vitro study, several HCC cell lines were cultured for cellular protein detection of LXR and other cytokines, including nuclear factor kappa (NFκB), Matrix metalloproteinases 2 and 9 (MMP-2 and -9). Meanwhile, the invasion ability of cultured HCC cell lines was performed. We found that LXR expression status in tumor samples is associated with the clinical characteristics, such as tumor stage and metastasis, of HCC patients. Prognosis analysis shows that tumor LXR expression status is closely related to the post-operative outcome in HCC patients who underwent surgical treatment. Patients with low LXR expression have a significantly lower mean 5-year overall survival rate and mean overall survival period than those with high LXR level. Our in vitro data reveal that HCC cell lines had increased NF-κB, MMP2, MMP9 and invasive ability than normal cell line, which are suppressed by LXR activation via NFκB pathway. Our data suggest that LXR could be used as a biomarker for HCC prognosis. Further study is warranted to explore the molecular mechanism under which LXR regulates tumor behaves.
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50
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Lee JS, Yoo JE, Kim H, Rhee H, Koh MJ, Nahm JH, Choi JS, Lee KH, Park YN. Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma. PLoS One 2017; 12:e0171922. [PMID: 28273155 PMCID: PMC5342190 DOI: 10.1371/journal.pone.0171922] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 12/12/2016] [Indexed: 02/07/2023] Open
Abstract
Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC.
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Affiliation(s)
- Jee San Lee
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Hyungjin Rhee
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myoung Ju Koh
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Sub Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kee-Ho Lee
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
- BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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