|
1
|
Boeckmans J, Rombaut M, Demuyser T, Declerck B, Piérard D, Rogiers V, De Kock J, Waumans L, Magerman K, Cartuyvels R, Rummens JL, Rodrigues RM, Vanhaecke T. Infections at the nexus of metabolic-associated fatty liver disease. Arch Toxicol 2021; 95:2235-2253. [PMID: 34027561 PMCID: PMC8141380 DOI: 10.1007/s00204-021-03069-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that affects about a quarter of the world population. MAFLD encompasses different disease stadia ranging from isolated liver steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although MAFLD is considered as the hepatic manifestation of the metabolic syndrome, multiple concomitant disease-potentiating factors can accelerate disease progression. Among these risk factors are diet, lifestyle, genetic traits, intake of steatogenic drugs, male gender and particular infections. Although infections often outweigh the development of fatty liver disease, pre-existing MAFLD could be triggered to progress towards more severe disease stadia. These combined disease cases might be underreported because of the high prevalence of both MAFLD and infectious diseases that can promote or exacerbate fatty liver disease development. In this review, we portray the molecular and cellular mechanisms by which the most relevant viral, bacterial and parasitic infections influence the progression of fatty liver disease and steatohepatitis. We focus in particular on how infectious diseases, including coronavirus disease-19, hepatitis C, acquired immunodeficiency syndrome, peptic ulcer and periodontitis, exacerbate MAFLD. We specifically underscore the synergistic effects of these infections with other MAFLD-promoting factors.
Collapse
Affiliation(s)
- Joost Boeckmans
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium.
| | - Matthias Rombaut
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Thomas Demuyser
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
- Center for Neurosciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Baptist Declerck
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Denis Piérard
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Vera Rogiers
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Luc Waumans
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Koen Magerman
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
- Department of Immunology and Infection, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium
| | - Reinoud Cartuyvels
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Jean-Luc Rummens
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| |
Collapse
|
|
2
|
Zhang J, Gao X, Yuan Y, Sun C, Zhao Y, Xiao L, Yang Y, Gu Y, Yang R, Hu P, Zhang L, Wang C, Ye J. Perilipin 5 alleviates HCV NS5A-induced lipotoxic injuries in liver. Lipids Health Dis 2019; 18:87. [PMID: 30954078 PMCID: PMC6451786 DOI: 10.1186/s12944-019-1022-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 03/19/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The homeostasis of lipid droplets (LDs) plays a crucial role in maintaining the physical metabolic processes in cells, and is regulated by many LD-associated proteins, including perilipin 5 (Plin5) in liver. As the putative sites of hepatitis C virus (HCV) virion assembly, LDs are vital to viral infection. In addition, the hepatic LD metabolism can be disturbed by non-structural HCV proteins, such as NS5A, but the details are still inexplicit. METHODS HCV NS5A was overexpressed in the livers and hepatocytes of wild-type and Plin5-null mice. BODIPY 493/503 and oil red O staining were used to detect the lipid content in mouse livers and hepatocytes. The levels of lipids, lipid peroxidation and inflammation biomarkers were further determined. Immunofluorescence assay and co-immunoprecipitation assay were performed to investigate the relationship of Plin5 and NS5A. RESULTS One week after adenovirus injection, livers expressing NS5A showed more inflammatory cell aggregation and more severe hepatic injuries in Plin5-null mice than in control mice, which was consistent with the increased serum levels of IL-2 and TNF-α (P < 0.05) observed in Plin5-null mice. Moreover, Plin5 deficiency in the liver and hepatocytes aggravated the elevation of MDA and 4-HNE levels induced by NS5A expression (P < 0.01). The triglyceride (TG) content was increased approximately 25% by NS5A expression in the wild-type liver and hepatocytes but was unchanged in the Plin5-null liver and hepatocytes. More importantly, Plin5 deficiency in the liver and hepatocytes exacerbated the elevation of non-esterified fatty acids (NEFAs) stimulated by NS5A expression (P < 0.05 and 0.01 respectively). Using triacsin C to block acyl-CoA biosynthesis, we found that Plin5 deficiency aggravated the NS5A-induced lipolysis of TG. In contrast, Plin5 overexpression in HepG2 cells ameliorated the NS5A-induced lipolysis and lipotoxic injuries. Immunofluorescent staining demonstrated that NS5A expression stimulated the targeting of Plin5 to the surface of the LDs in hepatocytes without altering the protein levels of Plin5. By co-IP, we found that the N-terminal domain (aa 32-128) of Plin5 was pivotal for its binding with NS5A. CONCLUSIONS Our data highlight a protective role of Plin5 against hepatic lipotoxic injuries induced by HCV NS5A, which is helpful for understanding the steatosis and injuries in liver during HCV infection.
Collapse
Affiliation(s)
- Jin Zhang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Xing Gao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yuan Yuan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Chao Sun
- Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yuanlin Zhao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Liming Xiao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Ying Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Yu Gu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Risheng Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Peizhen Hu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Lijun Zhang
- Department of Clinical Laboratory Medicine, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Chao Wang
- Department of Pathology, The General Hospital of Western Theater Command, No. 270, Tianhui Road, Rongdu Avenue, Chengdu, 610083, People's Republic of China.
| | - Jing Ye
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, No.169, Changle West Road, Xi'an, Shaanxi, 710032, People's Republic of China.
| |
Collapse
|
|
3
|
van Welzen BJ, Mudrikova T, El Idrissi A, Hoepelman AIM, Arends JE. A Review of Non-Alcoholic Fatty Liver Disease in HIV-Infected Patients: The Next Big Thing? Infect Dis Ther 2019; 8:33-50. [PMID: 30607807 PMCID: PMC6374241 DOI: 10.1007/s40121-018-0229-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Indexed: 12/14/2022] Open
Abstract
The burden of liver-related morbidity remains high among HIV-infected patients, despite advances in the treatment of HIV and viral hepatitis. Especially, the impact of non-alcoholic fatty liver disease (NAFLD) is significant with a prevalence of up to 50%. The pathogenesis of NAFLD and the reasons for progression to non-alcoholic steatohepatitis (NASH) are still not fully elucidated, but insulin resistance, mitochondrial dysfunction and dyslipidemia seem to be the main drivers. Both HIV-infection itself and combination antiretroviral therapy (cART) can contribute to the development of NAFLD/NASH in various ways. As ongoing HIV-related immune activation is associated with insulin resistance, early initiation of cART is needed to limit its duration. In addition, the use of early-generation nucleoside reverse transcriptase inhibitors and protease inhibitors is also associated with the development of NAFLD/NASH. Patients at risk should therefore receive antiretroviral drugs with a more favorable metabolic profile. Only weight reduction is considered to be an effective therapy for all patients with NAFLD/NASH, although certain drugs are available for specific subgroups. Since patients with NASH are at risk of developing liver cirrhosis and hepatocellular carcinoma, several non-antifibrotic and antifibrotic drugs are under investigation in clinical trials to broaden the therapeutic options. The epidemiology and etiology of NAFLD/NASH in HIV-positive patients is likely to change in the near future. Current guidelines recommend early initiation of cART that is less likely to induce insulin resistance, mitochondrial dysfunction and dyslipidemia. In contrast, as a result of increasing life expectancy in good health, this population will adopt the more traditional risk factors for NAFLD/NASH. HIV-treating physicians should be aware of the etiology, pathogenesis and treatment of NAFLD/NASH in order to identify and treat the patients at risk.
Collapse
Affiliation(s)
- Berend J van Welzen
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU) Utrecht, Utrecht, The Netherlands.
| | - Tania Mudrikova
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU) Utrecht, Utrecht, The Netherlands
| | - Ayman El Idrissi
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU) Utrecht, Utrecht, The Netherlands
| | - Andy I M Hoepelman
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU) Utrecht, Utrecht, The Netherlands
| | - Joop E Arends
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU) Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
4
|
ITRAQ-Based Quantitative Proteomics Reveals the Proteome Profiles of Primary Duck Embryo Fibroblast Cells Infected with Duck Tembusu Virus. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1582709. [PMID: 30809531 PMCID: PMC6369498 DOI: 10.1155/2019/1582709] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/26/2018] [Accepted: 12/13/2018] [Indexed: 11/18/2022]
Abstract
Outbreaks of duck Tembusu virus (DTMUV) have caused substantial economic losses in the major duck-producing regions of China since 2010. To improve our understanding of the host cellular responses to virus infection and the pathogenesis of DTMUV infection, we applied isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with multidimensional liquid chromatography-tandem mass spectrometry to detect the protein changes in duck embryo fibroblast cells (DEFs) infected and mock-infected with DTMUV. In total, 434 cellular proteins were differentially expressed, among which 116, 76, and 339 proteins were differentially expressed in the DTMUV-infected DEFs at 12, 24, and 42 hours postinfection, respectively. The Gene Ontology analysis indicated that the biological processes of the differentially expressed proteins were primarily related to cellular processes, metabolic processes, biological regulation, response to stimulus, and cellular organismal processes and that the molecular functions in which the differentially expressed proteins were mainly involved were binding and catalytic activity. Some selected proteins that were found to be differentially expressed in DTMUV-infected DEFs were further confirmed by real-time PCR. The results of this study provide valuable insight into DTMUV-host interactions. This could lead to a better understanding of DTMUV infection mechanisms.
Collapse
|
|
5
|
Lo AKF, Lung RWM, Dawson CW, Young LS, Ko CW, Yeung WW, Kang W, To KF, Lo KW. Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma. J Pathol 2018; 246:180-190. [PMID: 29968360 PMCID: PMC6175466 DOI: 10.1002/path.5130] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 05/25/2018] [Accepted: 06/26/2018] [Indexed: 12/13/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV-infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1-mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1-mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1-mediated lipogenesis promotes tumor cell growth and is involved in EBV-driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Angela Kwok-Fung Lo
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Raymond Wai-Ming Lung
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Christopher W Dawson
- Institute of Cancer & Genomic Science, Cancer Research UK Cancer Centre, University of Birmingham, Birmingham, UK
| | | | - Chuen-Wai Ko
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Walter Wai Yeung
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Kwok-Wai Lo
- Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| |
Collapse
|
|
6
|
Duan X, Anwar MI, Xu Z, Ma L, Yuan G, Chen Y, Liu X, Xia J, Zhou Y, Li YP. Adaptive mutation F772S-enhanced p7-NS4A cooperation facilitates the assembly and release of hepatitis C virus and is associated with lipid droplet enlargement. Emerg Microbes Infect 2018; 7:143. [PMID: 30087320 PMCID: PMC6081454 DOI: 10.1038/s41426-018-0140-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/17/2018] [Accepted: 06/23/2018] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and liver cancer worldwide. Adaptive mutations play important roles in the development of the HCV replicon and its infectious clones. We and others have previously identified the p7 mutation F772S and the co-presence of NS4A mutations in infectious HCV full-length clones and chimeric recombinants. However, the underlying mechanism of F772S function remains incompletely understood. Here, we investigated the functional role of F772S using an efficient JFH1-based reporter virus with Core-NS2 from genotype 2a strain J6, and we designated J6-p7/JFH1-4A according to the strain origin of the p7 and NS4A sequences. We found that replacing JFH1-4A with J6-4A (wild-type or mutated NS4A) or genotype 2b J8-4A severely attenuated the viability of J6-p7/JFH1-4A. However, passage-recovered viruses that contained J6-p7 all acquired F772S. Introduction of F772S efficiently rescued the viral spread and infectivity titers of J6-p7/J6-4A, which reached the levels of the original J6-p7/JFH1-4A and led to a concomitant increase in RNA replication, assembly and release of viruses with J6-specific p7 and NS4A. These data suggest that an isolate-specific cooperation existed between p7 and NS4A. NS4A exchange- or substitution-mediated viral attenuation was attributed to the RNA sequence, and no p7-NS4A protein interaction was detected. Moreover, we found that F772S-enhanced p7-NS4A cooperation was associated with the enlargement of intracellular lipid droplets. This study therefore provides new insights into the mechanisms of adaptive mutations and facilitates studies on the HCV life cycle and virus–host interaction.
Collapse
Affiliation(s)
- Xiaobing Duan
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China.,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Muhammad Ikram Anwar
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China.,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhanxue Xu
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China.,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ling Ma
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China.,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Guosheng Yuan
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yiyi Chen
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China.,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xi Liu
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Jinyu Xia
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Yuanping Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yi-Ping Li
- Institute of Human Virology and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 501180, China. .,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-Sen University, Guangzhou, 501180, China. .,Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-Sen University, Guangzhou, 510080, China. .,Program in Pathobiology, The Fifth Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-sen University, Zhuhai, 519000, China.
| |
Collapse
|
|
7
|
Wu Q, Li Z, Liu Q. An important role of SREBP-1 in HBV and HCV co-replication inhibition by PTEN. Virology 2018; 520:94-102. [PMID: 29803738 DOI: 10.1016/j.virol.2018.05.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 02/07/2023]
Abstract
HBV HCV co-infection leads to more severe liver diseases including liver cancer than mono-infections. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, inhibits sterol regulatory element binding protein-1 (SREBP-1). In this study, we characterized the effect of the PTEN - SREBP-1 pathway on HBV HCV co-replication in a cellular model. We found that HBV and HCV can co-replicate in Huh-7 cells with no interference. Overexpression of PTEN inhibits, whereas PTEN knockdown enhances, HBV replication as well as HBV and HCV co-replication. Knocking down SREBP-1 decreases HBV replication in an HBx-dependent manner. SREBP-1 knockdown also decreases HCV replication. PTEN knockdown is concomitant with increased nuclear SREBP-1 levels. PTEN and SREBP-1 double knockdown results in intermediate levels of HBV and HCV replication in mono- and co-replication scenarios. Taken together, we demonstrated, for the first time, that the PTEN - SREBP-1 pathway can regulate HBV HCV co-replication.
Collapse
Affiliation(s)
- Qi Wu
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; Department of Veterinary Microbiology, University of Saskatchewan, Canada
| | - Zhubing Li
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan 120 Veterinary Road, Saskatoon, Saskatchewan, Canada S7N 5E3; Department of Veterinary Microbiology, University of Saskatchewan, Canada; School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
| |
Collapse
|
|
8
|
Li Z, Liu Q. Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. J Gen Virol 2017; 99:44-61. [PMID: 29235977 DOI: 10.1099/jgv.0.000987] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease actively involved in regulating lipid homeostasis. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, the underlying mechanisms have not been thoroughly characterized. Moreover, whether PCSK9 regulates HCV translation and assembly/secretion has not been determined. We therefore further studied the effects of PCSK9 on the HCV life cycle. We showed that PCSK9 did not affect HCV translation or assembly/secretion. Overexpression of PCSK9 inhibited HCV replication in HCV genomic replicon cells in a dose-dependent manner and after cell culture-derived HCV (HCVcc) infection. Knocking down PCSK9 increased HCV replication. The gain-of-function (D374Y) or loss-of-function (Δaa. 31-52) PCSK9 mutants for low-density lipoprotein receptor (LDLR) degradation had no effect on HCV replication, suggesting that HCV replication inhibition by PCSK9 was not due to LDLR degradation. The uncleaved ProPCSK9, but not cleaved PCSK9, down-regulated HCV replication, suggesting that the auto-cleavage of PCSK9 affected HCV replication. We also found that PCSK9 interacted with NS5A through NS5A aa. 95-215, and this region played an important role in NS5A dimerization, NS5A-RNA binding and was essential for HCV replication. More importantly, NS5A dimerization and NS5A-RNA binding were suppressed by PCSK9 upon interaction. These results suggested that PCSK9 inhibited HCV replication through interaction with NS5A. Our study should help optimize anti-HCV treatment regimen in patients with abnormal lipid profiles.
Collapse
Affiliation(s)
- Zhubing Li
- VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,VIDO-InterVac, School of Public Health Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| |
Collapse
|
|
9
|
Hu L, Li J, Cai H, Yao W, Xiao J, Li YP, Qiu X, Xia H, Peng T. Avasimibe: A novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles. Antiviral Res 2017; 148:5-14. [PMID: 29074218 DOI: 10.1016/j.antiviral.2017.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/15/2017] [Accepted: 10/20/2017] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals (DAAs), which target hepatitis C virus (HCV) proteins, have exhibited impressive efficacy in the management of chronic hepatitis C. However, the concerns regarding high costs, drug resistance mutations and subsequent unexpected side effects still call for the development of host-targeting agents (HTAs) that target host factors involved in the viral life cycle and exhibit pan-genotypic antiviral activity. Given the close relationship between lipid metabolism and the HCV life cycle, we investigated the anti-HCV activity of a series of lipid-lowering drugs that have been approved by government administrations or proven safety in clinical trials. Our results showed that avasimibe, an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), exhibited marked pan-genotypic inhibitory activity and superior inhibition against HCV when combined with DAAs. Moreover, avasimibe significantly impaired the assembly of infectious HCV virions. Mechanistic studies demonstrated that avasimibe induced downregulation of microsomal triglyceride transfer protein expression, resulting in reduced apolipoprotein E and apolipoprotein B secretion. Therefore, the pan-genotypic antiviral activity and clinically proven safety endow avasimibe exceptional potential as a candidate for combination therapy with DAAs. In addition, the discovery of the antiviral properties of ACAT inhibitors also suggests that inhibiting the synthesis of cholesteryl esters might be an additional target for the therapeutic intervention for chronic HCV infection.
Collapse
Affiliation(s)
- Longbo Hu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jinqian Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hua Cai
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wenxia Yao
- The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Jing Xiao
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yi-Ping Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiu Qiu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Huimin Xia
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Department of Neonatal Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.
| |
Collapse
|
|
10
|
Pembroke T, Deschenes M, Lebouché B, Benmassaoud A, Sewitch M, Ghali P, Wong P, Halme A, Vuille-Lessard E, Pexos C, Klein MB, Sebastiani G. Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis. J Hepatol 2017; 67:801-808. [PMID: 28527666 DOI: 10.1016/j.jhep.2017.05.011] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/07/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear. METHODS The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective cohort study using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis, in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ⩾248dB/m), or transition to severe HS (CAP >292dB/m), for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM] >7.1kPa), or transition to cirrhosis (LSM >12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression. RESULTS A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs. 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection. CONCLUSION HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection. Lay summary: Fatty liver is the most frequent liver disease in Western countries. People living with HIV seem at high risk of fatty liver due to frequent metabolic disorders and the long-term effects of antiretroviral therapy. However, due to the invasiveness of liver biopsy, the traditional method of diagnosing fatty liver, there are few data regarding its frequency in people living with HIV. In this study, we used a non-invasive diagnostic tool to analyze the epidemiology of fatty liver in 726 HIV+ patients. We found that fatty liver affects over one-third of people living with HIV. When followed over time, we found that HIV+ patients without HCV co-infection develop fatty liver more frequently than those co-infected with HCV.
Collapse
Affiliation(s)
- Thomas Pembroke
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada; School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Marc Deschenes
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Bertrand Lebouché
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Amine Benmassaoud
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Maida Sewitch
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Peter Ghali
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Philip Wong
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Alex Halme
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | | | - Costa Pexos
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Marina B Klein
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Giada Sebastiani
- Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada.
| |
Collapse
|
|
11
|
Treatment with PTEN-Long protein inhibits hepatitis C virus replication. Virology 2017; 511:1-8. [PMID: 28783500 DOI: 10.1016/j.virol.2017.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 07/26/2017] [Accepted: 08/02/2017] [Indexed: 01/15/2023]
Abstract
Hepatitis C virus (HCV) infection is a confirmed risk factor for hepatocellular carcinoma (HCC). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) possesses tumor suppression function that is frequently defective in HCC tumors. PTEN-Long, a translation isoform of PTEN, functions in a cell non-autonomous manner. In this study, we demonstrated that intracellular overexpression of PTEN-Long inhibits HCV replication. More importantly, we showed that treatment with extracellular PTEN-Long protein inhibits HCV replication in a dose-dependent manner. Furthermore, we showed that PTEN-Long interacts with HCV core protein and this interaction is required for HCV replication inhibition by PTEN-Long. In summary, we demonstrated, for the first time, that PTEN-Long protein, an isoform of the canonical PTEN and in the form of extracellular protein treatment, inhibits HCV replication. Our study offers an opportunity for developing additional anti-HCV agents.
Collapse
|
|
12
|
Abstract
Metabolic disorders are common in patients with chronic hepatitis C virus (HCV) infection. Epidemiologic and clinical data indicate an overprevalence of lipids abnormalite, steatosis, insuline resistance (IR) and diabetes mellitus in HCV patients, suggesting that HCV itself may interact with glucido-lipidic metabolism. HCV interacts with the host lipid metabolism by several mechanisms leading to hepatic steatosis and hypolipidemia which are reversible after viral eradication. Liver and peripheral IR are HCV genotype/viral load dependent and improved after viral eradication. This article examines examine the relationship between HCV, lipid abnormalities, steatosis, IR, and diabetes and the pathogenic mechanisms accounting for these events in HCV-infected patients.
Collapse
Affiliation(s)
- Lawrence Serfaty
- Hepatology Department, INSERM UMR_S 938, APHP, Saint-Antoine Hospital, UPMC Univ Paris 06, Paris, France.
| |
Collapse
|
|
13
|
Abstract
Hepatitis C virus (HCV) infection leads to severe liver diseases including hepatocellular carcinoma (HCC). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumour suppressor, is frequently mutated or deleted in HCC tumors. PTEN has previously been demonstrated to inhibit HCV secretion. In this study, we determined the effects of PTEN on the other steps in HCV life cycle, including entry, translation, and replication. We showed that PTEN inhibits HCV entry through its lipid phosphatase activity. PTEN has no effect on HCV RNA translation. PTEN decreases HCV replication and the protein phosphatase activity of PTEN is essential for this function. PTEN interacts with the HCV core protein and requires R50 in domain I of HCV core and PTEN residues 1–185 for this interaction. This interaction is required for PTEN-mediated inhibition of HCV replication. This gives rise to a reduction in PTEN levels and intracellular lipid abundance, which may in turn regulate HCV replication. HCV core domain I protein increases the lipid phosphatase activity of PTEN in an in vitro assay, suggesting that HCV infection can also regulate PTEN. Taken together, our results demonstrated an important regulatory role of PTEN in the HCV life cycle.
Collapse
|
|
14
|
Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9:715-732. [PMID: 28652891 PMCID: PMC5468341 DOI: 10.4254/wjh.v9.i16.715] [Citation(s) in RCA: 502] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 04/18/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.
Collapse
Affiliation(s)
- Mark Benedict
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Xuchen Zhang
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
| |
Collapse
|
|
15
|
Abstract
PURPOSE OF REVIEW Direct-acting antiviral agents (DAAs) have markedly improved the prognosis of hepatitis C virus (HCV)-genotype 3 (GT3), a highly prevalent infection worldwide. However, in patients with hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), GT3 infection presents a treatment challenge compared with other genotypes. The dependence of the HCV life cycle on host lipid metabolism suggests the possible utility of targeting host cellular factors for combination anti-HCV therapy. We discuss current and emergent DAA regimens for HCV-GT3 treatment. We then summarize recent research findings on the reliance of HCV entry, replication, and virion assembly on host lipid metabolism. RECENT FINDINGS Current HCV treatment guidelines recommend the use of daclatasvir plus sofosbuvir (DCV/SOF) or sofosbuvir plus velpatasvir (SOF/VEL) for the management of GT3 based upon clinical efficacy [≥88% overall sustained virological response (SVR)] and tolerability. Potential future DAA options, such as SOF/VEL co-formulated with GS-9857, also look promising in treating cirrhotic GT3 patients. However, HCV resistance to DAAs will likely continue to impact the therapeutic efficacy of interferon-free treatment regimens. Disruption of HCV entry by targeting required host cellular receptors shows potential in minimizing HCV resistance and broadening therapeutic options for certain subpopulations of GT3 patients. The use of cholesterol biosynthesis and transport inhibitors may also improve health outcomes for GT3 patients when used synergistically with DAAs. Due to the morbidity and mortality associated with HCV-GT3 infection compared to other genotypes, efforts should be made to address current limitations in the therapeutic prevention and management of HCV-GT3 infection.
Collapse
|
|
16
|
Price JC, Ma Y, Scherzer R, Korn N, Tillinghast K, Peters MG, Noworolski SM, Tien PC. Human immunodeficiency virus-infected and uninfected adults with non-genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection. Hepatology 2017; 65:853-863. [PMID: 27981599 PMCID: PMC5319911 DOI: 10.1002/hep.28968] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/02/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
UNLABELLED Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids + water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF ≥ 0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA-IR) and liver fibrosis defined using the aspartate aminotransferase-to-platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV-monoinfected (28%), followed by the HCV-monoinfected (19%) and HIV/HCV-coinfected (11%) (P = 0.003 across groups). Compared with uninfected participants-and after adjusting for demographics, lifestyle, and metabolic factors-HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], -39% to 6%), 38% (95% CI, -55% to -12%), and 42% (95% CI, -59% to -18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA-IR were independently associated with greater LFF. CONCLUSION Contrary to expectations, HIV/HCV-coinfected and HCV-monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non-genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853-863).
Collapse
Affiliation(s)
- Jennifer C. Price
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Yifei Ma
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Rebecca Scherzer
- Department of Medicine, University of California, San Francisco, 94122 USA,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, CA, 94121, USA
| | - Natalie Korn
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Kyle Tillinghast
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Marion G. Peters
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Susan M. Noworolski
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Phyllis C. Tien
- Department of Medicine, University of California, San Francisco, 94122 USA,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, CA, 94121, USA
| |
Collapse
|
|
17
|
Li D, Cheng M, Niu Y, Chi X, Liu X, Fan J, Fan H, Chang Y, Yang W. Identification of a novel human long non-coding RNA that regulates hepatic lipid metabolism by inhibiting SREBP-1c. Int J Biol Sci 2017; 13:349-357. [PMID: 28367099 PMCID: PMC5370442 DOI: 10.7150/ijbs.16635] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 01/14/2017] [Indexed: 12/27/2022] Open
Abstract
Sterol regulatory element binding proteins (SREBPs) are master regulators of hepatic lipid homeostasis. Aberrant expression of SREBPs frequently leads to lipid metabolism dysregulation. Long non-coding RNAs (lncRNAs) have been identified with diverse biological functions, but the effects of lncRNAs on lipid metabolism are rarely reported. Here, we identified a novel human specific lncRNA, lncHR1, as a negative regulator of SREBP-1c expression. Overexpression of lncHR1 inhibited expression of SREBP-1c and fatty acid synthase (FAS) and then repressed oleic acid-induced hepatic cell triglyceride (TG) and lipid droplet (LD) accumulation. In vivo, the data of established transgenic animals showed that mice with lncHR1 expression had less hepatic expression of SREBP-1c, FAS, Acetyl-CoA carboxylase α (ACCα), and less hepatic and plasma TG after being fed a high-fat diet. Therefore, we report a novel lncRNA which can decrease lipid metabolism by repressing SREBP-1c gene expression.
Collapse
Affiliation(s)
- Duan Li
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China;; Department of Microbiology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Min Cheng
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| | - Yuqiang Niu
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| | - Xiaojing Chi
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| | - Xiuying Liu
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| | - Jingjing Fan
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| | - Heng Fan
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P.R. China
| | - Yongsheng Chang
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P.R. China
| | - Wei Yang
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100076, P.R. China
| |
Collapse
|
|
18
|
Abstract
Hepatitis C virus (HCV) represents a significant global disease burden, with an estimated 130-150 million people worldwide living with chronic HCV infection. Within the six major clinical HCV genotypes, genotype 3 represents 22-30% of all infection and is described as a unique entity with higher rates of steatosis, faster progression to cirrhosis, and higher rates of hepatocellular carcinoma. Hepatic steatosis in the setting of hepatitis C genotype 3 (HCV-3) is driven by viral influence on three major pathways: microsomal triglyceride transfer protein, sterol regulatory element-binding protein-1c, and peroxisome proliferator-associated receptor-α. Historically with direct-acting antivirals, the rates of cure for HCV-3 therapies lagged behind the other genotypes. As current therapies for HCV-3 continue to close this gap, it is important to be cognizant of common drug interactions such as acid-suppressing medication and amiodarone. In this review, we discuss the rates of steatosis in HCV-3, the mechanisms behind HCV-3-specific steatosis, and current and future therapies.
Collapse
Affiliation(s)
- Austin Chan
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
- Infectious Diseases Research, Duke Clinical Research Institute, Durham, NC, USA
| | - Keyur Patel
- Toronto Center for Liver Disease, University of Toronto, Toronto, ON, Canada
| | - Susanna Naggie
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
- Infectious Diseases Research, Duke Clinical Research Institute, Durham, NC, USA.
| |
Collapse
|
|
19
|
Takahashi S, Sato N, Kikuchi J, Kakinuma H, Okawa J, Masuyama Y, Iwasa S, Irokawa H, Hwang GW, Naganuma A, Kohara M, Kuge S. Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system. Genes Cells 2017; 22:160-173. [PMID: 28097745 DOI: 10.1111/gtc.12464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 11/29/2016] [Indexed: 01/18/2023]
Abstract
The structural protein Core of hepatitis C virus (HCV), a cytosolic protein, induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in hepatocytes, and is responsible for the pathogenesis of persistent HCV infection. Using yeast as a model system, we evaluated mechanisms underlying Core-induced interference of ER homeostasis and UPR, and found that UPR is induced by the immature Core (aa 1-191, Core191) but not by the mature Core (aa 1-177, Core177). Interestingly, Core191 inhibits both ERAD-L, a degradation system responsible for misfolded/unfolded proteins in the ER lumen, and ERAD-M, a degradation system responsible for proteins carrying a misfolded/unfolded region in the ER membrane. In contrast, Core177 inhibits ERAD-M but not ERAD-L. In addition, requirement of an unfolded protein sensor in the ER lumen suggested that inhibition of ERAD-L is probably responsible for Core191-dependent UPR activation. These results implicate inadequate maturation of Core as a trigger for induction of ER stress and UPR.
Collapse
Affiliation(s)
- Shota Takahashi
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
| | - Naoko Sato
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.,Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Junichi Kikuchi
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Hideaki Kakinuma
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Jun Okawa
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Yukiko Masuyama
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Singo Iwasa
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
| | - Hayato Irokawa
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
| | - Gi-Wook Hwang
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Akira Naganuma
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan
| | - Shusuke Kuge
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.,Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| |
Collapse
|
|
20
|
Rosales SM, Vega Thurber RL. Brain transcriptomes of harbor seals demonstrate gene expression patterns of animals undergoing a metabolic disease and a viral infection. PeerJ 2016; 4:e2819. [PMID: 28028481 PMCID: PMC5182994 DOI: 10.7717/peerj.2819] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 11/22/2016] [Indexed: 11/20/2022] Open
Abstract
Diseases of marine mammals can be difficult to diagnose because of their life history and protected status. Stranded marine mammals have been a particularly useful resource to discover and comprehend the diseases that plague these top predators. Additionally, advancements in high-throughput sequencing (HTS) has contributed to the discovery of novel pathogens in marine mammals. In this study, we use a combination of HTS and stranded harbor seals (Phoca vitulina) to better understand a known and unknown brain disease. To do this, we used transcriptomics to evaluate brain tissues from seven neonatal harbor seals that expired from an unknown cause of death (UCD) and compared them to four neonatal harbor seals that had confirmed phocine herpesvirus (PhV-1) infections in the brain. Comparing the two disease states we found that UCD animals showed a significant abundance of fatty acid metabolic transcripts in their brain tissue, thus we speculate that a fatty acid metabolic dysregulation contributed to the death of these animals. Furthermore, we were able to describe the response of four young harbor seals with PhV-1 infections in the brain. PhV-1 infected animals showed a significant ability to mount an innate and adaptive immune response, especially to combat viral infections. Our data also suggests that PhV-1 can hijack host pathways for DNA packaging and exocytosis. This is the first study to use transcriptomics in marine mammals to understand host and viral interactions and assess the death of stranded marine mammals with an unknown disease. Furthermore, we show the value of applying transcriptomics on stranded marine mammals for disease characterization.
Collapse
Affiliation(s)
- Stephanie M Rosales
- Department of Microbiology, Oregon State University , Corvallis , OR , United States
| | | |
Collapse
|
|
21
|
Sundaram V, Kowdley KV. Dual daclatasvir and sofosbuvir for treatment of genotype 3 chronic hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 2016; 10:13-20. [PMID: 26560449 DOI: 10.1586/17474124.2016.1116937] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is one of the most common etiologies of liver-related mortality throughout the world. Traditionally, therapy has been focused on pegylated interferon in combination with ribavirin, with clinical trials demonstrating that HCV genotype 1 had the lowest response rate (40-50%), while genotype 3 had an intermediate response rate (60-70%). Recently, significant advances have been made with all-oral direct-acting antiviral (DAA) therapy, which have significantly improved cure rates for HCV genotype 1. Accordingly, HCV genotype 3 is now potentially the most difficult to treat. One of the most potent DAA medications is sofosbuvir, a pan-genotypic nucleotide analogue that inhibits the NS5B polymerase of HCV. Daclatasvir, a pan-genotypic inhibitor of the HCV NS5A replication complex, was recently approved in the United States for treatment of HCV genotype 3 in conjunction with sofosbuvir. This combination may provide a powerful tool in the treatment of HCV genotype 3.
Collapse
Affiliation(s)
- Vinay Sundaram
- a Department of Medicine and Comprehensive Transplant Center , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | | |
Collapse
|
|
22
|
|
|
23
|
Affiliation(s)
- Gautam Das
- Prince Charles Hospital, Cwm Taf University Health Board; Merthyr Tydfil UK
| | - Hemanth Bolusani
- University Hospital of Wales, Cardiff and Vale University Health Board; Cardiff UK
| |
Collapse
|
|
24
|
Shi Q, Hoffman B, Liu Q. PI3K-Akt signaling pathway upregulates hepatitis C virus RNA translation through the activation of SREBPs. Virology 2016; 490:99-108. [PMID: 26855332 DOI: 10.1016/j.virol.2016.01.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 01/21/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) activates PI3K-Akt signaling to enhance entry and replication. Here, we found that this pathway also increased HCV translation. Knocking down the three Akt isoforms significantly decreased, whereas ectopic expression increased HCV translation. HCV translation upregulation by Akt required their kinase activities because Akt kinase-dead mutants downregulated HCV translation; and was dependent on PI3K activity since it was sensitive to PI3K inhibitor wortmannin. The viral 3'UTR was not involved in translation upregulation by Akt. HCV NS5A increased Akt phosphorylation/activity and HCV translation in the absence of the viral 3'UTR. Sterol regulatory element-binding proteins (SREBPs) were the downstream effectors of the PI3K-Akt pathway in regulating HCV translation because Akt1 and Akt2 activated both SREBP-1 and SREBP-2, whereas Akt3 upregulated SREBP-1. Knocking down SREBPs significantly decreased, while ectopic expression of SREBPs increased HCV translation. Taken together, we showed that the PI3K-Akt signaling pathway positively regulates HCV translation through SREBPs.
Collapse
Affiliation(s)
| | - Brett Hoffman
- VIDO-InterVac, Vaccinology and Immunotherapeutics, Canada
| | - Qiang Liu
- VIDO-InterVac, Vaccinology and Immunotherapeutics, Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
| |
Collapse
|
|
25
|
Kao CC, Yi G, Huang HC. The core of hepatitis C virus pathogenesis. Curr Opin Virol 2016; 17:66-73. [PMID: 26851516 DOI: 10.1016/j.coviro.2016.01.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 01/05/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Capsid proteins form protective shells around viral genomes and mediate viral entry. However, many capsid proteins have additional and important roles for virus infection and in modulating cellular response to infection, with important consequences on pathogenesis. Infection by the Hepatitis C virus (HCV) can lead to liver steatosis, cirrhosis, and hepatocellular carcinoma. Herein, we focus on the role in pathogenesis of Core, the capsid protein of the HCV.
Collapse
Affiliation(s)
- C Cheng Kao
- Dept of Molecular & Cellular Biochemistry, Indiana University, Bloomington, IN 47405, United States.
| | - Guanghui Yi
- Dept of Molecular & Cellular Biochemistry, Indiana University, Bloomington, IN 47405, United States
| | - Hsuan-Cheng Huang
- Inst. of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan
| |
Collapse
|
|
26
|
Haga Y, Kanda T, Sasaki R, Nakamura M, Nakamoto S, Yokosuka O. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis. World J Gastroenterol 2015; 21:12989-12995. [PMID: 26675364 PMCID: PMC4674717 DOI: 10.3748/wjg.v21.i46.12989] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/07/2015] [Accepted: 10/17/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.
Collapse
|
|
27
|
Wu Q, Liu Q. HBx truncation mutants differentially modulate SREBP-1a and -1c transcription and HBV replication. Virus Res 2015; 210:46-53. [DOI: 10.1016/j.virusres.2015.07.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 07/08/2015] [Accepted: 07/10/2015] [Indexed: 12/25/2022]
|
|
28
|
Rembeck K, Lagging M. Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection. Pharmacogenomics 2015; 16:1179-88. [PMID: 26250055 DOI: 10.2217/pgs.15.65] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic HCV infection comprises a broad spectrum of liver disease, ranging from no or minimal activity to active hepatitis that in time may progress to severe liver fibrosis, cirrhosis and hepatocellular carcinoma if left untreated. This review describes the impact of genetic variants of interleukin 28B (IL28B; also known as interferon-lambda 3), inosine triphosphate pyrophosphatase (ITPA) and patatin-like phospholipase domain-containing 3 (PNPLA3) on therapeutic outcome and liver disease severity in HCV-infected patients.
Collapse
Affiliation(s)
- Karolina Rembeck
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, SE-413 46, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, SE-413 46, Gothenburg, Sweden
| |
Collapse
|
|
29
|
González-Reimers E, Quintero-Platt G, Rodríguez-Gaspar M, Alemán-Valls R, Pérez-Hernández O, Santolaria-Fernández F. Liver steatosis in hepatitis C patients. World J Hepatol 2015; 7:1337-1346. [PMID: 26052379 PMCID: PMC4450197 DOI: 10.4254/wjh.v7.i10.1337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 01/31/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
There is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in “pure” steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients.
Collapse
|
|
30
|
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.
Collapse
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
| |
Collapse
|
|
31
|
Wu Q, Qiao L, Yang J, Zhou Y, Liu Q. Stronger activation of SREBP-1a by nucleus-localized HBx. Biochem Biophys Res Commun 2015; 460:561-5. [PMID: 25800871 DOI: 10.1016/j.bbrc.2015.03.069] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/12/2015] [Indexed: 12/17/2022]
Abstract
We previously showed that hepatitis B virus (HBV) X protein activates the sterol regulatory element-binding protein-1a (SREBP-1a). Here we examined the role of nuclear localization of HBx in this process. In comparison to the wild-type and cytoplasmic HBx, nuclear HBx had stronger effects on SREBP-1a and fatty acid synthase transcription activation, intracellular lipid accumulation and cell proliferation. Furthermore, nuclear HBx could activate HBV enhancer I/X promoter and was more effective on up-regulating HBV mRNA level in the context of HBV replication than the wild-type HBx, while the cytoplasmic HBx had no effect. Our results demonstrate the functional significance of the nucleus-localized HBx in regulating host lipogenic pathway and HBV replication.
Collapse
Affiliation(s)
- Qi Wu
- VIDO-InterVac, Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada
| | - Ling Qiao
- VIDO-InterVac, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Jian Yang
- Drug Discovery Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Yan Zhou
- VIDO-InterVac, Veterinary Microbiology, Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Qiang Liu
- VIDO-InterVac, Veterinary Microbiology, Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
| |
Collapse
|
|
32
|
Kwan HY, Niu X, Dai W, Tong T, Chao X, Su T, Chan CL, Lee KC, Fu X, Yi H, Yu H, Li T, Tse AKW, Fong WF, Pan SY, Lu A, Yu ZL. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers. Sci Rep 2015; 5:9114. [PMID: 25766252 PMCID: PMC4358044 DOI: 10.1038/srep09114] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 02/17/2015] [Indexed: 02/08/2023] Open
Abstract
Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism.
Collapse
Affiliation(s)
- Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Xuyan Niu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, China
| | - Wenlin Dai
- Department of Mathematics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Tiejun Tong
- Department of Mathematics, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xiaojuan Chao
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Tao Su
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Chi Leung Chan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Kim Chung Lee
- Agilent Technology, Hong Kong Limited, Hong Kong, China
| | - Xiuqiong Fu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Hua Yi
- Department of Pathology, Guangzhou University of Chinese Medicine, China
| | - Hua Yu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Ting Li
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Anfernee Kai Wing Tse
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Wang Fun Fong
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Si-Yuan Pan
- Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, China
| | - Aiping Lu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| | - Zhi-Ling Yu
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Institute of Integrated Bioinfomedicine & Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China
| |
Collapse
|
|
33
|
Moreau M, Rivière B, Vegna S, Aoun M, Gard C, Ramos J, Assenat E, Hibner U. Hepatitis C viral proteins perturb metabolic liver zonation. J Hepatol 2015; 62:278-85. [PMID: 25220251 DOI: 10.1016/j.jhep.2014.09.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 08/22/2014] [Accepted: 09/01/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The metabolic identity of a hepatocyte is determined by its position along the porto-centrilobular axis of a liver lobule. Altered patterns of metabolic liver zonation are associated with several pathologies. In hepatitis C, although only a minority of hepatocytes harbour the virus, the liver undergoes major systemic metabolic changes. We have investigated the HCV-driven mechanisms that allow the systemic loss of metabolic zonation. METHODS Transgenic mice with hepatocyte-targeted expression of all HCV proteins (FL-N/35 model) and needle biopsies from hepatitis C patients were studied with respect to patterns of lipid deposition in the context of metabolic zonation of the liver lobule. RESULTS We report that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. In mice, a major lipogenic enzyme, fatty acid synthase, was redistributed from its normal periportal expression into the midzone of the lobule, coinciding with a highly specific midzone accumulation of lipids. Strikingly, alteration of zonation was not limited to lipogenic enzymes and appeared to be driven by systemic signalling via the Wnt/β-catenin pathway. Importantly, we show that similarly perturbed metabolic zonation appears to precede steatosis in early stages of human disease associated with HCV infection. CONCLUSIONS Our results rationalize systemic effects on liver metabolism, triggered by a minority of infected cells, thus opening new perspectives for the investigation of HCV-related pathologies.
Collapse
Affiliation(s)
- Marie Moreau
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Benjamin Rivière
- Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Serena Vegna
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Manar Aoun
- Départment de Biochimie, CHU, Université Montpellier I, France
| | - Christopher Gard
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; University of Manchester, Manchester, UK
| | - Jeanne Ramos
- Département de Biopathologie Cellulaire et Tissulaire des Tumeurs, Hôpital Saint Eloi-Gui de Chauliac, Centre Hospitalier Universitaire, Montpellier, France; Université de Montpellier 1, Montpellier, France
| | - Eric Assenat
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France; Service d'Oncologie Médicale, CHU St Eloi, Montpellier, France
| | - Urszula Hibner
- CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France; Université de Montpellier 2, Montpellier, France; Université de Montpellier 1, Montpellier, France.
| |
Collapse
|
|
34
|
Lim T. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? Hepat Med 2014; 6:113-8. [PMID: 25506251 PMCID: PMC4259863 DOI: 10.2147/hmer.s60083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy.
Collapse
Affiliation(s)
- Tr Lim
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK
| |
Collapse
|
|
35
|
Kim S, Date T, Yokokawa H, Kono T, Aizaki H, Maurel P, Gondeau C, Wakita T. Development of hepatitis C virus genotype 3a cell culture system. Hepatology 2014; 60:1838-50. [PMID: 24797787 DOI: 10.1002/hep.27197] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/29/2014] [Indexed: 12/14/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) genotype 3a infection poses a serious health problem worldwide. A significant association has been reported between HCV genotype 3a infections and hepatic steatosis. Nevertheless, virological characterization of genotype 3a HCV is delayed due to the lack of appropriate virus cell culture systems. In the present study, we established the first infectious genotype 3a HCV system by introducing adaptive mutations into the S310 strain. HCV core proteins had different locations in JFH-1 and S310 virus-infected cells. Furthermore, the lipid content in S310 virus-infected cells was higher than Huh7.5.1 cells and JFH-1 virus-infected cells as determined by the lipid droplet staining area. CONCLUSION This genotype 3a infectious cell culture system may be a useful experimental model for studying genotype 3a viral life cycles, molecular mechanisms of pathogenesis, and genotype 3a-specific antiviral drug development.
Collapse
Affiliation(s)
- Sulyi Kim
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Ameer F, Scandiuzzi L, Hasnain S, Kalbacher H, Zaidi N. De novo lipogenesis in health and disease. Metabolism 2014; 63:895-902. [PMID: 24814684 DOI: 10.1016/j.metabol.2014.04.003] [Citation(s) in RCA: 376] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/01/2014] [Accepted: 04/06/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND De novo lipogenesis (DNL) is a complex and highly regulated metabolic pathway. In normal conditions DNL converts excess carbohydrate into fatty acids that are then esterified to storage triacylglycerols (TGs). These TGs could later provide energy via β-oxidation. In human body this pathway is primarily active in liver and adipose tissue. However, it is considered to be a minor contributor to the serum lipid homeostasis. Deregulations in the lipogenic pathway are associated with diverse pathological conditions. SCOPE OF REVIEW The present review focuses on our current understanding of the lipogenic pathway with special reference to the causes and consequences of aberrant DNL. MAJOR CONCLUSIONS The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies - including obesity, non-alcoholic fatty liver disease and metabolic syndrome. In addition to that de novo lipogenesis is reported to be exacerbated in cancer tissues, virus infected cells etc. These observations suggest that inhibitors of the DNL pathway might serve as therapeutically significant compounds. The effectiveness of these inhibitors in treatment of cancer and obesity has been suggested by previous works. GENERAL SIGNIFICANCE De novo lipogenesis - which is an intricate and highly regulated pathway - can lead to adverse metabolic consequences when deregulated. Therapeutic targeting of this pathway may open a new window of opportunity for combating various lipogenesis-driven pathological conditions - including obesity, cancer and certain viral infections.
Collapse
Affiliation(s)
- Fatima Ameer
- Microbiology and Molecular Genetics, University of the Punjab, Lahore-54590, Pakistan
| | - Lisa Scandiuzzi
- Department of Radiation Oncology, 1300 Morris Park Avenue, 10461, Bronx, NY, USA
| | - Shahida Hasnain
- Microbiology and Molecular Genetics, University of the Punjab, Lahore-54590, Pakistan
| | - Hubert Kalbacher
- Medical and Natural Sciences Research Centre, University of Tubingen, Germany
| | - Nousheen Zaidi
- Microbiology and Molecular Genetics, University of the Punjab, Lahore-54590, Pakistan.
| |
Collapse
|
|
37
|
Lonardo A, Adinolfi LE, Restivo L, Ballestri S, Romagnoli D, Baldelli E, Nascimbeni F, Loria P. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20:7089-7103. [PMID: 24966582 PMCID: PMC4064057 DOI: 10.3748/wjg.v20.i23.7089] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [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: 01/17/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a successful pathogen on the grounds that it exploits its host's metabolism to build up viral particles; moreover it favours its own survival by inducing chronic disease and the development of specific anatomic changes in the infected organ. Steatosis, therefore, is associated with HCV infection by necessity rather than by chance alone. Approximately 6% of HCV patients have steatohepatitis. Interestingly, HCV steatosis occurs in the setting of multiple metabolic abnormalities (hyperuricemia, reversible hypocholesterolemia, insulin resistance, arterial hypertension and expansion of visceral adipose tissue) collectively referred to as "hepatitis C-associated dysmetabolic syndrome" (HCADS). General, nonalcoholic fatty liver disease (NAFLD)-like, mechanisms of steatogenesis (including increased availability of lipogenic substrates and de novo lipogenesis; decreased oxidation of fatty substrates and export of fatty substrates) are shared by all HCV genotypes. However, genotype 3 seemingly amplifies such steatogenic molecular mechanisms reported to occur in NAFLD via more profound changes in microsomal triglyceride transfer protein; peroxisome proliferator-activated receptor alpha; sterol regulatory element-binding proteins and phosphatase and tensin homologue. HCV steatosis has a remarkable clinical impact in as much as it is an acknowledged risk factor for accelerated fibrogenesis; for impaired treatment response to interferon and ribavirin; and development of hepatocellular carcinoma. Recent data, moreover, suggest that HCV-steatosis contributes to premature atherogenesis via both direct and indirect mechanisms. In conclusion, HCV steatosis fulfills all expected requirements necessary to perpetuate the HCV life cycle. A better understanding of the physiology of HCADS will likely result in a more successful handling of disease with improved antiviral success rates.
Collapse
|
|
38
|
Li C, Lu L, Murphy DG, Negro F, Okamoto H. Origin of hepatitis C virus genotype 3 in Africa as estimated through an evolutionary analysis of the full-length genomes of nine subtypes, including the newly sequenced 3d and 3e. J Gen Virol 2014; 95:1677-1688. [PMID: 24795446 DOI: 10.1099/vir.0.065128-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We characterized the full-length genomes of nine hepatitis C virus genotype 3 (HCV-3) isolates: QC7, QC8, QC9, QC10, QC34, QC88, NE145, NE274 and 811. To the best of our knowledge, NE274 and NE145 were the first full-length genomes for confirming the provisionally assigned subtypes 3d and 3e, respectively, whereas 811 represented the first HCV-3 isolate that had its extreme 3' UTR terminus sequenced. Based on these full-length genomes, together with 42 references representing eight assigned subtypes and an unclassified variant of HCV-3, and 10 sequences of six other genotypes, a timescaled phylogenetic tree was reconstructed after an evolutionary analysis using a coalescent Bayesian procedure. The results indicated that subtypes 3a, 3d and 3e formed a subset with a common ancestor dated to ~202.89 [95% highest posterior density (HPD): 160.11, 264.6] years ago. The analysis of all of the HCV-3 sequences as a single lineage resulted in the dating of the divergence time to ~457.81 (95% HPD: 350.62, 587.53) years ago, whereas the common ancestor of all of the seven HCV genotypes dated to ~780.86 (95% HPD: 592.15, 1021.34) years ago. As subtype 3h and the unclassified variant were relatives, and represented the oldest HCV-3 lineages with origins in Africa and the Middle East, these findings may indicate the ancestral origin of HCV-3 in Africa. We speculate that the ancestral HCV-3 strains may have been brought to South Asia from Africa by land and/or across the sea to result in its indigenous circulation in that region. The spread was estimated to have occurred in the era after Vasco da Gama had completed his expeditions by sailing along the eastern coast of Africa to India. However, before this era, Arabians had practised slave trading from Africa to the Middle East and South Asia for centuries, which may have mediated the earliest spread of HCV-3.
Collapse
Affiliation(s)
- Chunhua Li
- Center for Viral Oncology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ling Lu
- Center for Viral Oncology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Donald G Murphy
- Institut national de santé publique du Québec, Laboratoire de santé publique du Québec, Sainte-Anne-de-Bellevue, QC, Canada
| | - Francesco Negro
- Divisions of Gastroenterology and Hepatology and of Clinical pathology, University Hospitals, Geneva, Switzerland
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan
| |
Collapse
|
|
39
|
Fierro NA, Gonzalez-Aldaco K, Torres-Valadez R, Martinez-Lopez E, Roman S, Panduro A. Immunologic, metabolic and genetic factors in hepatitis C virus infection. World J Gastroenterol 2014; 20:3443-3456. [PMID: 24707127 PMCID: PMC3974511 DOI: 10.3748/wjg.v20.i13.3443] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [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: 01/16/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
The mechanisms that regulate disease progression during hepatitis C virus (HCV) infection and the response to treatment are not clearly identified. Numerous studies have demonstrated that a strong host immune response against HCV favors HCV clearance. In addition, genetic factors and metabolic machinery, particularly cholesterol modulation, are involved in HCV infection. It is likely that the interplay between all of these factors contributes to the outcome of HCV infection. In recent years, the world has experienced its largest epidemic of obesity. Mexico and the United States are the leading sufferers from this epidemic at the global level. Obesity is associated with the development of numerous pathologies including hypercholesterolemia which is one of the eight most important risk factors for mortality in Mexico. This may be related to the course of HCV infection in this population. Here, we focus on the urgent need to study the progression of HCV infection in relation to ethnic characteristics. Discoveries are discussed that hold promise in identifying immune, metabolic and genetic factors that, in conjunction, could be therapeutic targets or predictors of the progression of HCV infection.
Collapse
|
|
40
|
Ampuero J, Romero-Gómez M, Reddy KR. Review article: HCV genotype 3 – the new treatment challenge. Aliment Pharmacol Ther 2014; 39:686-98. [PMID: 24612116 DOI: 10.1111/apt.12646] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 12/27/2013] [Accepted: 01/13/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Over the past several years, hepatitis C therapy has been pegylated interferon and ribavirin based. Although protease inhibitor-based therapy has enhanced response rates in genotype 1, the recent advances in therapy have demonstrated a challenge in genotype 3, a highly prevalent infection globally. AIM To provide a comprehensive summary of the literature evaluating the unique characteristics and evolving therapies in genotype 3. METHODS A structured search in PubMed, the Cochrane Library and EMBASE was performed using defined key words, including only full text papers and abstracts in English. RESULTS HCV genotype 3 is more prevalent in Asia and among intra-venous drug users. Furthermore, it interferes with lipid and glucose metabolism, and the natural history involves a more rapid progression of liver disease and a higher incidence of hepatocellular carcinoma (HCC). New therapies with protease inhibitors have focused on genotype 1 largely and have demonstrated enhanced responses, but have limited activity against genotype 3. Thus far, in clinical trials, NS5B and NS5A inhibitors have performed more poorly in genotype 3, while a cyclophilin inhibitor, alisporivir, has shown promise. CONCLUSIONS As treatments for HCV have evolved, genotype 3 has become the most difficult to treat. Furthermore, genotype 3 has special characteristics, such as insulin resistance and alterations in lipid metabolism, which may partly explain the lower treatment responses. A great deal of emphasis on advancing therapy is needed in this population that appears to have a more rapid progression of liver disease and a higher incidence of HCC.
Collapse
|
|
41
|
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.
Collapse
|
|
42
|
Cheng FKF, Torres DM, Harrison SA. Hepatitis C and lipid metabolism, hepatic steatosis, and NAFLD: still important in the era of direct acting antiviral therapy? J Viral Hepat 2014; 21:1-8. [PMID: 24329852 DOI: 10.1111/jvh.12172] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) have an individual prevalence of 1.8-3% and at least 30%, respectively, in the United States. It is therefore not surprising that there is overlap between these two common chronic liver diseases, although the relationship appears to go beyond isolated co-existence. Hepatic steatosis is a common feature of CHC infection and can be related to both metabolic and viral specific factors. Steatosis in the setting of nongenotype 3 CHC has been predictive of response to therapy prior to the advent of the direct acting antiviral medications (DAAs). Similarly, lipid metabolism appears important in response to CHC treatment. The pathways for both lipid homeostasis and NAFLD as it pertains to CHC infection as well as the utilization of statin therapy in CHC infection will be reviewed with a focus on the relevance of these topics in the era of DAA therapy.
Collapse
Affiliation(s)
- F-K F Cheng
- Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, DC, USA
| | | | | |
Collapse
|
|
43
|
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: 45] [Impact Index Per Article: 3.8] [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.
Collapse
|
|
44
|
Ydreborg M, Westin J, Rembeck K, Lindh M, Norrgren H, Holmberg A, Wejstål R, Norkrans G, Cardell K, Weiland O, Lagging M. Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection. PLoS One 2013; 8:e80172. [PMID: 24244641 PMCID: PMC3828208 DOI: 10.1371/journal.pone.0080172] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 10/09/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of hepatitis C virus (HCV) infection as well as outcome following pegylated interferon and ribavirin therapy among genotype 1 infected patients. Additionally the presence of the otherwise favorable IL28B genetic variants in the context of HCV genotype 3 infection reportedly entail more pronounced liver fibrosis and steatosis. The present study aimed to evaluate the impact of IL28B SNP variability on liver stiffness as accessed by transient elastography. METHODS Seven hundred and seventy-one Swedish HCV infected patients sequentially undergoing liver stiffness measurement by means of Fibroscan® in the context of a real-life trial had samples available for IL28B genotyping (rs12979860) and HCV genotyping. RESULTS CC(rs12979860) was more common among HCV genotype 2 or 3 infected treatment-naïve patients than among those infected with genotype 1 (P<0.0001). Additionally CC(rs12979860) among HCV genotype 3 infected patients was associated with higher liver stiffness values (P = 0.004), and higher AST to platelet ratio index (APRI; p = 0.02) as compared to carriers of the T allele. Among HCV genotype 1 infected patients, CC(rs12979860) was significantly associated with higher viral load (P = 0.001), with a similar non-significant trend noted among HCV genotype 3 infected patients. CONCLUSION This study confirms previous reports that the CC(rs12979860) SNP is associated with more pronounced liver pathology in patients chronically infected with HCV genotype 3 as compared to genotype 1, suggesting that IL28B genetic variants differently regulates the course of HCV infection across HCV genotypes.
Collapse
Affiliation(s)
- Magdalena Ydreborg
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Johan Westin
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Karolina Rembeck
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Hans Norrgren
- Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden
| | - Anna Holmberg
- Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden
| | - Rune Wejstål
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Kristina Cardell
- Department of Infectious Diseases, Linköping University Hospital, Linköping, Sweden
| | - Ola Weiland
- Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Karolinska, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
45
|
Lyn RK, Hope G, Sherratt AR, McLauchlan J, Pezacki JP. Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV core DII protein. PLoS One 2013; 8:e78065. [PMID: 24223760 PMCID: PMC3815211 DOI: 10.1371/journal.pone.0078065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 09/09/2013] [Indexed: 12/16/2022] Open
Abstract
Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV.
Collapse
Affiliation(s)
- Rodney K. Lyn
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
| | - Graham Hope
- Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow, Scotland, United Kingdom
| | | | - John McLauchlan
- Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow, Scotland, United Kingdom
- * E-mail: (JPP); (JM)
| | - John Paul Pezacki
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
- * E-mail: (JPP); (JM)
| |
Collapse
|
|
46
|
Nasheri N, Joyce M, Rouleau Y, Yang P, Yao S, Tyrrell DL, Pezacki JP. Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication. ACTA ACUST UNITED AC 2013; 20:570-82. [PMID: 23601646 DOI: 10.1016/j.chembiol.2013.03.014] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 02/22/2013] [Accepted: 03/19/2013] [Indexed: 02/07/2023]
Abstract
The hepatitis C virus (HCV) induces alterations of host cells to facilitate its life cycle. Fatty acid synthase (FASN) is a multidomain enzyme that plays a key role in the biosynthesis of fatty acids and is upregulated during HCV infection. Herein, we applied activity-based protein profiling (ABPP) that allows for the identification of differentially active enzymes in complex proteomic samples, to study the changes in activity of FASN during HCV replication. For this purpose, we used an activity-based probe based on the FASN inhibitor Orlistat, and observed an increase in the activity of FASN in the presence of a subgenomic and a genomic HCV replicon as well as in chimeric SCID/Alb-uPA mice infected with HCV genotype 1a. To study the molecular basis for this increase in FASN activity, we overexpressed individual HCV proteins in Huh7 cells and observed increased expression and activity of FASN in the presence of core and NS4B, as measured by western blots and ABPP, respectively. Triglyceride levels were also elevated in accordance with FASN expression and activity. Lastly, immunofluorescence and ABPP imaging analyses demonstrated that while the abundance and activity of FASN increases significantly in the presence of HCV, its localization does not change. Together these data suggest that the HCV-induced production of fatty acids and neutral lipids is provided by an increase in FASN abundance and activity that is sufficient to allow HCV propagation without transporting FASN to the replication complexes.
Collapse
Affiliation(s)
- Neda Nasheri
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Tapper EB, Afdhal NH. Is 3 the new 1: perspectives on virology, natural history and treatment for hepatitis C genotype 3. J Viral Hepat 2013; 20:669-77. [PMID: 24010641 DOI: 10.1111/jvh.12168] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Affecting 2-3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50-70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, after recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C.
Collapse
Affiliation(s)
- E B Tapper
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | | |
Collapse
|
|
48
|
Clément S, Fauvelle C, Branche E, Kaddai V, Conzelmann S, Boldanova T, Bartosch B, Minehira K, Negro F. Role of seipin in lipid droplet morphology and hepatitis C virus life cycle. J Gen Virol 2013; 94:2208-2214. [PMID: 23907395 DOI: 10.1099/vir.0.054593-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Infectious hepatitis C virus (HCV) particle assembly starts at the surface of lipid droplets, cytoplasmic organelles responsible for neutral fat storage. We analysed the relationship between HCV and seipin, a protein involved in lipid droplet maturation. Although seipin overexpression did not affect the total mean volume occupied by lipid droplets nor the total triglyceride and cholesterol ester levels per cell, it caused an increase in the mean diameter of lipid droplets by 60 %, while decreasing their total number per cell. The latter two effects combined resulted in a 34 % reduction of the total outer surface area of lipid droplets per cell, with a proportional decrease in infectious viral particle production, probably due to a defect in particle assembly. These results suggest that the available outer surface of lipid droplets is a critical factor for HCV release, independent of the neutral lipid content of the cell.
Collapse
Affiliation(s)
- Sophie Clément
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| | - Catherine Fauvelle
- Department of Immunology and Pathology, Faculty of Medicine, University of Geneva, Switzerland
| | - Emilie Branche
- Department of Immunology and Pathology, Faculty of Medicine, University of Geneva, Switzerland
| | - Vincent Kaddai
- Department of Immunology and Pathology, Faculty of Medicine, University of Geneva, Switzerland
| | - Stéphanie Conzelmann
- Department of Immunology and Pathology, Faculty of Medicine, University of Geneva, Switzerland
| | - Tujana Boldanova
- Department of Biomedicine, University Hospital Basel, Switzerland
| | - Birke Bartosch
- CRCL, INSERM U1052, CNRS 5286, University of Lyon, France
| | - Kaori Minehira
- Department of Physiology, University of Lausanne, Switzerland
| | - Francesco Negro
- Gastroenterology and Hepatology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.,Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| |
Collapse
|
|
49
|
Yim SA, Lim YS, Kim JW, Hwang SB. Nonstructural 5A protein of hepatitis C virus interacts with pyruvate carboxylase and modulates viral propagation. PLoS One 2013; 8:e68170. [PMID: 23861867 PMCID: PMC3701667 DOI: 10.1371/journal.pone.0068170] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 05/26/2013] [Indexed: 01/15/2023] Open
Abstract
Hepatitis C virus (HCV) is highly dependent on cellular factors for its own propagation. By employing tandem affinity purification method, we identified pyruvate carboxylase (PC) as a cellular partner for NS5A protein. NS5A interacted with PC through the N-terminal region of NS5A and the biotin carboxylase domain of PC. PC expression was decreased in cells expressing NS5A and HCV-infected cells. Promoter activity of PC was also decreased by NS5A protein. However, FAS expression was increased in cells expressing NS5A and cell culture grown HCV (HCVcc)-infected cells. Silencing of PC promoted fatty acid synthase (FAS) expression level. These data suggest HCV may modulate PC via NS5A protein for its own propagation.
Collapse
Affiliation(s)
- Seung-Ae Yim
- National Research Laboratory of Hepatitis C Virus, Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Yun-Sook Lim
- National Research Laboratory of Hepatitis C Virus, Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Jong-Wook Kim
- National Research Laboratory of Hepatitis C Virus, Ilsong Institute of Life Science, Hallym University, Anyang, Korea
| | - Soon B. Hwang
- National Research Laboratory of Hepatitis C Virus, Ilsong Institute of Life Science, Hallym University, Anyang, Korea
- * E-mail:
| |
Collapse
|
|
50
|
Mazumder N, Lyn RK, Singaravelu R, Ridsdale A, Moffatt DJ, Hu CW, Tsai HR, McLauchlan J, Stolow A, Kao FJ, Pezacki JP. Fluorescence lifetime imaging of alterations to cellular metabolism by domain 2 of the hepatitis C virus core protein. PLoS One 2013; 8:e66738. [PMID: 23826122 PMCID: PMC3691201 DOI: 10.1371/journal.pone.0066738] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 05/09/2013] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) co-opts hepatic lipid pathways to facilitate its pathogenesis. The virus alters cellular lipid biosynthesis and trafficking, and causes an accumulation of lipid droplets (LDs) that gives rise to hepatic steatosis. Little is known about how these changes are controlled at the molecular level, and how they are related to the underlying metabolic states of the infected cell. The HCV core protein has previously been shown to independently induce alterations in hepatic lipid homeostasis. Herein, we demonstrate, using coherent anti-Stokes Raman scattering (CARS) microscopy, that expression of domain 2 of the HCV core protein (D2) fused to GFP is sufficient to induce an accumulation of larger lipid droplets (LDs) in the perinuclear region. Additionally, we performed fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotides [NAD(P)H], a key coenzyme in cellular metabolic processes, to monitor changes in the cofactor’s abundance and conformational state in D2-GFP transfected cells. When expressed in Huh-7 human hepatoma cells, we observed that the D2-GFP induced accumulation of LDs correlated with an increase in total NAD(P)H fluorescence and an increase in the ratio of free to bound NAD(P)H. This is consistent with an approximate 10 fold increase in cellular NAD(P)H levels. Furthermore, the lifetimes of bound and free NAD(P)H were both significantly reduced – indicating viral protein-induced alterations in the cofactors’ binding and microenvironment. Interestingly, the D2-expressing cells showed a more diffuse localization of NAD(P)H fluorescence signal, consistent with an accumulation of the co-factor outside the mitochondria. These observations suggest that HCV causes a shift of metabolic control away from the use of the coenzyme in mitochondrial electron transport and towards glycolysis, lipid biosynthesis, and building of new biomass. Overall, our findings demonstrate that HCV induced alterations in hepatic metabolism is tightly linked to alterations in NAD(P)H functional states.
Collapse
Affiliation(s)
- Nirmal Mazumder
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - Rodney K. Lyn
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
| | - Ragunath Singaravelu
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Andrew Ridsdale
- National Research Council of Canada, Ottawa, Ontario, Canada
| | | | - Chih-Wei Hu
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - Han-Ruei Tsai
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - John McLauchlan
- Medical Research Council - University of Glasgow Center for Virus Research, Glasgow, United Kingdom
| | - Albert Stolow
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Physics, Queen’s University, Kingston, Ontario, Canada
| | - Fu-Jen Kao
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
- * E-mail: (JPP); (FK)
| | - John Paul Pezacki
- National Research Council of Canada, Ottawa, Ontario, Canada
- Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
- * E-mail: (JPP); (FK)
| |
Collapse
|