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1
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Liu CJ, Seto WK, Yu ML. Dual-etiology MAFLD: the interactions between viral hepatitis B, viral hepatitis C, alcohol, and MAFLD. Hepatol Int 2024; 18:897-908. [PMID: 39115632 DOI: 10.1007/s12072-024-10699-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/03/2024] [Indexed: 10/05/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) and viral hepatitis due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are common liver diseases worldwide. Excessive alcohol consumption and alcoholic liver disease (ALD) are also emerging health problems. Therefore, in clinical practice, we may encounter subjects with dual etiology of liver diseases such as coexisting MAFLD/HBV, MAFLD/HCV, and MAFLD/ALD. In this review, we summarize the epidemiology, clinical features, and mutual interactions of MAFLD with coexisting HBV, HCV, or ALD. The impact of MAFLD on the progression of liver diseases and treatment outcomes in patients with chronic viral hepatitis and the clinical questions to be addressed regarding dual MAFLD and ALD are also discussed.
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Affiliation(s)
- Chun-Jen Liu
- Hepatitis Research Center, National Taiwan University College of Medicine and, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pok Fu Lam, China.
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Center of Hepatitis Research, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan.
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Yeh ML, Huang JF, Yu ML. Fatty liver and viral hepatitis: Prevalence, risk factors, natural course, pathogenesis, and management. METABOLIC STEATOTIC LIVER DISEASE 2024:261-275. [DOI: 10.1016/b978-0-323-99649-5.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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3
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Cheng PN, Chen WJ, Hou CJY, Lin CL, Chang ML, Wang CC, Chang WT, Wang CY, Lin CY, Hung CL, Peng CY, Yu ML, Chao TH, Huang JF, Huang YH, Chen CY, Chiang CE, Lin HC, Li YH, Lin TH, Kao JH, Wang TD, Liu PY, Wu YW, Liu CJ. Taiwan Association for the Study of the Liver-Taiwan Society of Cardiology Taiwan position statement for the management of metabolic dysfunction- associated fatty liver disease and cardiovascular diseases. Clin Mol Hepatol 2024; 30:16-36. [PMID: 37793641 PMCID: PMC10776290 DOI: 10.3350/cmh.2023.0315] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.
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Affiliation(s)
- Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Jone Chen
- Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan; Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Chih-Lin Lin
- Department of Gastroenterology, Renai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wei-Ting Chang
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chao-Yung Wang
- Division of Cardiology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Lieh Hung
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Ming-Lung Yu
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ting-Hsing Chao
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hsiang Huang
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan
| | - Chern-En Chiang
- General Clinical Research Center, and Cardiovascular Center, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Heng Li
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Hsien Lin
- Division of Cardiology, Department of Internal Medicine Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzung-Dau Wang
- Cardiovascular Center, MacKay Memorial Hospital, Taipei, Taiwan
- MacKay Medical College, New Taipei City, Taiwan
| | - Ping-Yen Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Wen Wu
- Division of Cardiology, Cardiovascular Medical Center, and Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- School of Medicine, National Yang Ming Chao Tung University, Taipei, Taiwan
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan
| | - Chun-Jen Liu
- Hepatitis Research Center, Department of Internal Medicine and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
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Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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Samji NS, Heda R, Kovalic AJ, Satapathy SK. Similarities and Differences Between Nonalcoholic Steatohepatitis and Other Causes of Cirrhosis. Gastroenterol Clin North Am 2020; 49:151-164. [PMID: 32033761 DOI: 10.1016/j.gtc.2019.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Nonalcoholic fatty liver disease includes a spectrum of liver disorders that range from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Risk factors such as obesity, hypertension, hyperlipidemia, chronic kidney disease, and smoking status increase risk of progression to cirrhosis among patients with NASH. Cirrhosis derived from non-NASH causes may share similar features with patients with NASH but embody distinct pathogenetic mechanisms, genetic associations, prognosis, and outcomes. This article discusses in detail the comparison of clinical, genetic, and outcome characteristics between patients with NASH cirrhosis as opposed to alternative causes of chronic liver disease.
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Affiliation(s)
- Naga Swetha Samji
- Tenova Cleveland Hospital, 2305 Chambliss Avenue Northwest, Cleveland, TN 37311, USA
| | - Rajiv Heda
- University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA
| | - Alexander J Kovalic
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, USA
| | - Sanjaya K Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases & Transplantation, Donald and Barbara Zucker School of Medicine/Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
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Yahaghi L, Ebrahim‐Habibi A, Hayati‐Roodbari N, Irani S, Yaghmaei P. A simple method for inducing nonalcoholic steatohepatitis with fibrosis. Animal Model Exp Med 2019; 2:282-290. [PMID: 31942560 PMCID: PMC6930990 DOI: 10.1002/ame2.12089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is increasingly occurring in sedentary people, and may progress to NASH and hepatocellular carcinoma. It is essential to design affordable animal models for the study of various diseases, including fatty liver, which was the aim of the study. In this study, a high-fat diet was devised that triggers NASH's animal model quickly and easily. High-fat diet (HFD) was used both with intra-mouth oral gavage and in combination with animal pellets. METHODS Twenty-four male C57BL/6J mice were divided into HFD and ND groups, which received a high-fat diet and a normal diet, respectively. At the end of the experiment (fourth week of treatment), body and liver weights, biochemical parameters, PPAR-α gene expression and histopathologic characteristics of the liver were evaluated. RESULTS During 4 weeks, body weight of mice did not show a significant increase in the HFD group compared to the ND group, while weight gain of the liver was significant. Histological assessment of the HFD group's liver confirmed NASH symptoms. In the HFD group, HDL-c, SOD, catalase, FRAP, adiponectin, and PPAR-α decreased significantly, and lipid profiles, hepatic enzymes, MDA, leptin, and TNF-α showed a significant increase compared to the ND group. CONCLUSION Our high-fat diet has successfully induced all aspects of NASH with fibrosis in 4 weeks, and with low cost.
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Affiliation(s)
- Leyla Yahaghi
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | - Azadeh Ebrahim‐Habibi
- Biosensor Research CenterEndocrinology and Metabolism Molecular‐Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research CenterTehran University of Medical SciencesTehranIran
| | | | - Shiva Irani
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
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Patra T, Ray RB, Ray R. Strategies to Circumvent Host Innate Immune Response by Hepatitis C Virus. Cells 2019; 8:E274. [PMID: 30909456 PMCID: PMC6468774 DOI: 10.3390/cells8030274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immune responses generate interferons, proinflammatory cytokines, complement activation, and natural killer (NK) cell response. Ultimately, this leads to the induction of a robust virus-specific adaptive immunity. Although the host innate immune system senses and responds to eliminate virus infection, hepatitis C virus (HCV) evades immune attack and establishes persistent infection within the liver. Spontaneous clearance of HCV infection is associated with a prompt induction of innate immunity generated in an infected host. In this review, we have highlighted the current knowledge of our understanding of host⁻HCV interactions, especially for endogenous interferon production, proinflammatory response, NK cell response, and complement activation, which may impair the generation of a strong adaptive immune response for establishment of chronicity. The information may provide novel strategies in augmenting therapeutic intervention against HCV.
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Affiliation(s)
- Tapas Patra
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Departments of Pathology, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ranjit Ray
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
- Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO 63104, USA.
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Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, Dharmarajan A, Sethi G, Shivananju NS, Bishayee A. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol 2017; 12:1-10. [PMID: 27510230 DOI: 10.1007/s11523-016-0452-7] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy.
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Affiliation(s)
- Supritha G Swamy
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India
| | - Vivek H Kameshwar
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India
| | - Priya B Shubha
- Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, Karnataka, India
| | - Chung Yeng Looi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Frank Arfuso
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Arunasalam Dharmarajan
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia, 6009, Australia
| | - Nanjunda Swamy Shivananju
- Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka, 570006, India.
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL, 33169, USA.
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11
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Liu J, Wang L, Wang W, Li Y, Jia X, Zhai S, Shi J, Dang S. Application of network construction to estimate functional changes to insulin receptor substrates 1 and 2 in Huh7 cells following infection with the hepatitis C virus. Mol Med Rep 2016; 14:2379-2388. [PMID: 27432476 PMCID: PMC4991679 DOI: 10.3892/mmr.2016.5527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 05/03/2016] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is closely associated with insulin resistance (IS), acting primarily by interfering with insulin signaling pathways, increasing cytokine-mediated (tumor necrosis factor α, interleukin 6) inflammatory responses and enhancing oxidative stress. In the insulin signaling pathways, the insulin receptor substrate (IRS) is one of the key regulatory factors. The present study constructed gene regulatory sub‑networks specific for IRS1 and IRS2 in Huh7 cells and HCV‑infected Huh7 (HCV‑Huh7) cells using linear programming and a decomposition algorithm, and investigated the possible mechanisms underlying the function of IRS1/2 in HCV‑induced IS in Huh7 cells. All data were obtained from GSE20948 of the Gene Expression Omnibus database from the National Center for Biotechnology Information. Genes which were significantly differentially expressed between Huh7 and HCV‑Huh7 cells were analyzed using the significance analysis of microarray algorithm. The top 50 genes, including IRS1/2, were used as target genes to determine the gene regulatory networks and next the sub‑networks of IRS1 and IRS2 in HCV‑Huh7 and Huh7 cells using Gene Regulatory Network Inference Tool, an algorithm based on linear programming and the decomposition process. The IRS1/2 sub‑networks were divided into upstream/downstream groups and activation/suppression clusters, and were further analyzed using Molecule Annotation System 3.0 and Database for Annotation, Visualization, and Integrated Discovery software, two online platforms for enrichment and clustering analysis and visualization. The results indicated that in Huh7 cells, the downstream network of IRS2 is more complex than that of IRS1, indicating that the insulin metabolism in Huh7 cells may be primarily mediated by IRS2. In HCV‑Huh7 cells, the downstream pathway of IRS2 is blocked, suggesting that this may be the underlying mechanism in HCV infection that leads to insulin resistance. The present findings add a further dimension to the understanding of the pathological mechanisms of HCV infection-associated insulin resistance, and provide novel concepts for insulin resistance and glucose metabolism research.
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Affiliation(s)
- Jingkun Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Linbang Wang
- The First Clinical Department, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Song Zhai
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Juan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004
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12
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Bhattacharya A, Hegazy AN, Deigendesch N, Kosack L, Cupovic J, Kandasamy RK, Hildebrandt A, Merkler D, Kühl AA, Vilagos B, Schliehe C, Panse I, Khamina K, Baazim H, Arnold I, Flatz L, Xu HC, Lang PA, Aderem A, Takaoka A, Superti-Furga G, Colinge J, Ludewig B, Löhning M, Bergthaler A. Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage. Immunity 2016; 43:974-86. [PMID: 26588782 PMCID: PMC4658338 DOI: 10.1016/j.immuni.2015.10.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 05/29/2015] [Accepted: 08/03/2015] [Indexed: 12/23/2022]
Abstract
Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.
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Affiliation(s)
- Anannya Bhattacharya
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Ahmed N Hegazy
- Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK
| | - Nikolaus Deigendesch
- Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
| | - Lindsay Kosack
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Jovana Cupovic
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
| | - Richard K Kandasamy
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Andrea Hildebrandt
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Doron Merkler
- Department of Pathology and Immunology, University of Geneva, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva, Switzerland; Department of Neuropathology, University Medicine Göttingen, Robert-Koch Strasse 40, 37099 Goettingen, Germany
| | - Anja A Kühl
- Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Bojan Vilagos
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Christopher Schliehe
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Isabel Panse
- Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany
| | - Kseniya Khamina
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Hatoon Baazim
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Isabelle Arnold
- Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK
| | - Lukas Flatz
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
| | - Haifeng C Xu
- Department of Gastroenterology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Philipp A Lang
- Department of Gastroenterology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany; Department of Molecular Medicine II, Heinrich Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Alan Aderem
- Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5219, USA
| | - Akinori Takaoka
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan
| | - Giulio Superti-Furga
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria
| | - Jacques Colinge
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria
| | - Burkhard Ludewig
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
| | - Max Löhning
- Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria.
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Liu D, Li S, Li Z. Adiponectin: A biomarker for chronic hepatitis C? Cytokine 2015; 89:27-33. [PMID: 26683021 DOI: 10.1016/j.cyto.2015.10.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 10/30/2015] [Accepted: 10/30/2015] [Indexed: 12/14/2022]
Abstract
Adiponectin, a hormone primarily synthesized and secreted by adipose tissue, plays a pivotal role in lipid metabolism. Chronic hepatitis C (CHC) infection is characterized by disordered lipid metabolism, which may potentially evolve into steatosis over a period of time. A growing body of evidence appears to link decreased adiponectin plasma levels with severe CHC-related steatosis, which suggests a potential role of this adipokine as a diagnostic and therapeutic target for clinical application. In this review, we have attempted to summarize the current status of adiponectin research in the context of CHC, concentrating predominantly on its roles in CHC, and its potential relevance as a biomarker for CHC.
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Affiliation(s)
- Ding Liu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shengyu Li
- Department of General Surgery, The Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhihong Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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Khadem Ansari MH, Omrani MD, Kheradmand F. Oxidative stress response in patients infected by diverse hepatitis C virus genotypes. HEPATITIS MONTHLY 2015; 15:e22069. [PMID: 25788953 PMCID: PMC4350251 DOI: 10.5812/hepatmon.22069] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/12/2014] [Accepted: 02/01/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The molecular mechanism of hepatitis C-virus (HCV) genome-specific pathogenesis remains unclear. Oxidative stress is an important pathophysiological mechanism in chronic HCV infection, but its relation to HCV genotypes has not been thoroughly examined. OBJECTIVES In the present case-control study, the effect of diverse HCV genotypes on oxidative status changes was investigated. PATIENTS AND METHODS From 310 patients examined by enzyme immunoassay and PCR, 160 patients with positive results for HCV with previously determined genotypes were chosen. For the control group, 160 first time blood donors referred to the Regional Blood Transfusion organization of the West Azerbaijan province, northwestern Iran were selected. Oxidative stress markers such as total antioxidant status (TAS), serum levels of reduced (GSH) and oxidized (GSSG) glutathione, Gamma-glutamyl transferase (GGT) and malondialdehyde (MDA) were evaluated in patients infected with diverse HCV genotypes and those in the control group. RESULTS In the patient and control groups, the mean ± SE of TAS, GSH, GSSG, GGT and MDA were 1.04 ± 0.35 vs. 2.68 ± 0.77, 1.25 ± 0.37 vs. 3.12 ± 0.58, 0.20 ± 0.05 vs. 0.08 ± 0.04, 26.82 ± 5.62 vs 8.28 ± 2.03 and 2.56 ± 0.60 vs. 0.93 ± 0.34. All markers had statistical difference between the two groups (P <0.05). Obvious differences were found in oxidant/antioxidant balance among diverse HCV genotypes with an ascending trend in antioxidant levels among patients infected with genotypes 1a/b, 4, 2a/c, 2b, 3a and healthy controls and a vice versa trend in measures of oxidative markers except for malondialdehyde with a variable pattern. CONCLUSIONS More serious disease in HCV genetic subtype 1a/1b might be associated with more severe oxidative stress. Milder damage in subtypes 4, 2a/c, 2b and 3a could be related to lower oxidative response, respectively. A combination of antiviral and antioxidative therapies may enhance the overall response rate of patients with HCV infection, especially with more destructive genotypes.
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Affiliation(s)
| | - Mir-Davood Omrani
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Fatemeh Kheradmand
- Cellular and Molecular Research Center, Clinical Biochemistry Department, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, IR Iran
- Corresponding Author: Fatemeh Kheradmand, Cellular and Molecular Research Center, Clinical Biochemistry Department, Faculty of Medicine, Urmia University of Medical Sciences, 11th Km of Sero (Nazloo) Road, Urmia, IR Iran. Tel: +98-4412770397, Fax: +98-4412780800, E-mail:
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Peta V, Torti C, Milic N, Focà A, Abenavoli L. Adiponectin serum level in chronic hepatitis C infection and therapeutic profile. World J Hepatol 2015; 7:44-52. [PMID: 25624996 PMCID: PMC4295193 DOI: 10.4254/wjh.v7.i1.44] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 07/20/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is commonly seen in the patients with chronic hepatitis C virus (HCV) infection. HCV is closely associated with lipid metabolism, and viral steatosis is more common in genotype 3 infection owing to a direct cytopathic effect of HCV core protein. In non-genotype 3 infection, hepatic steatosis is considered largely to be the result of the alterations in host metabolism; metabolic steatosis is primarily linked with HCV genotype 1. Adipose tissue secretes different hormones involved in glucose and lipid metabolisms. It has been demonstrated that adipocytokines are involved in the pathogenesis of non-alcoholic fatty liver disease, as the decreased plasma adiponectin levels, a soluble matrix protein expressed by adipoctyes and hepatocyte, are associated with liver steatosis. Various studies have shown that steatosis is strongly correlated negatively with adiponectin in the patients with HCV infection. The role of adiponectin in hepatitis C virus induced steatosis is still not completely understood, but the relationship between adiponectin low levels and liver steatosis is probably due to the ability of adiponectin to protect hepatocytes from triglyceride accumulation by increasing β-oxidation of free fatty acid and thus decreasing de novo free fatty acid production.
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Abenavoli L, Masarone M, Peta V, Milic N, Kobyliak N, Rouabhia S, Persico M. Insulin resistance and liver steatosis in chronic hepatitis C infection genotype 3. World J Gastroenterol 2014; 20:15233-15240. [PMID: 25386071 PMCID: PMC4223256 DOI: 10.3748/wjg.v20.i41.15233] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 04/28/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a common chronic liver disease worldwide. Non-alcoholic fatty liver disease and insulin resistance (IR) are the major determinants of fibrosis progression and response to antiviral therapy. The pathogenetic link between IR and chronic HCV infection is complex, and is associated with HCV genotype. Liver steatosis is the most common in the patients infected with genotype 3 virus, possibly due to direct effects of genotype 3 viral proteins. To the contrary, hepatic steatosis in the patients infected with other genotypes is thought to be mostly due to the changes in host metabolism, involving IR. In HCV genotype 3, liver steatosis correlates with viral load, reverts after reaching the sustained virologic response and reoccurs in the relapsers. A therapeutic strategy to improve IR and liver steatosis and subsequently the response to antiviral treatment in these patients is warranted.
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Abstract
Hepatitis C virus (HCV) is one of the major etiologic agents of liver cancer. HCV is an RNA virus that, unlike hepatitis B virus, is unable to integrate into the host genome. Through complex interactions between viral and host proteins that induce host responses and promote inflammation, fibrosis, and ultimately cirrhosis, HCV infection can result in the development of hepatocellular carcinoma (HCC). The HCV oncogenic process involves genetic and epigenetic alterations and oncogenic effects mediated by viral proteins in the activation of cellular oncogenes, inactivation of tumor-suppressor genes, and dysregulation of multiple signal-transduction pathways. Advances in genetics and gene expression profiling have enhanced our current understanding of the pathways involved in HCV-associated liver cancer development. In this review, we summarize the current understanding of mechanisms of hepatocarcinogenesis induced by HCV infection.
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Affiliation(s)
- Ming V Lin
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; , ,
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Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol 2014; 61:S79-90. [PMID: 25443348 PMCID: PMC4435677 DOI: 10.1016/j.jhep.2014.07.010] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 07/03/2014] [Accepted: 07/10/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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Affiliation(s)
- Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, United States.
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, United States
| | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, United States
| | - Thomas F Baumert
- INSERM Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, France; Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, United States.
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Arciello M, Gori M, Balsano C. Mitochondrial dysfunctions and altered metals homeostasis: new weapons to counteract HCV-related oxidative stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:971024. [PMID: 24371505 PMCID: PMC3859171 DOI: 10.1155/2013/971024] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 10/18/2013] [Accepted: 10/28/2013] [Indexed: 02/06/2023]
Abstract
The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the "power plants" of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients.
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Affiliation(s)
- Mario Arciello
- Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Via del Policlinico 155, 00161 Rome, Italy
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
| | - Manuele Gori
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
| | - Clara Balsano
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
- Institute of Molecular Biology and Pathology (IBPM); CNR, Piazzale Aldo Moro 7, 00185 Rome, Italy
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Himoto T, Tani J, Miyoshi H, Morishita A, Yoneyama H, Kurokohchi K, Inukai M, Masugata H, Goda F, Senda S, Haba R, Ueno M, Yamaoka G, Masaki T. Investigation of the factors associated with circulating soluble CD36 levels in patients with HCV-related chronic liver disease. Diabetol Metab Syndr 2013; 5:51. [PMID: 24016701 PMCID: PMC3846866 DOI: 10.1186/1758-5996-5-51] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 09/02/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND CD36, a class B scavenger receptor, participates in the pathogenesis of metabolic dysregulation such as insulin resistance, hepatic steatosis, and atherosclerosis. Persistent hepatitis C virus (HCV) infection often evokes these metabolic abnormalities. The primary purpose of this study was to investigate the role of CD36 in the pathogenesis of insulin resistance and hepatic steatosis caused by chronic HCV infection. METHODS Forty-five patients with HCV-related chronic liver disease (CLD-C) were enrolled in this study. CD36 expression in the liver specimen was examined by an immunohistochemical procedure. The concentrations of circulating soluble form of CD36 (sCD36) and oxLDL were determined by the enzyme-linked innunosorbent assay. Insulin resistance was estimated by the values of HOMA-IR. RESULTS Moderate to extensive hepatic CD36 expression was observed in the sinusoids of all enrolled CLD-C patients. CD36-positive sinusoids appeared to be identical to Kupffer cells. The severity of CD36 expression in the hepatic sinusoids was significantly correlated with the sCD36 level in sera of patients with CLD-C. The serum sCD36 levels were significantly correlated with body mass index and serum oxLDL levels in those patients. However, the serum sCD36 concentrations were independent of the values of HOMA-IR and the severity of hepatic steatosis. CONCLUSIONS These data suggest that the serum sCD36 levels reflect the severity of CD36 expression on the Kupffer cells in patients with CLD-C, and that the serum sCD36 levels were associated with obesity, although the levels were independent of insulin resistance and hepatic steatosis in those patients.
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Affiliation(s)
- Takashi Himoto
- Department of Integrated Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-Cho, Kagawa 7610-79, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Kazutaka Kurokohchi
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Michio Inukai
- Department of Integrated Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-Cho, Kagawa 7610-79, Japan
| | - Hisashi Masugata
- Department of Integrated Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-Cho, Kagawa 7610-79, Japan
| | - Fuminori Goda
- Department of Integrated Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-Cho, Kagawa 7610-79, Japan
| | - Shoichi Senda
- Department of Integrated Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-Cho, Kagawa 7610-79, Japan
| | - Reiji Haba
- Department of Diagnosis Pathology, Kagawa University School of Medicine, Kagawa, Japan
| | - Masaki Ueno
- Department of Pathology and Host Defense, Kagawa University School of Medicine, Kagawa, Japan
| | - Genji Yamaoka
- Department of Clinical Laboratory, Hospital of Kagawa University School of Medicine, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
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Sikorska K, Stalke P, Romanowski T, Rzepko R, Bielawski KP. Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2013; 12:377-84. [PMID: 23924495 DOI: 10.1016/s1499-3872(13)60059-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non-alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serum markers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.
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Affiliation(s)
- Katarzyna Sikorska
- Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland
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Yang J, Li S, Liu YX. Systematic analysis of diabetes- and glucose metabolism-related proteins and its application to Alzheimer’s disease. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jbise.2013.66078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012; 287:40161-72. [PMID: 23066023 DOI: 10.1074/jbc.m112.417014] [Citation(s) in RCA: 341] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
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Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem 2012. [PMID: 23066023 DOI: 10.10747/jbc.m112.417014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. RESULTS Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNFα production, chemokine induction, and monocyte recruitment. The silencing of TNFα in myeloid cells reduces NASH progression. CONCLUSION Increase of TNFα-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. SIGNIFICANCE Myeloid cells-targeted silencing of TNFα might be a tenable therapeutic approach. Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1.
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Matsushima-Nishiwaki R, Adachi S, Yoshioka T, Yasuda E, Yamagishi Y, Matsuura J, Muko M, Iwamura R, Noda T, Toyoda H, Kaneoka Y, Okano Y, Kumada T, Kozawa O. Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogen-activated protein kinases and AKT pathways. J Cell Biochem 2012; 112:3430-9. [PMID: 21769911 DOI: 10.1002/jcb.23270] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Heat shock protein (HSP) 20, one of the low-molecular weight HSPs, is known to have versatile functions, such as vasorelaxation. However, its precise role in cancer proliferation remains to be elucidated. While HSP20 is constitutively expressed in various tissues including the liver, we have previously reported that HSP20 protein levels in human hepatocellular carcinoma (HCC) cells inversely correlate with the progression of HCC. In this study, we investigated the role of HSP20 in HCC proliferation. The activities of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and AKT were negatively correlated with the HSP20 protein levels in human HCC tissues. Since HSP20 proteins were hardly detected in HCC-derived cell lines, the effects of HSP20 expression were evaluated using human HCC-derived HuH7 cells that were stably transfected with wild-type human HSP20 (HSP20 overexpressing cells). In HSP20 overexpressing cells, cell proliferation was retarded, and the activation of the mitogen-activated protein kinases (MAPKs) signaling pathways, including the ERK and JNK, and AKT pathways, as well as cyclin D1 accumulation induced by either transforming growth factor-α (TGFα) or hepatocyte growth factor, were significantly suppressed compared with the empty vector-transfected cells (control cells). Taken together, our findings strongly suggest that HSP20 suppresses the growth of HCC cells via the MAPKs and AKT signaling pathways, thus suggesting that the HSP20 could be a new therapeutic target for HCC.
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Jahan S, Ashfaq UA, Qasim M, Khaliq S, Saleem MJ, Afzal N. Hepatitis C virus to hepatocellular carcinoma. Infect Agent Cancer 2012; 7:2. [PMID: 22289144 PMCID: PMC3293064 DOI: 10.1186/1750-9378-7-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 01/30/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus causes acute and chronic hepatitis and can lead to permanent liver damage and hepatocellular carcinoma (HCC) in a significant number of patients via oxidative stress, insulin resistance (IR), fibrosis, liver cirrhosis and HCV induced steatosis. HCV induced steatosis and oxidative stress causes steato-hepatitis and these pathways lead to liver injury or HCC in chronic HCV infection. Steatosis and oxidative stress crosstalk play an important role in liver damage in HCV infection. This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC. It also expresses Molecular cascade which leads oxidative stress and steatosis to HCC.
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Affiliation(s)
- Shah Jahan
- Department of Immunology, University of Health Sciences, Lahore, Pakistan.
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Xue HL, Feng GH. Establishment of a CHO cell model expressing hepatitis C virus core protein in vitro. Shijie Huaren Xiaohua Zazhi 2011; 19:3117-3121. [DOI: 10.11569/wcjd.v19.i30.3117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a non-hepatic cell model expressing hepatitis C virus (HCV) core protein in vitro.
METHODS: Recombinant plasmid pCMH6K containing the gene encoding HCV 1b core protein was identified by restriction digestion and temporarily or stably transfected into Chinese hamster ovary (CHO) cells using Lipofectamine 2000. CHO cells transfected with the pCMH6K plasmid were passaged continuously for 110 days. Distribution of HCV core protein in transfected CHO cells was examined by immune fluorescence. The mRNA expression of HCV core protein in transfected CHO cells was examined by RT-PCR.
RESULTS: The pCMH6K plasmid contains the gene encoding HCV1b core protein. HCV core protein was mainly distributed in the cytoplasm and scarcely in the membrane of CHO cells temporarily or stably transfected with the pCMH6K plasmid. The mRNA expression of HCV core protein was also detected in CHO cells transfected with the pCMH6K plasmid.
CONCLUSION: CHO cells transfected with the pCMH6K plasmid could express HCV core protein persistently.
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Aoki YH, Ohkoshi S, Yamagiwa S, Yano M, Takahashi H, Waguri N, Igarashi K, Sugitani SI, Takahashi T, Ishikawa T, Kamimura T, Wakabayashi H, Watanabe T, Matsuda Y, Nomoto M, Aoyagi Y. Characterization of elevated alanine aminotransferase levels during pegylated-interferon α-2b plus ribavirin treatment for chronic hepatitis C. Hepatol Res 2011; 41:118-125. [PMID: 21269381 DOI: 10.1111/j.1872-034x.2010.00749.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Elevation of alanine aminotransferase (ALT) levels during pegylated-interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon. METHODS Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN α-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN α-2a plus ribavirin were also included for partial analysis. RESULTS Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with α-2a when compared to those treated with α-2b. CONCLUSION Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause.
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Affiliation(s)
- Yo-Hei Aoki
- Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University Niigata Municipal Hospital Tachikawa General Hospital Nagaoka Red Cross Hospital Sai-sei-kai Second Hospital Takeda General Hospital Watanabe Clinic, Niigata, Japan
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Conrotto D, Bugianesi E, Chiusa L, Carrozzo M. Non-alcoholic steatohepatitis (NASH) and oral lichen planus: a rare occurrence. Int J Oral Maxillofac Surg 2010; 40:553-6. [PMID: 21146362 DOI: 10.1016/j.ijom.2010.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Revised: 05/20/2010] [Accepted: 11/05/2010] [Indexed: 11/16/2022]
Abstract
Oral lichen planus (OLP) is frequently associated with hepatitis C virus infection but uncommonly with other causes of liver disorder. The authors report the case of a 41-year-old male patient with a clinical and histological diagnosis of OLP who presented with a marked alteration of the transaminase values, with no signs of past or present HBV, HCV, HGV or TTV infection. The patient did not consume alcohol and no exposure to hepatotoxic substances was reported. All autoantibodies were negative. Hepatic fine needle biopsy showed macrovesicular steatosis with a slight chronic portal inflammatory infiltrate and signs of siderosis. Iron metabolism was slightly altered. Genetic tests showed a heterozygotic mutation for hereditary haemochromatosis gene (HLA-H C282Y) but not for HLA-H63D. The patient presented slight insulin resistance but had normal glycaemic values. The results are consistent with a diagnosis of non-alcoholic steatohepatitis (NASH). This is the first reported case of NASH associated with OLP.
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Affiliation(s)
- D Conrotto
- Division of Otorhinolaryngology, Department of Clinical Physiopathology, Oral Medicine Section, University of Turin, Italy
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31
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Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2:2108-2133. [PMID: 21994721 PMCID: PMC3185750 DOI: 10.3390/v2092108] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
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Affiliation(s)
- Arup Banerjee
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ratna B. Ray
- Department of Pathology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 2nd Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ranjit Ray
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
- Molecular Microbiology & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 1-314- 977-9034; Fax: 1-314-771-3816
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Asahina Y, Tsuchiya K, Tamaki N, Hirayama I, Tanaka T, Sato M, Yasui Y, Hosokawa T, Ueda K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Izumi N. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology 2010; 52:518-27. [PMID: 20683951 DOI: 10.1002/hep.23691] [Citation(s) in RCA: 227] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED An increase in the aging population is an impending problem. A large cohort study was carried out to determine the influence of aging and other factors on hepatocarcinogenesis in patients treated with interferon. Biopsy-proven 2547 chronic hepatitis C patients registered at our referral center since 1992 were included. Of these, 2166 were treated with interferon-based therapy. Incidences of hepatocellular carcinoma (HCC) associated with interferon were analyzed by Kaplan-Meier and person-years methods for an average follow-up of 7.5 years. Factors associated with HCC risk were determined by Cox proportional hazard analysis. HCC developed in 177 interferon-treated patients. The risk for HCC depended on age at primary biopsy and increased more than 15-fold after 65 years of age. Even when stratified by stage of fibrosis, the cumulative and annual incidences of HCC were significantly higher in older patients than in younger patients (P < 0.001) at the same stage of fibrosis, except for cirrhosis. Progression of fibrosis over time was significantly accelerated in older patients. The impact of viral eradication on HCC prevention was less significant in older patients than in younger patients. Multivariate analysis confirmed that age, gender, liver fibrosis, liver steatosis, total cholesterol level, fasting blood sugar level, baseline and postinterferon alpha-fetoprotein level, and virological response to interferon were independent risk factors associated with HCC. Aging was the strongest risk factor for a nonvirological response to interferon-based antiviral therapy. CONCLUSION Elderly patients are at a higher risk for HCC. Hepatitis C viral eradication had a smaller effect on hepatocarcinogenesis in older patients. Patients should therefore be identified at an earlier age and treatment should be initiated.
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Affiliation(s)
- Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant complication of obesity and is recognized as the hepatic manifestation of the metabolic syndrome. The process occurs in adults and children and is characterized by the presence of increased amounts of fat in the liver (steatosis). With inflammation, cell death and scarring (fibrosis), the process may result in end-stage liver disease, or be a precursor for hepatocellular carcinoma. Excess hepatic fat is now recognized as an independent marker for increased cardiovascular risk. Even though imaging studies and laboratory-based tests are accurate at detecting significant steatosis and/or advanced fibrosis, respectively, the diagnosis and characterization of NAFLD ultimately depend on histopathologic evaluation, as the parenchymal alterations that comprise the spectrum of injury in NAFLD include patterns as well as specific lesions. Histologic findings in children may differ from those in adults. In this Review, the histologic features that are diagnostic and discriminatory between steatosis and steatohepatitis, the significance of the distinction between steatosis and steatohepatitis, the types and locations of fibrosis, and the histologic variances between adult and pediatric NAFLD are discussed. Clinical advantages as well as potential drawbacks of liver biopsy are presented. Current pathophysiologic concepts relevant to histologic findings are discussed.
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Abstract
The finding of lipid accumulation in the liver, so-called hepatic steatosis or non-alcoholic fatty liver disease, is a common condition frequently found in healthy subjects. Its prevalence, in fact, has been estimated by magnetic resonance studies to be about 35% in the general population and 75% in obese persons. Nevertheless, its presence generates liver damage only in a small percentage of subjects not affected by other liver diseases. It should be defined as a “co-factor” capable of affecting severity and progression, and also therapeutic perspectives, of liver diseases to which it is associated. Herein we will evaluate the impact of hepatic steatosis and obesity on the most common liver diseases: chronic viral hepatitis C and B, and alcoholic liver disease.
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Williamson CD, Colberg-Poley AM. Access of viral proteins to mitochondria via mitochondria-associated membranes. Rev Med Virol 2009; 19:147-64. [PMID: 19367604 DOI: 10.1002/rmv.611] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
By exploiting host cell machineries, viruses provide powerful tools for gaining insight into cellular pathways. Proteins from two unrelated viruses, human CMV (HCMV) and HCV, are documented to traffic sequentially from the ER into mitochondria, probably through the mitochondria-associated membrane (MAM) compartment. The MAM are sites of ER-mitochondrial contact enabling the direct transfer of membrane bound lipids and the generation of high calcium (Ca2+) microdomains for mitochondria signalling and responses to cellular stress. Both HCV core protein and HCMV UL37 proteins are associated with Ca2+ regulation and apoptotic signals. Trafficking of viral proteins to the MAM may allow viruses to manipulate a variety of fundamental cellular processes, which converge at the MAM, including Ca2+ signalling, lipid synthesis and transfer, bioenergetics, metabolic flow, and apoptosis. Because of their distinct topologies and targeted MAM sub-domains, mitochondrial trafficking (albeit it through the MAM) of the HCMV and HCV proteins predictably involves alternative pathways and, hence, distinct targeting signals. Indeed, we found that multiple cellular and viral proteins, which target the MAM, showed no apparent consensus primary targeting sequences. Nonetheless, these viral proteins provide us with valuable tools to access the poorly characterised MAM compartment, to define its cellular constituents and describe how virus infection alters these to its own end. Furthermore, because proper trafficking of viral proteins is necessary for their function, discovering the requirements for MAM to mitochondrial trafficking of essential viral proteins may provide novel targets for the rational design of anti-viral drugs.
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Affiliation(s)
- Chad D Williamson
- Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010, USA.
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Persico M, Masarone M, La Mura V, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol 2009. [PMID: 19152451 DOI: 10.3748/wjg.v15.i4.462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). METHODS We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). RESULTS Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. CONCLUSION These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.
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Affiliation(s)
- Marcello Persico
- Internal Medicine and Hepatology Unit, Second University of Naples, Via F. Petrarca, 101/b, Naples 80122, Italy.
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Koike K. Steatosis, liver injury, and hepatocarcinogenesis in hepatitis C viral infection. J Gastroenterol 2009; 44 Suppl 19:82-8. [PMID: 19148799 DOI: 10.1007/s00535-008-2276-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Accepted: 08/10/2008] [Indexed: 02/04/2023]
Abstract
In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several hepatic and extrahepatic manifestations. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has been shown, implying hepatitis C as a metabolic disease. Furthermore, recent epidemiological studies have suggested a linkage between insulin resistance and chronic HCV infection. In addition to the data indicating the presence of lipid metabolism disturbance and insulin resistance in the cohort of chronic hepatitis C patients, we found evidence showing the association between these two conditions and HCV infection using mice transgenic for the HCV core gene. These mice develop HCC late in life after the phase of hepatic steatosis and insulin resistance. The nonappearance of both steatosis and HCC in HCV core gene transgenic mice that are null for the proteasome activator 28gamma implies a close relationship between lipid metabolism disturbance and hepatocarcinogenesis. Also, the core protein is shown to bind with retinoid X receptor (RXR)-alpha, resulting in the upregulation of some lipid metabolism enzymes, including cellular retinol binding protein II and acyl-CoA oxidase. In addition, the persistent activation of peroxisome proliferator activated receptor (PPAR)-alpha has recently been found in the liver of HCV core gene transgenic mice, yielding dramatic changes in lipid metabolism and hepatocyte proliferation, including HCC development. These results would provide a clue for further understanding of the role of lipid metabolism in pathogenesis of HCV infection, including liver injury and hepatocarcinogenesis.
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Affiliation(s)
- Kazuhiko Koike
- Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Abstract
Abnormal accumulation of fat in the liver (steatosis) is commonly observed in hepatitis C virus (HCV) infection, and the severity of steatosis has been well correlated with the degree of hepatic fibrosis. In patients with chronic HCV infection, steatosis may occur in conjunction with other metabolic risk factors such as insulin resistance and the metabolic syndrome. This was observed primarily in patients infected with non-genotype 3 virus. Otherwise, in HCV-infected patients, especially those infected with genotype 3a, reductions in total cholesterol as well as high-density lipoprotein and low-density lipoprotein cholesterol are observed compared with matched controls, and the normalization of these parameters appears to be an important correlate of the response to antiviral therapy. In that setting, the pathogenic mechanisms involved in HCV-induced steatosis are mediated in large part by the HCV core protein, whose expression is associated with lipid droplet accumulation, changes in lipogenic gene expression and/or the activity of lipogenic proteins, and effects on mitochondrial oxidative function. The importance of genes such as peroxisome proliferator-activated receptor-alpha and the proteasome activator PA28-gamma in HCV-mediated steatosis has been elucidated from studies in genetically altered mice, and the manipulation of these and other pathways may provide an avenue for therapeutic intervention.
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Affiliation(s)
- Francesco Negro
- Viropathology Unit, University Hospitals, Geneva, Switzerland.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of clinical entities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with possible evolution to cirrhosis and hepatocellular carcinoma. Iron is considered a putative element that interacts with oxygen radicals in inducing liver damage and fibrosis. The role of hepatic iron in the progression of NASH remains controversial, but in some patients, iron may have a role in the pathogenesis of NASH. Though genetic factors, insulin resistance, dysregulation of iron-regulatory molecules, erythrophagocytosis by Kupffer cells may be responsible for hepatic iron accumulation in NASH, exact mechanisms involved in iron overload remain to be clarified. Iron reduction therapy such as phlebotomy or dietary iron restriction may be promising in patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities.
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Affiliation(s)
- Yoshio Sumida
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
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41
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Persico M, Masarone M, Mura VL, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol 2009; 15:462-466. [PMID: 19152451 PMCID: PMC2653368 DOI: 10.3748/wjg.15.462] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Revised: 10/31/2008] [Accepted: 11/07/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). METHODS We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). RESULTS Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. CONCLUSION These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.
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Chang ML, Chen JC, Chang MY, Yeh CT, Lin WP, Liang CK, Huang SF, Dang KN, Chiu CT, Lin DY. Acute expression of hepatitis C core protein in adult mouse liver: Mitochondrial stress and apoptosis. Scand J Gastroenterol 2008; 43:747-55. [PMID: 18569993 DOI: 10.1080/00365520701875987] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE In infection with hepatitis C virus (HCV), spontaneous clearance of the virus occurs in 30-40% of cases. By contrast, in chronic infection, this is rare. The basis for viral clearance in acute disease is unknown. Whereas cellular immune responses have been studied in detail, few data exist on the role of viral structural proteins, such as the core protein. The purpose of this study was to investigate the effects of core produced de novo within adult mouse hepatocytes by using a new transgenic mouse line in which expression of HCV core is regulated by tetracycline (tet-off). MATERIAL AND METHODS In this work, transgenic mice with conditional HCV core were created, to study the acute expression of HCV core protein in the context of the mature liver. The subcellular distribution of the core, hepatocellular oxidative stress and apoptosis were monitored. RESULTS Core protein is readily detectable and strongly associated with cytoplasmic lipid vesicles, endoplasmic reticulum and mitochondria. Mitochondrial oxidative stress was evidenced by a reduction in thioredoxin-2 (trx2). Concurrently, caspase-3 activity and TUNEL increased and, over time, the level of core protein in the liver declined. CONCLUSIONS Mice that are conditionally transgenic for HCV core protein, which is readily detected and morphologically associated with steatosis in individual hepatocytes, were developed. Acute expression of core protein causes mitochondrial stress, as demonstrated by a reduction in trx2 and in the apoptosis of core-positive hepatocytes. We speculate that these events could be involved in the clearance of virus during acute hepatitis C, by both reducing the burden of virus in the liver and effectively priming the immune response.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center and Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
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Lonardo A, Loria P, Carulli N. Dysmetabolic changes associated with HCV: a distinct syndrome? Intern Emerg Med 2008; 3:99-108. [PMID: 18274709 DOI: 10.1007/s11739-008-0127-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Accepted: 07/17/2007] [Indexed: 02/07/2023]
Abstract
Although not associated with the metabolic syndrome, HCV is linked with impaired insulin signalling, insulin resistance, hypocholesterolemia and steatosis which represent a distinct HCV-associated dysmetabolic syndrome. Insulin resistance affects the development of diabetes, fibrosis, impaired response to antivirals and perhaps hepatocellular carcinoma risk. HCV infection is associated with hypocholesterolemia and steatosis reversible after sustained virologic response. A "viral", and a "metabolic" steatosis exist as function of viral genotypes. Little is known about the possible role of HCV in further components of the metabolic syndrome such as atherosclerosis, obesity, arterial hypertension, hyperuricemia and thrombotic risk factors.
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Affiliation(s)
- Amedeo Lonardo
- Dipartimento Integrato di Medicina, Endocrinologia, Metabolismo e Geriatria, Università degli Studi di Modena e Reggio Emilia, Nuovo Ospedale S. Agostino Estense, Modena, Italy.
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Koike K, Tsutsumi T, Miyoshi H, Shinzawa S, Shintani Y, Fujie H, Yotsuyanagi H, Moriya K. Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol 2008; 23 Suppl 1:S87-91. [PMID: 18336672 DOI: 10.1111/j.1440-1746.2007.05292.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In addition, heavy alcohol use has been linked with earlier progression to HCC in chronic hepatitis C patients. However, in the pathogenesis of HCV-associated HCC, it still remains controversial as to whether the virus plays a direct or an indirect role, and as to how alcohol operates in the acceleration of HCC development. Several studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, although other factors such as continuous inflammation or environmental factors seem also to play a role. The downstream events of the HCV core protein expression in the transgenic mouse HCC model are segregated into two pathways. One is the augmented production of oxidative stress in the absence of inflammation along with the attenuation of some scavenging systems in the putative preneoplastic stage with steatosis in the liver. The other pathway is the alteration in cellular gene expression and intracellular signaling, including the mitogen-activated protein kinase cascade. The combination of these pathways would explain the unusually high incidence and multicentric nature of HCC development in HCV infection. In addition, alcohol feeding in this animal model further activated the two pathways synergistically with HCV, leading to an earlier development of HCC. Such a synergy would reveal the molecular basis for the acceleration of HCC development by alcohol in HCV infection.
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Affiliation(s)
- Kazuhiko Koike
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
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Koike K. [Status of chronic viral hepatitis: a world-wide trend and problems in Japan]. ACTA ACUST UNITED AC 2008; 97:3-9. [PMID: 18360954 DOI: 10.2169/naika.97.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Masarone M, La Mura V, Bruno S, Gaeta GB, Vecchione R, Carrino F, Moschella F, Torella R, Persico M. Steatohepatitis is associated with diabetes and fibrosis in genotype 1b HCV-related chronic liver disease. J Viral Hepat 2007; 14:714-720. [PMID: 17875006 DOI: 10.1111/j.1365-2893.2007.00861.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Liver steatosis, diabetes mellitus and hepatitis C virus (HCV) genotype have been implicated in liver fibrosis in HCV-related chronic active hepatitis (CAH). The aim of this study was to evaluate whether steatosis and diabetes were associated with more severe liver fibrosis in patients with genotype 1b HCV-related CAH. One-hundred and eighty patients (98 men, 82 women; age range 17-68 years; median 51) infected with genotype 1b HCV underwent ultrasound examination and liver biopsy because of elevated levels of serum alanine transaminase. Based on liver histology, patients were divided into three steatosis classes: 1 (involving <33% of hepatocytes), 2 (34-66%) and 3 (>66%). Fibrosis was graded with the Ishak score (range: 0-6). Virological and epidemiologic characteristics, biochemical data, body mass index, and apparent duration of disease were recorded. Diabetes was identified according to American Diabetes Association criteria. The median fibrosis grade was 2 (23 patients had liver cirrhosis) in the three steatosis classes, with no significant differences between classes. At multivariate analysis, fibrosis was significantly related to age, alanine transaminase, diabetes, hepatitis B core antibody, steatohepatitis and grading. At binary logistic regression analysis, only diabetes and fibrosis stage were significantly associated with steatohepatitis. Steatosis was not an independent risk factor for liver disease severity in our CAH/genotype 1b HCV-infected patients. Steatohepatitis was associated as well as diabetes and affected the severity of liver fibrosis.
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Affiliation(s)
- M Masarone
- Department of Internal Medicine, Gastroenterology, Hepatology and Endocrinology, Second University of Naples, Naples, Italy
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Koike K. Pathogenesis of HCV-associated HCC: Dual-pass carcinogenesis through activation of oxidative stress and intracellular signaling. Hepatol Res 2007; 37 Suppl 2:S115-20. [PMID: 17877471 DOI: 10.1111/j.1872-034x.2007.00173.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk toward development of hepatocellular carcinoma (HCC). It remains controversial, however, in the pathogenesis of HCC associated with HCV, whether the virus plays a direct role or merely an indirect one. The studies using transgenic mouse models by us and others, in which the core protein of HCV has oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation would play a role, as well. The downstream events of the core protein are segregated into two components. One is the augmented production of oxidative stress along with the activation of scavenging system including catalase and glutathion (GSH) in the putative preneoplastic stage with steatosis in the liver. Thus, oxidative stress production in the absence of inflammation by the core protein would partly contribute to the development of HCC. The generation of oxidative stress is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other is the alteration of intracellular signaling cascade of MAPK (JNK),AP-1, cyclin D1, and CDK4. The combination of these pathways, collective with HCV-associated alterations in lipid and glucose metabolism, would lead to the frequent development of HCC in persistent HCV infection. Our results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for other cancers. Similar to the pathogenesis of other cancers, the accumulation of a set of genetic aberrations may also be necessary for multistage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore, unlike other cancers, HCV infection can elicit HCC in the absence of a complete set of genetic aberrations. Such a scenario, "non-Vogelstein-type" carcinogenesis, would explain the unusually high incidence and multicentric nature of HCC development in HCV infection.
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Affiliation(s)
- Kazuhiko Koike
- Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J, Kinnman N, Hultcrantz R. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol 2007; 46:1111-8. [PMID: 17399848 DOI: 10.1016/j.jhep.2007.01.024] [Citation(s) in RCA: 147] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Revised: 12/24/2006] [Accepted: 01/15/2007] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS We investigated the impact of diabetes mellitus type 2, overweight, alcohol over-consumption, and chronic hepatitis B or C as risk factors, for liver fibrosis in psoriasis patients treated with methotrexate. METHODS One hundred and sixty-nine liver biopsies from 71 patients who underwent liver biopsies as part of the monitoring of methotrexate treatment for psoriasis were reviewed. Fibrosis, steatosis and inflammation were staged according to the NAFLD activity score. RESULTS Twenty-six patients had one or more of the risk factors and 25 (96%) of these (median cumulative dose methotrexate 1500 mg) developed liver fibrosis. Of those without risk factor, 26 (58%) (p=0.012) developed fibrosis (median cumulative dose methotrexate 2100 mg). Ten (38%) of the patients with risk factor(s) had severe fibrosis (stage 3-4) (mean cumulative dose methotrexate 1600 mg), while four (9%) (p=0.0012) of those without risk factors had severe fibrosis (median cumulative dose methotrexate 1900 mg). CONCLUSIONS Patients with methotrexate treated psoriasis and risk factors for liver disease, especially diabetes type 2 or overweight, are at higher risk of developing severe liver fibrosis compared to those without such risk factors, even when lower cumulative methotrexate doses are given.
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Affiliation(s)
- Peter Rosenberg
- Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden.
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Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007; 22 Suppl 1:S108-11. [PMID: 17567457 DOI: 10.1111/j.1440-1746.2006.04669.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Persistent infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV as to whether the virus plays a direct or an indirect role. The studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation would also play a role. The downstream events of the core protein are segregated into two components. One is the augmented production of oxidative stress along with the activation of scavenging system, including catalase and glutathione, in the putative pre-neoplastic stage with steatosis in the liver. Thus, oxidative stress production in the absence of inflammation by the core protein would partly contribute to the development of HCC. The generation of oxidative stress is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other component is the alteration of intracellular signaling cascade of mitogen-activated protein kinase and activating factor (AP)-1, leading to the activation of cell cycle control. The combination of these pathways, collective with HCV-associated alterations in lipid and glucose metabolism, would lead to the frequent development of HCC in persistent HCV infection. These results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for the other cancers. Similar to the pathogenesis of other cancers, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore unlike for other cancers, HCV infection may be able to cause HCC in the absence of a complete set of genetic aberrations. Such a scenario, 'non-Vogelstein-type' carcinogenesis, would explain the rare feature of hepatocarcinogenesis in HCV infection, the extraordinarily high incidence and the multicentric nature of HCC development.
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Affiliation(s)
- Kazuhiko Koike
- Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
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