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Rajewski P, Pawłowska M, Kozielewicz D, Dybowska D, Olczak A, Cieściński J. Hepatitis C Infection Is Not a Cardiovascular Risk Factor in Young Adults. Biomedicines 2024; 12:2400. [PMID: 39457712 PMCID: PMC11505620 DOI: 10.3390/biomedicines12102400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Cardiovascular diseases are one of the leading causes of hospitalization and death in Poland and around the world and are still an ongoing problem for modern medicine. Despite advances in diagnosis and treatment, both conservative and invasive, the prevention of cardiovascular disease directed at reducing risk factors remains a problem. The main classical risk factors for the development of cardiovascular disease in Poland include hypertension, lipid disorders, obesity, diabetes and smoking. A new non-classical risk factor is HCV infection. Most of the studies on the impact of HCV infection on cardiovascular disease involve elderly populations with long-term infections and advanced liver fibrosis. Methods: Hence, we set out to analyze the prevalence of risk factors and cardiovascular disease in a population of young adults under 45 years of age infected with HCV, according to gender, HCV genotype and the duration of infection. The study group consisted of 217 patients of both sexes aged 21 to 45 years (mean age 36 years). Results: No cardiovascular disease was found among the young adults infected with HCV in the study group. The most common risk factor was cigarette smoking, which affected 20.7% of the subjects, followed by hypertension (12%) and diabetes mellitus (5.5%); the prevalence was lower than in the general population. Most of the patients were characterized as overweight, with a mean BMI of 26.39 kg/m2. The mean values of other metabolic parameters-total cholesterol, LDL, HDL, uric acid and glucose-were within the population norm. The mean value of CRP was 1.43, which may indicate a moderate cardiovascular risk. Conclusions: Based on the conducted research, it was found that HCV infection in young individuals was not a risk factor for cardiovascular diseases, and the prevalence of risk factors was similar to that in the general population. The effect of HCV on the increase in C-reactive protein requires further study. The early detection of HCV infection and treatment can be considered as a prevention of cardiovascular disease.
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Affiliation(s)
- Paweł Rajewski
- Department of Internal and Infectious Diseases, Provincial Infectious Disease Hospital, 85-030 Bydgoszcz, Poland;
- Faculty of Health Sciences, University of Health Sciences in Bydgoszcz, 85-067 Bydgoszcz, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Dorota Kozielewicz
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Anita Olczak
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, 87-100 Torun, Poland; (M.P.); (D.K.); (D.D.); (A.O.)
| | - Jakub Cieściński
- Department of Internal and Infectious Diseases, Provincial Infectious Disease Hospital, 85-030 Bydgoszcz, Poland;
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Żychowska J, Ćmil M, Skórka P, Olejnik-Wojciechowska J, Plewa P, Bakinowska E, Kiełbowski K, Pawlik A. The Role of Epigenetic Mechanisms in the Pathogenesis of Hepatitis C Infection. Biomolecules 2024; 14:986. [PMID: 39199374 PMCID: PMC11352264 DOI: 10.3390/biom14080986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.
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Affiliation(s)
- Justyna Żychowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Maciej Ćmil
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Patryk Skórka
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | | | - Paulina Plewa
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland;
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
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Li YM, He HW, Zhang N. Targeting Protein Phosphatases for the Treatment of Chronic Liver Disease. Curr Drug Targets 2024; 25:171-189. [PMID: 38213163 DOI: 10.2174/0113894501278886231221092522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 01/13/2024]
Abstract
There exists a huge number of patients suffering from chronic liver disease worldwide. As a disease with high incidence and mortality worldwide, strengthening the research on the pathogenesis of chronic liver disease and the development of novel drugs is an important issue related to the health of all human beings. Phosphorylation modification of proteins plays a crucial role in cellular signal transduction, and phosphatases are involved in the development of liver diseases. Therefore, this article summarized the important role of protein phosphatases in chronic liver disease with the aim of facilitating the development of drugs targeting protein phosphatases for the treatment of chronic liver disease.
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Affiliation(s)
- Yi-Ming Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Hong-Wei He
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
| | - Na Zhang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
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Lin D, Chen Y, Koksal AR, Dash S, Aydin Y. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients. Cell Commun Signal 2023; 21:102. [PMID: 37158967 PMCID: PMC10165818 DOI: 10.1186/s12964-023-01081-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 02/13/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed. METHODS Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. RESULTS Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. CONCLUSION Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.
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Affiliation(s)
- Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
| | - Yijia Chen
- The College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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McKay LGA, Thomas J, Albalawi W, Fattaccioli A, Dieu M, Ruggiero A, McKeating JA, Ball JK, Tarr AW, Renard P, Pollakis G, Paxton WA. The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway. Front Immunol 2022; 13:831695. [PMID: 35371105 PMCID: PMC8964954 DOI: 10.3389/fimmu.2022.831695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be driven by host and viral genetic factors as well as HCV encoded immunomodulatory proteins. Using the HIV-1 LTR as a tool to measure NF-κB activity, we identified that the HCV E1E2 glycoproteins and more so the E2 protein down-modulates HIV-1 LTR activation in 293T, TZM-bl and the more physiologically relevant Huh7 liver derived cell line. We demonstrate this effect is specifically mediated through inhibiting NF-κB binding to the LTR and show that this effect was conserved for all HCV genotypes tested. Transcriptomic analysis of 293T cells expressing the HCV glycoproteins identified E1E2 mediated stimulation of the endoplasmic reticulum (ER) stress response pathway and upregulation of stress response genes such as ATF3. Through shRNA mediated inhibition of ATF3, one of the components, we observed that E1E2 mediated inhibitory effects on HIV-1 LTR activity was alleviated. Our in vitro studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-κB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis.
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Affiliation(s)
- Lindsay G. A. McKay
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Jordan Thomas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Wejdan Albalawi
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Antoine Fattaccioli
- Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), Namur, Belgium
| | - Marc Dieu
- MaSUN, Mass Spectrometry Facility, University of Namur (UNamur), Namur, Belgium
| | - Alessandra Ruggiero
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Jane A. McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jonathan K. Ball
- Wolfson Centre for Global Virus Research and School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Alexander W. Tarr
- Wolfson Centre for Global Virus Research and School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Patricia Renard
- Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), Namur, Belgium,MaSUN, Mass Spectrometry Facility, University of Namur (UNamur), Namur, Belgium
| | - Georgios Pollakis
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - William A. Paxton
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom,*Correspondence: William A. Paxton,
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Pascale RM, Simile MM, Calvisi DF, Feo CF, Feo F. S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent. Cells 2022; 11:409. [PMID: 35159219 PMCID: PMC8834208 DOI: 10.3390/cells11030409] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/10/2022] [Accepted: 01/14/2022] [Indexed: 02/07/2023] Open
Abstract
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
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Affiliation(s)
- Rosa M. Pascale
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Maria M. Simile
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Diego F. Calvisi
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Claudio F. Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Surgery, University of Sassari, 07100 Sassari, Italy;
| | - Francesco Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
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HCV Genotype Has No Influence on the Incidence of Diabetes-EpiTer Multicentre Study. J Clin Med 2022; 11:jcm11020379. [PMID: 35054072 PMCID: PMC8780546 DOI: 10.3390/jcm11020379] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/30/2021] [Accepted: 01/05/2022] [Indexed: 12/17/2022] Open
Abstract
HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.
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Ke W, Zhou Y, Lai Y, Long S, Fang L, Xiao S. Porcine reproductive and respiratory syndrome virus nsp4 positively regulates cellular cholesterol to inhibit type I interferon production. Redox Biol 2021; 49:102207. [PMID: 34911669 PMCID: PMC8758914 DOI: 10.1016/j.redox.2021.102207] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/26/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular cholesterol plays an important role in the life cycles of enveloped viruses. Previous studies by our group and other groups have demonstrated that the depletion of cellular cholesterol by methyl-β-cyclodextrin (MβCD) reduces the proliferation of porcine reproductive and respiratory syndrome virus (PRRSV), a porcine Arterivirus that has been devastating the swine industry worldwide for over two decades. However, how PRRSV infection regulates cholesterol synthesis is not fully understood. In this study, we showed that PRRSV infection upregulated the activity of protein phosphatase 2 (PP2A), which subsequently activated 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in the cholesterol synthesis pathway, to increase the levels of cellular cholesterol. By screening the PRRSV-encoded proteins, we showed that nsp4 dominated the upregulation of cellular cholesterol, independently of the 3C-like protease activity of nsp4. A mutation analysis showed that domain I (amino acids 1–80) of PRRSV nsp4 interacted with PR65 alpha (PR65α), the structural subunit, and PP2Ac, the catalytic subunit, of PP2A. Importantly, domain I of nsp4 inhibited Sendai virus-induced interferon β production, and this inhibitory effect was eliminated by Lovastatin, an HMGCR inhibitor, indicating that the upregulation of cellular cholesterol by nsp4 is a strategy used by PRRSV to suppress the antiviral innate immunity of its host. Collectively, we here demonstrated the mechanism by which PRRSV regulates cellular cholesterol synthesis and reported a novel strategy by which PRRSV evades its host's antiviral innate immune response.
PRRSV nsp4 up-regulates cellular cholesterol via the PP2A-HMGCR pathway. Nsp4 domain I (amino acids 1–80) interacts with A and C subunits of PP2A. Nsp4 domain I inhibits IFN-I production by upregulating cellular cholesterol. The HMGCR inhibitor Lovastatin inhibits PRRSV proliferation.
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Affiliation(s)
- Wenting Ke
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Yanrong Zhou
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Yinan Lai
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Siwen Long
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China
| | - Liurong Fang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
| | - Shaobo Xiao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
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Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
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Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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10
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Adinolfi LE, Petta S, Fracanzani AL, Nevola R, Coppola C, Narciso V, Rinaldi L, Calvaruso V, Pafundi PC, Lombardi R, Staiano L, Di Marco V, Solano A, Marrone A, Saturnino M, Rini F, Guerrera B, Troina G, Giordano M, Craxì A, Sasso FC. Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study. Diabetes Obes Metab 2020; 22:2408-2416. [PMID: 32761721 DOI: 10.1111/dom.14168] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022]
Abstract
AIM To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence. METHODS A prospective multicentre case-control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0-F2 and 58% of whom had liver fibrosis stage F3-F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct-acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow-up period of 30 (28-42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan-Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated-measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis. RESULTS The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person-years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA-insulin resistance and HOMA-β-cell function and an increase in HOMA-insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk. CONCLUSION The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV-induced alteration of glucose homeostasis mechanisms.
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Affiliation(s)
- Luigi E Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Salvatore Petta
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Anna L Fracanzani
- Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carmine Coppola
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Vincenzo Narciso
- Unit of Hepatology, Pellegrini Hospital, ASL Napoli 1 Centro, Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Vincenza Calvaruso
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Rosa Lombardi
- Department of Pathophysiology and Transplantation, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Laura Staiano
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Vito Di Marco
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Antonio Solano
- Unit of Hepatology, Pellegrini Hospital, ASL Napoli 1 Centro, Naples, Italy
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mariarosaria Saturnino
- Unit of Internal Medicine and Hepatolology, Gragnano Hospital, ASL Napoli 3 Sud, Naples, Italy
| | - Francesca Rini
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Barbara Guerrera
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Graziano Troina
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Antonio Craxì
- Division of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Ferdinando C Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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11
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Cázares-Cortazar A, Uribe-Noguez LA, Mata-Marín JA, Gaytán-Martínez J, de la Luz Martínez-Rodríguez M, Villavicencio-Ferrel PE, Chapararro-Sánchez A, Mauss S, Ocaña-Mondragón A. A decrease in hepatitis C virus RNA to undetectable levels in chronic hepatitis C patients after PegIFNα + RVB or sofosbuvir + NS5A inhibitor treatment is associated with decreased insulin resistance and persistent oxidative stress. Arch Virol 2020; 165:2759-2766. [PMID: 32885325 DOI: 10.1007/s00705-020-04797-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 08/04/2020] [Indexed: 12/21/2022]
Abstract
Oxidative stress (OS) and insulin resistance (IR) induced by hepatitis C virus (HCV) infection, are involved in the development of chronic hepatitis C (CHC) complications and progression to hepatocellular carcinoma. The aim of this study was to investigate the effect of pegylated interferon alpha (IFNα) + ribavirin (PegIFNα+RVB) or sofosbuvir + NS5A inhibitor (SOF+InNS5A) on IR and the components of OS. HCV was genotyped in 20 CHC patients grouped by treatment with either PegIFNα+RVB (n = 10) or SOF+InNS5A (n = 10). The treatment's effect on OS-induced damage to lipids (HNE-HDL), proteins (advanced glycation end products [AGEs]), and DNA (8-OHdG) as well as the concentrations of proinflammatory cytokines (IL-2, TNFα, IFNγ), ALT, AST, GSH and platelets was determined. Superoxide dismutase (SOD) and catalase activity as well as IR, determined by the HOMA1-IR index, was evaluated. The HCV genotypes (GT) found were GT1b (45%), GT1a (30%), GT2b (20%), and GT2a (5%). Viral RNA became undetectable by week 12 with SOF+InNS5A in 100% of the cases and with PegIFNα+RVB in 70% of the cases. After viral RNA became undetectable, regardless of treatment and GT, a significant increase in the platelet concentration and SOD activity was observed, whereas ALT, insulin, and IR decreased (p < 0.05). However, only for the SOF+InNS5A treated group was there an increase in oxidative damage to lipids (p < 0.017) and proteins (p < 0.05). None of the other parameters demonstrated any differences. These data confirm that OS persisted after treatment with either SOF+InNS5A or PegIFNα+RVB. IR could be considered a response biomarker to treatment with direct-acting antivirals.
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Affiliation(s)
- Allison Cázares-Cortazar
- Laboratorio Central de Epidemiología, División de Laboratorios de Vigilancia e Investigación Epidemiológica, Instituto Mexicano del Seguro Social, IMSS, Calzada vallejo s/n Col. La Raza, Del. Azcapotzalco, CP 02990, México City, México
| | - Luis A Uribe-Noguez
- Laboratorio Central de Epidemiología, División de Laboratorios de Vigilancia e Investigación Epidemiológica, Instituto Mexicano del Seguro Social, IMSS, Calzada vallejo s/n Col. La Raza, Del. Azcapotzalco, CP 02990, México City, México
| | - José Antonio Mata-Marín
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, IMSS, México City, México
| | - Jesús Gaytán-Martínez
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, IMSS, México City, México
| | - María de la Luz Martínez-Rodríguez
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, IMSS, México City, México
| | - Pedro Esteban Villavicencio-Ferrel
- Laboratorio de Medicina Nuclear, Unidad Médica de Alta Especialidad, Hospital de Especialidades, CMN "La Raza", Instituto Mexicano del Seguro Social, IMSS, México City, México
| | - Alberto Chapararro-Sánchez
- Departamento de Enfermedades Infecciosas, Hospital de Infectología, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social, IMSS, México City, México
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
| | - Alicia Ocaña-Mondragón
- Laboratorio Central de Epidemiología, División de Laboratorios de Vigilancia e Investigación Epidemiológica, Instituto Mexicano del Seguro Social, IMSS, Calzada vallejo s/n Col. La Raza, Del. Azcapotzalco, CP 02990, México City, México.
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12
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037366. [PMID: 31501266 DOI: 10.1101/cshperspect.a037366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.,Institut Universitaire de France (IUF), 75231 Paris, France
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
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13
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Joyce MA, Berry-Wynne KM, dos Santos T, Addison WR, McFarlane N, Hobman T, Tyrrell DL. HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response. PLoS Pathog 2019; 15:e1007949. [PMID: 31374104 PMCID: PMC6677295 DOI: 10.1371/journal.ppat.1007949] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 06/29/2019] [Indexed: 12/22/2022] Open
Abstract
Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response. The response of cells to an invading pathogen must be swift and well controlled because of the detrimental effects of chronic inflammation. However, viruses often hijack host control mechanisms. HCV and flaviviruses are known to suppress the innate immune response in cells by a variety of mechanisms. This study clarifies and expands a specific cellular mechanism for global control of the antiviral response after the induction of interferon expression. It shows how several viruses hijack this control mechanism to suppress the innate interferon response.
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Affiliation(s)
- Michael A. Joyce
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
- * E-mail: (MAJ); (DLT)
| | - Karyn M. Berry-Wynne
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - Theodore dos Santos
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - William R. Addison
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - Nicola McFarlane
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - Tom Hobman
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
- Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada
| | - D. Lorne Tyrrell
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
- * E-mail: (MAJ); (DLT)
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14
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Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017; 37:950-962. [PMID: 27943508 DOI: 10.1111/liv.13337] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in β-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.
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Affiliation(s)
- Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
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15
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Lerat H, Imache MR, Polyte J, Gaudin A, Mercey M, Donati F, Baudesson C, Higgs MR, Picard A, Magnan C, Foufelle F, Pawlotsky JM. Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice. J Biol Chem 2017; 292:12860-12873. [PMID: 28559285 DOI: 10.1074/jbc.m117.785030] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/18/2017] [Indexed: 12/15/2022] Open
Abstract
Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.
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Affiliation(s)
- Hervé Lerat
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France.
| | - Mohamed Rabah Imache
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Jacqueline Polyte
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Aurore Gaudin
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Marion Mercey
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Flora Donati
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Camille Baudesson
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Martin R Higgs
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France
| | - Alexandre Picard
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Christophe Magnan
- Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France
| | - Fabienne Foufelle
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 75006 Paris, France
| | - Jean-Michel Pawlotsky
- INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France; Université Paris-Est Créteil Val de Marne, 94010 Créteil, France; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France
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16
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Morales AL, Junga Z, Singla MB, Sjogren M, Torres D. Hepatitis C eradication with sofosbuvir leads to significant metabolic changes. World J Hepatol 2016; 8:1557-1563. [PMID: 28050236 PMCID: PMC5165269 DOI: 10.4254/wjh.v8.i35.1557] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control.
METHODS This is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis.
RESULTS Two hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684).
CONCLUSION Eradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.
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17
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Xian L, Hou S, Huang Z, Tang A, Shi P, Wang Q, Song A, Jiang S, Lin Z, Guo S, Gao X. Liver-specific deletion of Ppp2cα enhances glucose metabolism and insulin sensitivity. Aging (Albany NY) 2016; 7:223-32. [PMID: 25888638 PMCID: PMC4429087 DOI: 10.18632/aging.100725] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Protein phosphatase 2A (PP2A) is a key negative regulator of phosphatidylinositol 3-kinase/Akt pathway. Previous study showed that, in the liver, the catalytic subunit of PP2A (PP2Ac) is closely associated with insulin resistance syndrome, which is characterized by glucose intolerance and dyslipidemia. Here we studied the role of liver PP2Ac in glucose metabolism and evaluated whether PP2Ac is a suitable therapeutic target for treating insulin resistance syndrome. Liver-specific Ppp2cα knockout mice (Ppp2cαloxp/loxp: Alb) exhibited improved glucose homeostasis compared with littermate controls in both normal and high-fat diet conditions, despite no significant changes in body weight and liver weight under chow diet. Ppp2cαloxp/loxp: Alb mice showed enhanced glycogen deposition, serum triglyceride, cholesterol, low density lipoprotein and high density lipoprotein, activated insulin signaling, decreased expressions of gluconeogenic genes G6P and PEPCK, and lower liver triglyceride. Liver-specific Ppp2cα knockout mice showed enhanced glucose homeostasis and increased insulin sensitivity by activation of insulin signaling through Akt. These findings suggest that inhibition of hepatic Ppp2cα may be a useful strategy for the treatment of insulin resistance syndrome.
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Affiliation(s)
- Li Xian
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Siyuan Hou
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Zan Huang
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - An Tang
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Peiliang Shi
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Qinghua Wang
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Anying Song
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Shujun Jiang
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Zhaoyu Lin
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Shiying Guo
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Xiang Gao
- Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
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18
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Knobler H, Malnick S. Hepatitis C and insulin action: An intimate relationship. World J Hepatol 2016; 8:131-138. [PMID: 26807209 PMCID: PMC4716529 DOI: 10.4254/wjh.v8.i2.131] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 12/10/2015] [Accepted: 12/29/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection has been shown to be linked to a higher prevalence of type 2 diabetes compared with the general population or with patients with chronic hepatitis B infection and diabetes is the most common extra-hepatic manifestation of HCV. The HCV-diabetes association is due to insulin resistance (IR) that occurs early in the course of the disease even in patients without or with minimal fibrosis. The mechanisms for HCV-induced IR are only partly understood and include a direct inhibitory effect of HCV on insulin signaling pathway. IR in chronic HCV results in an increased progression rate of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Some but not all studies found that IR reduces the response rate to interferon/ribavirin therapy. Whether IR affects the response to the new direct-acting antiviral treatments is still unknown.
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Affiliation(s)
- Hilla Knobler
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
| | - Stephen Malnick
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
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19
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Desrochers GF, Sherratt AR, Blais DR, Nasheri N, Ning Z, Figeys D, Goto NK, Pezacki JP. Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe. ACS Infect Dis 2015; 1:443-52. [PMID: 27617927 DOI: 10.1021/acsinfecdis.5b00083] [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] [Indexed: 02/06/2023]
Abstract
To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells. We utilized an ABPP probe, wortmannin-yne, based on the kinase inhibitor wortmannin, which contains a pendant alkyne group for bioconjugation using bioorthogonal chemistry. We observed changes in the activity of kinases involved in the mitogen-activated protein kinase pathway, apoptosis pathways, and cell cycle control. These results establish changes to the active kinome, as reported by wortmannin-yne, in the proteome of human hepatoma cells actively replicating HCV. The observed changes include kinase activity that affect viral entry, replication, assembly, and secretion, implying that HCV is regulating the pathways that it uses for its life cycle through modulation of the active kinome.
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Affiliation(s)
- Geneviève F. Desrochers
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - Allison R. Sherratt
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - David R. Blais
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | - Neda Nasheri
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
| | | | | | | | - John Paul Pezacki
- Life Sciences Division, National Research Council of Canada, 100
Sussex Drive, Ottawa, Canada
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20
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Madejón A, Sheldon J, Francisco-Recuero I, Perales C, Domínguez-Beato M, Lasa M, Sánchez-Perez I, Muntané J, Domingo E, García-Samaniego J, Sánchez-Pacheco A. Hepatitis C virus-mediated Aurora B kinase inhibition modulates inflammatory pathway and viral infectivity. J Hepatol 2015; 63:312-9. [PMID: 25733156 DOI: 10.1016/j.jhep.2015.02.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 02/16/2015] [Accepted: 02/23/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. DNA methylation and histone covalent modifications constitute crucial mechanisms of genomic instability in human disease, including liver fibrosis and hepatocellular carcinoma. The present work studies the consequences of HCV-induced histone modifications in early stages of infection. METHODS Human primary hepatocytes and HuH7.5 cells were transiently transfected with the core protein of hepatitis C virus (HCV) genotypes 1a, 1b, and 2a. Infectious genotype 2a HCV in culture was also used. RESULTS We show that HCV and core protein inhibit the phosphorylation of Serine 10 in histone 3. The inhibition is due to the direct interaction between HCV core and Aurora B kinase (AURKB) that results in a decrease of AURKB activity. HCV and core significantly downregulate NF-κB and COX-2 transcription, two proteins with anti-apoptotic and proliferative effects implicated in the control of the inflammatory response. AURKB depletion reduced HCV and core repression of NF-κB and COX-2 gene transcription and AURKB overexpression reversed the viral effect. AURKB abrogation increased HCV specific infectivity which was decreased when AURKB was overexpressed. CONCLUSIONS The core-mediated decrease of AURKB activity may play a role in the inflammatory pathway during the initial steps of viral infection, while ensuring HCV infectivity.
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Affiliation(s)
- Antonio Madejón
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria "La Paz", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain
| | - Julie Sheldon
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
| | - Irene Francisco-Recuero
- Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Celia Perales
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain
| | - Mariela Domínguez-Beato
- Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Marina Lasa
- Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Isabel Sánchez-Perez
- Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | - Jordi Muntané
- Oncology Surgery, Cell Therapy and Transplant Organs, Institute of Biomedicine of Seville (IBiS)-Virgen del Rocio Universitary Hospital (CSIC), University of Seville, Seville, Spain
| | - Esteban Domingo
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain
| | - Javier García-Samaniego
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria "La Paz", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain
| | - Aurora Sánchez-Pacheco
- Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
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Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [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: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
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Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
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Huang CR, Lo SJ. Hepatitis D virus infection, replication and cross-talk with the hepatitis B virus. World J Gastroenterol 2014; 20:14589-14597. [PMID: 25356023 PMCID: PMC4209526 DOI: 10.3748/wjg.v20.i40.14589] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 05/12/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis remains a worldwide public health problem. The hepatitis D virus (HDV) must either coinfect or superinfect with the hepatitis B virus (HBV). HDV contains a small RNA genome (approximately 1.7 kb) with a single open reading frame (ORF) and requires HBV supplying surface antigens (HBsAgs) to assemble a new HDV virion. During HDV replication, two isoforms of a delta antigen, a small delta antigen (SDAg) and a large delta antigen (LDAg), are produced from the same ORF of the HDV genome. The SDAg is required for HDV replication, whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA. Various clinical outcomes of HBV/HDV dual infection have been reported, but the molecular interaction between HBV and HDV is poorly understood, especially regarding how HBV and HDV compete with HBsAgs for assembling virions. In this paper, we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export. Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications (PTMs), including acetylation, phosphorylation, and isoprenylation, we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling, LDAg PTMs, and nuclear export mechanisms in this review.
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23
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Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, Fabiani S, Marchi S, Ferri C, Ferrannini E, Fallahi P. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes 2014; 5:586-600. [PMID: 25317237 PMCID: PMC4138583 DOI: 10.4239/wjd.v5.i5.586] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/10/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.
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Kuo YC, Chen IY, Chang SC, Wu SC, Hung TM, Lee PH, Shimotohno K, Chang MF. Hepatitis C virus NS5A protein enhances gluconeogenesis through upregulation of Akt-/JNK-PEPCK signalling pathways. Liver Int 2014; 34:1358-68. [PMID: 25360475 DOI: 10.1111/liv.12389] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) infection is highly associated with the type 2 diabetes mellitus, but the detailed mechanisms by which the viral proteins are involved in the clinical outcome remain unclear. METHODS A cDNA microarray analysis was performed following introducing an NS5A-encoding plasmid or a control vector into a mouse system by hydrodynamics- based transfection. Differentially expressed genes that are associated with gluconeogenesis were selected and their expression levels in HCV patients, in NS5A-expressing systems, and in the viral subgenomic replicon system were further examined by real-time quantitative polymerase chain reaction and Western blot analysis. RESULTS Differential gene expression including an upregulation of the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) compared with controls was detected in mouse hepatocytes expressing HCV NS5A and in HCV patients with diabetes. In addition, an NS5A-dependent increase in glucose production was demonstrated in human primary hepatocytes. The upregulation of PEPCK and peroxisome proliferator-activated receptor-c coactivator-1a (PGC-1a) were also detected in NS5A-expressing cells and in the viral genotype 1b subgenomic replicon system. Further studies demonstrated that the NS5A-mediated upregulation of PEPCK and PGC-1a genes were resulted from the activation of PI3K-Akt and JNK signalling pathways. In addition, the expression levels of the forkhead transcription factor FoxO1 and the liver-enriched transcription factor HNF-4a were increased in HCV NS5A expressing cells. CONCLUSIONS By upregulating the expression of PEPCK gene via its transactivators FoxO1 and HNF-4a, and the coactivator PGC-1a, the NS5A promotes the production of hepatic glucose which may contribute to the development of HCV-associated type 2 diabetes mellitus.
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Affiliation(s)
- Yi-Chen Kuo
- Institute of Biochemistry and Molecular Biology; National Taiwan University College of Medicine; Taipei Taiwan
| | - I-Yin Chen
- Institute of Biochemistry and Molecular Biology; National Taiwan University College of Medicine; Taipei Taiwan
- Institute of Microbiology; National Taiwan University College of Medicine; Taipei Taiwan
| | - Shin C. Chang
- Institute of Microbiology; National Taiwan University College of Medicine; Taipei Taiwan
| | - Shun-Chi Wu
- Institute of Biochemistry and Molecular Biology; National Taiwan University College of Medicine; Taipei Taiwan
| | - Tzu-Min Hung
- Department of Surgery; National Taiwan University Hospital; Taipei Taiwan
- Department of Medical Research; E-DA Hospital; Kaohsiung Taiwan
| | - Po-Huang Lee
- Department of Surgery; National Taiwan University Hospital; Taipei Taiwan
| | - Kunitada Shimotohno
- Laboratory of Human Tumor Viruses; Institute of Virus Research; Kyoto University; Kyoto Japan
| | - Ming-Fu Chang
- Institute of Biochemistry and Molecular Biology; National Taiwan University College of Medicine; Taipei Taiwan
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25
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Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1α/liver-specific PGC-1α upregulation. J Virol 2014; 88:8361-74. [PMID: 24829353 DOI: 10.1128/jvi.01202-14] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1α) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1α was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1α was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1α/L-PGC-1α and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1α isoforms promote HCV production in turn. IMPORTANCE HCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1α (WT-PGC-1α), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV regulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. WT-PGC-1α upregulation was mediated by CREB phosphorylation, whereas L-PGC-1α upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1α/L-PGC-1α upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1α/L-PGC-1α and highlights the novel intervention of HCV-ER stress-PGC-1α signaling for HCV therapy and HCV-induced IR therapy.
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26
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Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
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27
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Kawaguchi Y, Mizuta T. Interaction between hepatitis C virus and metabolic factors. World J Gastroenterol 2014; 20:2888-2901. [PMID: 24659880 PMCID: PMC3961972 DOI: 10.3748/wjg.v20.i11.2888] [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: 09/27/2013] [Revised: 11/15/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.
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28
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Ross-Thriepland D, Harris M. Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation. J Virol 2014; 88:1421-32. [PMID: 24257600 PMCID: PMC3911623 DOI: 10.1128/jvi.03017-13] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 11/11/2013] [Indexed: 01/11/2023] Open
Abstract
The hepatitis C virus nonstructural NS5A protein has roles in genome replication, virus assembly, and modulation of host pathways. NS5A is a phosphoprotein, and it has been proposed that differential phosphorylation could regulate the various roles of the protein. By SDS-PAGE, two forms of NS5A with distinct apparent molecular weights can be observed, referred to as basally phosphorylated and hyperphosphorylated species. However, the sites of phosphorylation on these two species have not been unequivocally identified, hampering our understanding of the function and regulation of NS5A. To address this, we purified tagged NS5A from cells harboring a replicating subgenomic replicon and analyzed the purified protein by mass spectrometry. We identified six peptide fragments containing 12 phosphorylated residues and were able to assign four of these to serines 146, 222, and 225 and threonine 348. A serine-rich peptide fragment spanning residues 221 to 240 was highly phosphorylated. Using mutagenesis, we identified roles for a subset of these phosphoacceptors in virus genome replication. We further showed that phosphorylation at S146 regulates hyperphosphorylation, and by generating a phospho-specific antibody targeted to pS222, we identified that S222 phosphorylation predominates in the hyperphosphorylated species. Last, by introducing phosphomimetic mutations across residues 221 to 240, we demonstrated changes in the mobility of the basally phosphorylated species suggestive of a sequential phosphorylation cascade within this serine-rich cluster. We propose that this regulation could drive a conformational switch between the dimeric structures of NS5A and could also explain the different functions of the protein in the virus life cycle.
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Affiliation(s)
- Douglas Ross-Thriepland
- School of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
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Bernsmeier C, Calabrese D, Heim MH, Duong HTF. Hepatitis C virus dysregulates glucose homeostasis by a dual mechanism involving induction of PGC1α and dephosphorylation of FoxO1. J Viral Hepat 2014; 21:9-18. [PMID: 24329853 DOI: 10.1111/jvh.12208] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 10/15/2013] [Indexed: 12/11/2022]
Abstract
The maintenance of glucose homeostasis is a complex process in which the insulin signalling pathway plays a major role. Disruption of insulin-regulated glucose homeostasis is frequently observed in chronic hepatitis C (CHC) infection and might potentially contribute to type 2 diabetes mellitus (T2DM) development. Presently, the mechanism that links HCV infection to insulin resistance remains unclear. Previously, we have reported that HCV protein expression in HCV transgenic mice (B6HCV) leads to an overexpression of protein phosphatase 2A (PP2A) through an ER stress response. In the present work, we describe an association of FoxO1 hypophosphorylation and upregulation of both PGC-1α and G6Pase to phenotypic hyperglycaemia and insulin resistance in B6HCV mice. In vitro, we observed that PGC1α is concomitantly induced with PP2A. Moreover, we show that the enhanced PP2A expression is sufficient to inhibit insulin-induced FoxO1 phosphorylation via blockade of insulin-mediated Akt activation or/and through direct association and dephosphorylation of pS-FoxO1. Consequently, we found that the gluconeogenic gene glucose-6-phosphatase is upregulated. These observations were confirmed in liver biopsies obtained from CHC patients. In summary, our results show that HCV-mediated upregulation of PP2A catalytic subunit alters signalling pathways that control hepatic glucose homeostasis by inhibiting Akt and dephosphorylation of FoxO1.
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Affiliation(s)
- C Bernsmeier
- Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University of Basel, Basel, Switzerland
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Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013; 19:7896-7909. [PMID: 24307784 PMCID: PMC3848138 DOI: 10.3748/wjg.v19.i44.7896] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 10/13/2013] [Indexed: 02/06/2023] Open
Abstract
This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.
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31
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Soto-Acosta R, Mosso C, Cervantes-Salazar M, Puerta-Guardo H, Medina F, Favari L, Ludert JE, del Angel RM. The increase in cholesterol levels at early stages after dengue virus infection correlates with an augment in LDL particle uptake and HMG-CoA reductase activity. Virology 2013; 442:132-47. [DOI: 10.1016/j.virol.2013.04.003] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 01/03/2013] [Accepted: 04/05/2013] [Indexed: 01/26/2023]
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Naing C, Mak JW, Wai N, Maung M. Diabetes and infections-hepatitis C: is there type 2 diabetes excess in hepatitis C infection? Curr Diab Rep 2013; 13:428-434. [PMID: 23463119 DOI: 10.1007/s11892-013-0370-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARα/γ, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue.
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Affiliation(s)
- Cho Naing
- School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur, Malaysia.
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Chiou YL, Shih CJ, Ko WS. The increased ratio of CD4+/CD8+ was positively correlated with inflammation in hepatitis C patients with metabolic syndrome. Clin Biochem 2013; 46:745-9. [PMID: 23562575 DOI: 10.1016/j.clinbiochem.2013.03.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Revised: 03/12/2013] [Accepted: 03/25/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS The incidence of metabolic syndrome (MS) in hepatitis C patients in Taiwan is not well known. Although the ratio of CD4(+)/CD8(+) T lymphocytes is considered to possibly affect the pathogenesis of hepatitis C, the effects of MS on CD4(+)/CD8(+) T lymphocytes remain unknown. The aims of this study to assess (1) the incidence of MS, (2) the inflammation status and fatty changes of liver, and (3) changes in their CD4(+)/CD8(+) T-lymphocyte ratio in patients with hepatitis C. METHODS 60 hepatitis C patients were classified into MS or non-MS group. The terms of anthropometric data, MS components, and T-lymphocytes were assessed. RESULTS The proportion of hepatitis C patients suffering from MS was 26.7% in this study. The CD4(+)/CD8(+) T-lymphocyte ratios were higher in patients with MS than non-MS group. Hepatitis C patients with MS also had higher levels of ferritin than non-MS. Moreover, the level of ferritin positively correlated with the severity of fatty liver. The CD4(+)/CD8(+) T-lymphocyte ratio is also positively correlated with ferritin level and the severity of fatty liver. CONCLUSIONS Hepatitis C patients with MS had higher ratio of CD4(+)/CD8(+) T lymphocyte, which is associated with a high inflammatory response and a fatty change of liver.
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Affiliation(s)
- Ya-Ling Chiou
- Department of Nutrition & Institute of BioMedical Nutrition, Hungkuang University, Taichung, Taiwan
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Association of insulin resistance, viral load, and adipokine levels with liver histology in patients with chronic hepatitis C: an observational, multicenter study in Turkey. Eur J Gastroenterol Hepatol 2012; 24:1393-9. [PMID: 23114743 DOI: 10.1097/meg.0b013e3283585863] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the association of insulin resistance (IR), viral load, and adipokine levels with liver histology in patients with chronic hepatitis C (CHC). PATIENTS AND METHODS In this noninterventional, multicenter study carried out at 11 infectious diseases clinics in Turkey, 103 CHC patients [mean (SD) age: 50.2 (11.0) years, 60 (58.3%) women] planned to be treated by ribavirin and peginterferon-α2a were included. Data on hepatic fibrosis and steatosis, IR, viral load, and hepatitis C virus-RNA genotyping, adipokine, and cytokine levels were collected. RESULTS The mean (SD) Knodell score was 8.1 (3.6); grade I steatosis was evident in 46 (44.7%) patients and IR was identified in 56 (54.9%). There was a significant positive correlation of the homeostasis model assessment-IR index with Knodell fibrosis (r=0.235; P=0.027) and hepatic steatosis (r=0.435; P<0.001). There was a significant positive correlation of leptin levels with Knodell fibrosis (r=0.265; P=0.013) and hepatic activity index (r=0.218; P=0.041). Hepatic steatosis was correlated negatively with adiponectin (r=-0.320; P=0.001) and positively with leptin (r=-0.368; P<0.001) levels. Logistic regression analysis showed that increase in age [odds ratio (OR), 1.056; 95% confidence interval (CI), 1.005-1.110; P=0.030] was the only significant predictor of hepatic fibrosis (OR, 1.056; 95% CI, 1.005-1.110; P=0.030), whereas increase in age (OR, 1.066; 95% CI, 1.006-1.130; P=0.030), the presence of IR (OR, 5.621; 95% CI, 1.547-20.425; P=0.009), and decrease in adiponectin levels (OR, 0.808; 95% CI, 0.682-0.957; P=0.013) were the significant predictors of hepatic steatosis. CONCLUSION Our findings indicate a significant relationship of hepatic fibrosis and hepatic steatosis with IR and leptin levels, but not with the viral load in Turkish patients with CHC.
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Chung WJ. [Chronic hepatitis C and insulin resistance]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:268-74. [PMID: 22544023 DOI: 10.4166/kjg.2012.59.4.268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Insulin resistance is frequently associated with chronic liver disease, and the interaction between hepatitis C virus (HCV) infection and insulin resistance is a major public health issue, bound to increase in the near term. Because of their potential synergism on liver disease severity, a better understanding of the clinical consequences of the relationship between HCV infection and insulin resistance is needed. This translates into accelerated liver disease progression, reduced response to anti-viral agents and, in susceptible individuals, increased risk of developing type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Little is known regarding the effect of anti-diabetic agents on HCV infection, and a possible association between use of exogenous insulin or a sulfonylurea agents and the development of hepatocellular carcinoma has recently been reported. Thus, modified lifestyle and pharmacological modalities are urgently warranted in chronic hepatitis C with metabolic alterations.
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Affiliation(s)
- Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
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Modulation of autophagy-like processes by tumor viruses. Cells 2012; 1:204-47. [PMID: 24710474 PMCID: PMC3901111 DOI: 10.3390/cells1030204] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 06/13/2012] [Accepted: 06/14/2012] [Indexed: 02/07/2023] Open
Abstract
Autophagy is an intracellular degradation pathway for long-lived proteins and organelles. This process is activated above basal levels upon cell intrinsic or environmental stress and dysregulation of autophagy has been linked to various human diseases, including those caused by viral infection. Many viruses have evolved strategies to directly interfere with autophagy, presumably to facilitate their replication or to escape immune detection. However, in some cases, modulation of autophagy appears to be a consequence of the virus disturbing the cell’s metabolic signaling networks. Here, we summarize recent advances in research at the interface of autophagy and viral infection, paying special attention to strategies that human tumor viruses have evolved.
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Hsieh MJ, Lan KP, Liu HY, Zhang XZ, Lin YF, Chen TY, Chiou HL. Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3β signaling in hepatocytes. BMC Gastroenterol 2012; 12:74. [PMID: 22721429 PMCID: PMC3464126 DOI: 10.1186/1471-230x-12-74] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 06/21/2012] [Indexed: 12/25/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection may cause liver diseases of various severities ranging from primary acute infection to life-threatening diseases, such as cirrhosis or hepatocellular carcinoma with poor prognosis. According to clinical findings, HCV infection may also lead to some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Since insulin resistance is the major etiology for type 2 DM and numerous evidences showed that HCV infection associated with insulin resistance, the involvement of E2 in the pathogenesis of type 2 DM and underlying mechanisms were investigated in this study. Methods Reverse transcription and real-time PCR, Western blot assay, Immunoprecipitation, Glucose uptake assay and analysis of cellular glycogen content. Results Results showed that E2 influenced on protein levels of insulin receptor substrate-1 (IRS-1) and impaired insulin-induced Ser308 phosphorylation of Akt/PKB and Ser9 phosphorylation of GSK3β in Huh7 cells, leading to an inhibition of glucose uptake and glycogen synthesis, respectively, and eventually insulin resistance. Conclusions Therefore, HCV E2 protein indeed involved in the pathogenesis of type 2 DM by inducing insulin resistance.
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Affiliation(s)
- Ming-Ju Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
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Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012; 56 Suppl 1:S56-65. [PMID: 22300466 DOI: 10.1016/s0168-8278(12)60007-5] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Given the pandemic spread of the hepatitis C virus (HCV) infection and the metabolic syndrome (MS), the burden of their interaction is a major public health issue, bound to increase in the near term. A better appreciation of the clinical consequences of the relationship between HCV and MS is needed, not only due to their potential synergism on liver disease severity, but also because of the multifaceted interactions between HCV and glucose and lipid metabolism. HCV infection per se does not carry an increased risk of MS, but is able to perturb glucose homeostasis through several direct and indirect mechanisms, leading to both hepatic and extrahepatic insulin resistance. This translates into accelerated liver disease progression (including the development of hepatocellular carcinoma), reduced response to antivirals and, in susceptible individuals, increased risk of developing full-blown type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Possibly as a result of HCV-induced insulin resistance, and despite a paradoxically favourable lipid profile, the cardiovascular risk is moderately increased in chronic hepatitis C. In addition, the interaction with the MS further increases the risks of cirrhosis, hepatocellular carcinoma, diabetes, and cardiovascular events. Thus, targeted lifestyle and pharmacological measures are urgently warranted in chronic hepatitis C with metabolic alterations.
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Hassan M, Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O. Hepatitis C virus-host interactions: Etiopathogenesis and therapeutic strategies. World J Exp Med 2012; 2:7-25. [PMID: 24520529 PMCID: PMC3905577 DOI: 10.5493/wjem.v2.i2.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Revised: 04/16/2012] [Accepted: 04/18/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies.
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Affiliation(s)
- Mohamed Hassan
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Denis Selimovic
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Abdelouahid El-Khattouti
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Hanan Ghozlan
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Youssef Haikel
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Ola Abdelkader
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
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García-Ruiz I, Solís-Muñoz P, Gómez-Izquierdo E, Muñoz-Yagüe MT, Valverde AM, Solís-Herruzo JA. Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice. J Biol Chem 2012; 287:19564-73. [PMID: 22493491 DOI: 10.1074/jbc.m112.342709] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Insulin resistance is a risk factor for non-response to interferon/ribavirin therapy in patients with chronic hepatitis C. The aim of this study was to determine the role played by protein-tyrosine phosphatases (PTPs) in the absence of interferon-α (IFNα) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-α (TNFα) and analyzed insulin response by evaluating Akt phosphorylation and IFNα response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFNα was also measured in insulin-resistant obese mice (high fat diet and ob/ob mice) untreated and treated with metformin. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFNα response. Likewise, TNFα suppresses insulin and IFNα response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFNα response. Both silencing IRS-2 and TNFα treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFNα response in insulin-resistant cells. Insulin-resistant ob/ob mice have increased PTP-1B gene expression and activity in the liver and do not respond to IFNα administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFNα resistance, which is associated with an increased PTP-1B activity in the liver. Inhibition of PTP-1B activity with pervanadate and metformin or knocking down PTP-1B reestablishes IFNα response. Likewise, metformin decreases PTP-1B activity and improves response to IFNα in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFNα/ribavirin therapy.
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Affiliation(s)
- Inmaculada García-Ruiz
- Research Institute, University Hospital 12 de Octubre, School of Medicine, Universidad Complutense, Madrid 28041, Spain
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Khattab MA, Eslam M. The impact of host factors on management of hepatitis C virus. HEPATITIS MONTHLY 2012; 12:235-241. [PMID: 22690229 PMCID: PMC3360931 DOI: 10.5812/hepatmon.709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 05/25/2011] [Accepted: 06/25/2011] [Indexed: 02/07/2023]
Affiliation(s)
| | - Mohammed Eslam
- Department of Internal Medicine, Minia University, Minia, Egypt
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Khattab MA, Eslam M. The Impact of Host Factors on Management of Hepatitis C Virus. HEPATITIS MONTHLY 2012; 12:235-241. [DOI: 10.5812/hepatmon.5883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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Association of Hepatitis C Virus With Insulin Resistance: Evidences From Animal Studies and Clinical Studie. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hepatmon.4295] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Association of Hepatitis C Virus With Insulin Resistance: Evidences From Animal Studies and Clinical Studie. HEPATITIS MONTHLY 2012. [DOI: 10.5812/kowsar.1735143x.4295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Abstract
This review will focus on the impact of steatosis and insulin resistance on the response to antiviral therapy for chronic hepatitis C. Hepatitis C virus (HCV) infection is known to have direct and/or indirect effects on lipid and glucose metabolism, leading to, among other disturbances, steatosis and insulin resistance, respectively. Some of these disturbances have a marked HCV genotype distribution. For example, on average, patients with HCV genotype 3 have the highest prevalence and severity of viral fatty liver. On the other hand, the current global spread of the metabolic syndrome represents a formidable cofactor of morbidity in HCV-related chronic liver disease. Thus, the pathogenesis of steatosis and insulin resistance in patients with chronic hepatitis C may often be dual, i.e. viral and metabolic. This distinction is relevant because the effect (if any) of steatosis or insulin resistance on the response to antiviral agents seems to depend on their pathogenesis. Accumulating data suggest that viral fatty liver may not impact on response to therapy, while metabolic steatosis does. Similarly, viral insulin resistance may not reduce the rate of response to therapy to the same extent that metabolic insulin resistance does. Some implications for patient management are discussed.
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Affiliation(s)
- F Negro
- Divisions of Gastroenterology and Hepatology and Clinical Pathology, University Hospitals, Geneva, Switzerland.
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Hsieh PS, Hsieh YJ. Impact of liver diseases on the development of type 2 diabetes mellitus. World J Gastroenterol 2011; 17:5240-5. [PMID: 22219592 PMCID: PMC3247687 DOI: 10.3748/wjg.v17.i48.5240] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 09/09/2011] [Accepted: 09/16/2011] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is higher in patients who have liver diseases such as nonalcoholic fatty liver disease, chronic viral hepatitis, hemochromatosis, alcoholic liver disease and cirrhosis. It is suggested that there is a pathogenic link between the presence of T2DM and the severity of liver injury. However, evidence related to the impact of hepatic inflammation on the development of T2DM has not yet emerged. This article provides an overview of the evidence for an increased prevalence of diabetes in a range of liver diseases, the impact of liver diseases on insulin resistance and β cell dysfunction, and the potential mechanisms whereby coexistent liver diseases exacerbate the development of T2DM.
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Parvaiz F, Manzoor S, Tariq H, Javed F, Fatima K, Qadri I. Hepatitis C virus infection: molecular pathways to insulin resistance. Virol J 2011; 8:474. [PMID: 22008087 PMCID: PMC3206488 DOI: 10.1186/1743-422x-8-474] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 10/18/2011] [Indexed: 12/19/2022] Open
Abstract
Chronic Hepatitis C virus has the potential of inducing insulin resistance and type 2 Diabetes Mellitus in vitro as well as in vivo . Structural and non-structural proteins of HCV modulate cellular gene expression in such a way that insulin signaling is hampered, concomitantly leads toward diabetes mellitus. A number of mechanisms have been proposed in regard to the HCV induced insulin resistance involving the upregulation of Inflammatory cytokine TNF-α, hypophosphorylation of IRS-1 and IRS-2, phosphorylation of Akt, up-regulation of gluconeogenic genes, accumulation of lipids and targeting lipid storage organelles. This review provides an insight of molecular mechanisms by which HCV structural and non-structural proteins can induce insulin resistance.
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Affiliation(s)
- Fahed Parvaiz
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Sobia Manzoor
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Huma Tariq
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Farakh Javed
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Kaneez Fatima
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Ishtiaq Qadri
- NUST Center of Virology and Immunology (NCVI), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
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Hung CH, Lee CM, Lu SN. Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications. Expert Rev Anti Infect Ther 2011; 9:525-33. [PMID: 21609264 DOI: 10.1586/eri.11.33] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
It is now widely recognized that chronic hepatitis C is a metabolic disease, strongly associated with Type 2 diabetic mellitus and insulin resistance (IR). Chronic hepatitis C virus (HCV) infection promotes IR mainly through interfering with the insulin signaling pathway in hepatocytes, increasing the inflammatory response with production of cytokines such as TNF-α and IL-6, and increasing oxidative stress. Accumulated evidence indicates that HCV-associated IR may lead to fibrosis progression, resistance to antiviral therapy, hepatocarcinogenesis and extrahepatic manifestations. Thus, HCV-associated IR is a therapeutic target at any stage of HCV infection. However, specific pharmaceutical treatments of IR are still being evaluated in clinical trials, but available data do not warrant their use in all chronic hepatitis C patients with IR.
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Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5:503-16. [PMID: 21780897 DOI: 10.1586/egh.11.43] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.
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Affiliation(s)
- Vincent Kaddai
- Department of Pathology and Immunology, Centre Médical Universitaire, Rue Michel-Servet 1, Geneva, Switzerland
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