|
1
|
Gjorgjieva M, Calo N, Sobolewski C, Portius D, Pitetti JL, Berthou F, Ay AS, Peyrou M, Bourgoin L, Maeder C, Fournier M, Correia de Sousa M, Delangre E, Vinet L, Montet X, Sempoux C, Nef S, Foti M. Hepatic IR and IGF1R signaling govern distinct metabolic and carcinogenic processes upon PTEN deficiency in the liver. JHEP Rep 2025; 7:101305. [PMID: 40115165 PMCID: PMC11925173 DOI: 10.1016/j.jhepr.2024.101305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 03/23/2025] Open
Abstract
Background & Aims Hepatocyte-specific deficiency of the phosphatase and tensin homolog (PTEN) triggers steatosis and the development of hepatic tumors. The hepatoprotective effect of PTEN may partly depend on its ability to block insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) signaling. This study aimed to evaluate the individual/combined contributions of IR and IGF1R to hepatic metabolism and tumorigenesis induced by PTEN deficiency. Methods Mouse models with hepatocyte-specific deletions of Insr, Igf1r, or both, in addition to Pten, were used to investigate the distinct/combined roles of IR and IGF1R. Analyses focused on the impact of these deletions on hepatic steatosis and metabolism, whole-body adiposity, and liver tumor incidence. Results IR and IGF1R signaling contribute to steatosis induced by Pten ablation through distinct mechanisms. Hepatic IGF1R regulates hepatic glucose output and glycogen storage (2.1-fold increase in hepatic glycogen in PTEN-IGF1RKO mice [n = 10], compared with PTENKO mice [n = 7], p <0.0001). In contrast, hepatic IR exerts a stringent regulation on whole-body adiposity (4-fold increase in white adipose tissue volume in PTEN-IRKO mice [n = 5], compared with PTENKO mice [n = 6], p = 0.0004). Interestingly, triple knockout (Insr, Igf1r, and Pten) in hepatocytes of young adult mice is largely asymptomatic, indicating that PTEN deficiency exerts a major overriding control on the effects of Insr and Igf1r deletion. Furthermore, the combined loss of IR and IGF1R signaling in PTEN-deficient livers restrains liver carcinogenesis, but both receptors have individually distinct effects on the malignancy of liver cancers, with IR deficiency reducing overall cancer incidence and IGF1R deficiency promoting malignancy. Conclusions These findings increase our understanding of the intricate interplay between PTEN, IR, and IGF1R signaling and provide valuable insights into potential therapeutic interventions in hepatic disorders and hepatocellular carcinoma. Impact and implications This study underscores the pivotal roles of phosphatase and tensin homolog (PTEN), insulin receptor (IR), and IGF-1 receptor (IGF1R) in controlling liver metabolism, systemic adiposity, and liver cancer progression. Our findings on the distinct and combined effects of these receptors in PTEN-deficient mice offer key insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease and related hepatocarcinogenesis. In addition, this research reveals the potential of IR and IGF1R as biomarkers in liver cancer development, presenting new opportunities for therapeutic targeting and disease monitoring.
Collapse
Affiliation(s)
- Monika Gjorgjieva
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Nicolas Calo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Dorothea Portius
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jean-Luc Pitetti
- Animal Sciences Department, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Flavien Berthou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Anne-Sophie Ay
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marion Peyrou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marta Correia de Sousa
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Etienne Delangre
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Laurent Vinet
- Department of Radiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Xavier Montet
- Department of Radiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Serge Nef
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| |
Collapse
|
|
2
|
Tavakolian S, Eshkiki ZS, Akbari A, Faghihloo E, Tabaeian SP. PTEN regulation in virus-associated cancers. Pathol Res Pract 2024; 266:155749. [PMID: 39642806 DOI: 10.1016/j.prp.2024.155749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/10/2024] [Accepted: 11/29/2024] [Indexed: 12/09/2024]
Abstract
Despite advancements in science, researchers still face challenges in curing patients with malignancies. This health issue is linked to various risk factors, including alcohol consumption, age, sex, and infectious diseases. Among these, viral agents play a significant role in cancer-related health problems and are currently a subject of ongoing research. In this review, we summarize how several viruses-such as herpesviruses, human papillomavirus, hepatitis B virus, hepatitis C virus, and adenovirus-impact cancer signaling pathways through their effects on the tumor suppressor PTEN.
Collapse
Affiliation(s)
- Shaian Tavakolian
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Seidamir Pasha Tabaeian
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
3
|
Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
Collapse
Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
| |
Collapse
|
|
4
|
Hu Y, Wang R, Liu J, Wang Y, Dong J. Lipid droplet deposition in the regenerating liver: A promoter, inhibitor, or bystander? Hepatol Commun 2023; 7:e0267. [PMID: 37708445 PMCID: PMC10503682 DOI: 10.1097/hc9.0000000000000267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/29/2023] [Indexed: 09/16/2023] Open
Abstract
Liver regeneration (LR) is a complex process involving intricate networks of cellular connections, cytokines, and growth factors. During the early stages of LR, hepatocytes accumulate lipids, primarily triacylglycerol, and cholesterol esters, in the lipid droplets. Although it is widely accepted that this phenomenon contributes to LR, the impact of lipid droplet deposition on LR remains a matter of debate. Some studies have suggested that lipid droplet deposition has no effect or may even be detrimental to LR. This review article focuses on transient regeneration-associated steatosis and its relationship with the liver regenerative response.
Collapse
Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics. Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
| |
Collapse
|
|
5
|
Qu Y, Wang W, Xiao MZX, Zheng Y, Liang Q. The interplay between lipid droplets and virus infection. J Med Virol 2023; 95:e28967. [PMID: 37496184 DOI: 10.1002/jmv.28967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/28/2023]
Abstract
As an intracellular parasite, the virus usurps cellular machinery and modulates cellular metabolism pathways to replicate itself in cells. Lipid droplets (LDs) are universally conserved energy storage organelles that not only play vital roles in maintaining lipid homeostasis but are also involved in viral replication. Increasing evidence has demonstrated that viruses take advantage of cellular lipid metabolism by targeting the biogenesis, hydrolysis, and lipophagy of LD during viral infection. In this review, we summarize the current knowledge about the modulation of cellular LD by different viruses, with a special emphasis on the Hepatitis C virus, Dengue virus, and SARS-CoV-2.
Collapse
Affiliation(s)
- Yafei Qu
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weili Wang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Maggie Z X Xiao
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuejuan Zheng
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai University of Traditional Medicine, Shanghai, China
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Medicine, Shanghai, China
| | - Qiming Liang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
6
|
Lai M, De Carli A, Filipponi C, Iacono E, La Rocca V, Lottini G, Piazza CR, Quaranta P, Sidoti M, Pistello M, Freer G. Lipid balance remodelling by human positive-strand RNA viruses and the contribution of lysosomes. Antiviral Res 2022; 206:105398. [PMID: 35985406 DOI: 10.1016/j.antiviral.2022.105398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/03/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022]
Abstract
A marked reorganization of internal membranes occurs in the cytoplasm of cells infected by single stranded positive-sense RNA viruses. Most cell compartments change their asset to provide lipids for membrane rearrangement into replication organelles, where to concentrate viral proteins and enzymes while hiding from pathogen pattern recognition molecules. Because the endoplasmic reticulum is a central hub for lipid metabolism, when viruses hijack the organelle to form their replication organelles, a cascade of events change the intracellular environment. This results in a marked increase in lipid consumption, both by lipolysis and lipophagy of lipid droplets. In addition, lipids are used to produce energy for viral replication. At the same time, inflammation is started by signalling lipids, where lysosomal processing plays a relevant role. This review is aimed at providing an overview on what takes place after human class IV viruses have released their genome into the host cell and the consequences on lipid metabolism, including lysosomes.
Collapse
Affiliation(s)
- Michele Lai
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Alessandro De Carli
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy; Department of Medical Biotechnologies, University of Siena, Italy.
| | - Carolina Filipponi
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Elena Iacono
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Veronica La Rocca
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy; Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy.
| | - Giulia Lottini
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy; Department of Medical Biotechnologies, University of Siena, Italy.
| | - Carmen Rita Piazza
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy; Department of Medical Biotechnologies, University of Siena, Italy.
| | - Paola Quaranta
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Maria Sidoti
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Mauro Pistello
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| | - Giulia Freer
- Centro Retrovirus, Dipartimento di Ricerca Traslazionale, Strada Statale del Brennero 2, University of Pisa, Pisa, 56127, Italy.
| |
Collapse
|
|
7
|
Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
Collapse
Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
| |
Collapse
|
|
8
|
Xu Y, Hou X, Zhu Q, Mao S, Ren J, Lin J, Xu N. Phenotype Identification of HeLa Cells Knockout CDK6 Gene Based on Label-Free Raman Imaging. Anal Chem 2022; 94:8890-8898. [PMID: 35704426 DOI: 10.1021/acs.analchem.2c00188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Identifying cell phenotypes is essential for understanding the function of biological macromolecules and molecular biology. We developed a noninvasive, label-free, single-cell Raman imaging analysis platform to distinguish between the cell phenotypes of the HeLa cell wild type (WT) and cyclin-dependent kinase 6 (CDK6) gene knockout (KO) type. Via large-scale Raman spectral and imaging analysis, two phenotypes of the HeLa cells were distinguished by their intrinsic biochemical profiles. A significant difference was found between the two cell lines: large lipid droplets formed in the knockout HeLa cells but were not observed in the WT cells, which was confirmed by Oil Red O staining. The band ratio of the Raman spectrum of saturated/unsaturated fatty acids was identified as the Raman spectral marker for HeLa cell WT or gene knockout type differentiation. The interaction between organelles involved in lipid metabolism was revealed by Raman imaging and Lorentz fitting, where the distribution intensity of the mitochondria and the endoplasmic reticulum membrane decreased. At the same time, lysosomes increased after the CDK6 gene knockout. The parameters obtained from Raman spectroscopy are based on hierarchical cluster analysis and one-way ANOVA, enabling highly accurate cell classification.
Collapse
Affiliation(s)
- Ying Xu
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| | - Xiaoli Hou
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China
| | - Qiaoqiao Zhu
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| | - Shijie Mao
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| | - Jie Ren
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| | - Jidong Lin
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| | - Ning Xu
- Institute of Drug Development & Chemical Biology, College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, Zhejiang 313200, People's Republic of China
| |
Collapse
|
|
9
|
Liu X, Liang Z, Duan H, Yu J, Qin Z, Li J, Zhu L, Wu Q, Xiao W, Shen C, Wan C, Wu K, Ye H, Zhang B, Zhao W. Dengue virus is involved in insulin resistance via the downregulation of IRS-1 by inducing TNF-α secretion. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166472. [PMID: 35752384 DOI: 10.1016/j.bbadis.2022.166472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/29/2022]
Abstract
During the epidemic, the individuals with underlying diseases usually have a higher rate of mortality. Diabetes is highly prevalent worldwide, making it a frequent comorbidity in dengue fever patients. Therefore, understanding the relationship between dengue virus (DENV) infection and diabetes is important. We first demonstrated that DENV-3 infection down-regulated the expression of IRS-1. In vitro, treatment of HepG2 cells with TNF-α inhibitors and siRNA proved that after DENV-3 infection in HepG2 cells, cellular TNF-α secretion was increased, which negatively regulated IRS-1, thereby leading to an insulin-resistant state. In vivo, DENV-3 induced insulin resistance (IR) in hepatocytes by promoting the secretion of TNF-α and inhibiting the expression of IRS-1 was proved. In vivo approaches also showed that after DENV-3 infection, TNF-α levels in the serum of C57BL/6 mice with insulin resistance increased, and upon TNF-α antagonist III treatment, IRS-1 expression in the liver, reduced by infection, was upregulated. In addition, transcriptomic analysis revealed more negative regulatory events in the insulin receptor signaling pathway after DENV-3 infection. This is the first report of a link between DENV-3 infection and insulin resistance, and it lays a foundation for further research.
Collapse
Affiliation(s)
- Xuling Liu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zuxin Liang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hongwei Duan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jianhai Yu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zhiran Qin
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jingshu Li
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Li Zhu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Qinghua Wu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Weiwei Xiao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chenguang Shen
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chengsong Wan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Kefeng Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
| | - Hua Ye
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China.
| | - Bao Zhang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
| | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
| |
Collapse
|
|
10
|
Hao L, Guo Y, Peng Q, Zhang Z, Ji J, Liu Y, Xue Y, Li C, Zheng K, Shi X. Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153913. [PMID: 35026515 DOI: 10.1016/j.phymed.2021.153913] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/04/2021] [Accepted: 12/24/2021] [Indexed: 05/16/2023]
Abstract
BACKGROUND Anti-PD-1 was used to treat for many cancers, but the overall response rate of monoclonal antibodies blocking the inhibitory PD-1/PD-L1 was less than 20%. Lipid droplet (LD) deposition reduced chemotherapy efficacy, but whether LD deposition affects anti-PD-1 treatment and its mechanism remains unclear. Dihydroartemisinin (DHA) was FDA proved antimalarial medicine, but its working mechanism on LD deposition has not been clarified. PURPOSE This study aimed to elucidate the mechanism of DHA reducing LDs deposition and improving the efficacy of anti-PD-1. METHODS LD numbers and area were separately detected by electron microscopy and oil Red O staining. The expression of YAP1 and PLIN2 was detected by immunohistochemical staining in liver cancer tissues. Transcription and protein expression levels of YAP1 and PLIN2 in cells were detected by qRT-PCR and Western blot after DHA treated HepG2215 cells and Yap1LKO mice. RESULTS LD accumulation was found in the liver tumor cells of DEN/TOPBCOP-induced liver tumor mice with anti-PD-1 treatment. But DHA treatment or YAP1 knockdown reduced LD deposition and PLIN2 expression in HepG2215 cells. Furthermore, DHA reduced the LD deposition, PLIN2 expression and triglycerides (TG) content in the liver tumor cells of Yap1LKO mice with liver tumor. CONCLUSION Anti-PD-1 promoted LD deposition, while YAP1 knockdown/out reduced LD deposition in HCC. DHA reduced LD deposition by inhibiting YAP1, enhancing the effect of anti-PD-1 therapy.
Collapse
Affiliation(s)
- Liyuan Hao
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yinglin Guo
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Qing Peng
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Zhiqin Zhang
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Jingmin Ji
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yiwei Liu
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Yu Xue
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Caige Li
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Kangning Zheng
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Xinli Shi
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
| |
Collapse
|
|
11
|
Siphepho PY, Liu YT, Shabangu CS, Huang JF, Huang CF, Yeh ML, Yu ML, Wang SC. The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments. Biomedicines 2021; 9:1491. [PMID: 34680608 PMCID: PMC8533513 DOI: 10.3390/biomedicines9101491] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes.
Collapse
Affiliation(s)
- Phumelele Yvonne Siphepho
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
| | - Yi-Ting Liu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ciniso Sylvester Shabangu
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| |
Collapse
|
|
12
|
He T, Zhang X, Hao J, Ding S. Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor. Front Physiol 2021; 12:684529. [PMID: 34140896 PMCID: PMC8204087 DOI: 10.3389/fphys.2021.684529] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.
Collapse
Affiliation(s)
- Tianyu He
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiaoyun Zhang
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Shigang Ding
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| |
Collapse
|
|
13
|
Galli A, Ramirez S, Bukh J. Lipid Droplets Accumulation during Hepatitis C Virus Infection in Cell-Culture Varies among Genotype 1-3 Strains and Does Not Correlate with Virus Replication. Viruses 2021; 13:389. [PMID: 33671086 PMCID: PMC7999684 DOI: 10.3390/v13030389] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 12/26/2022] Open
Abstract
Liver steatosis is a common complication of chronic hepatitis C virus (HCV) infection, which can result in accelerated liver fibrosis development, especially in patients infected with genotype 3a. The precise mechanisms of HCV-induced liver steatosis remain unclear, but it is often posited that increased intracellular lipid accumulation is the underlying cause of steatosis. To study experimentally how HCV infection in human liver derived cells by different genotypes and subtypes might affect lipid accumulation, we performed detailed cytofluorimetric and microscopy analyses of intracellular lipid droplets (LDs) in relation to the viral Core and to cell endoplasmic reticulum proteins. Following culture infection with HCV genotype 1a, 2a, 2b, 2c, and 3a strains, we found variable levels of intracellular LDs accumulation, associated to the infecting strain rather than to the specific genotype. Although two genotype 3a strains showed high levels of lipid accumulation, as previously observed, some strains of other genotypes displayed a similar phenotype. Moreover, the analyses of LDs size, number, and shape indicated that the apparent increase in lipid accumulation is due to an increase in the overall number rather than in the size of droplets. Finally, differences in total lipid content across genotypes did not correlate to differences in Core distribution nor Core levels. In conclusion, our study provides a quantitative in-depth analysis of the effect of HCV infection on LDs accumulation in cell-culture.
Collapse
Affiliation(s)
- Andrea Galli
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, 2650 Hvidovre, Denmark; (A.G.); (S.R.)
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Santseharay Ramirez
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, 2650 Hvidovre, Denmark; (A.G.); (S.R.)
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, 2650 Hvidovre, Denmark; (A.G.); (S.R.)
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| |
Collapse
|
|
14
|
Liu B, Gao TT, Fu XY, Xu ZH, Ren H, Zhao P, Qi ZT, Qin ZL. PTEN Lipid Phosphatase Activity Enhances Dengue Virus Production through Akt/FoxO1/Maf1 Signaling. Virol Sin 2020; 36:412-423. [PMID: 33044659 DOI: 10.1007/s12250-020-00291-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 07/31/2020] [Indexed: 01/19/2023] Open
Abstract
Dengue virus (DENV) is an arthropod-borne viral pathogen and a global health burden. Knowledge of the DENV-host interactions that mediate virus pathogenicity remains limited. Host lipid metabolism is hijacked by DENV for virus replication in which lipid droplets (LDs) play a key role during the virus lifecycle. In this study, we reveal a novel role for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in LDs-mediated DENV infection. We demonstrate that PTEN expression is downregulated upon DENV infection through post-transcriptional regulation and, in turn, PTEN overexpression enhances DENV replication. PTEN lipid phosphatase activity was found to decrease cellular LDs area and number through Akt/FoxO1/Maf1 signaling, which, together with autophagy, enhanced DENV replication and virus production. We therefore provide mechanistic insight into the interaction between lipid metabolism and the DENV replication cycle.
Collapse
Affiliation(s)
- Bin Liu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Ting-Ting Gao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.,Department of Nephrology, The Air Force Hospital from Northern Theater of PLA, Shenyang 110042, China
| | - Xiao-Yu Fu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Zhen-Hao Xu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China
| | - Zhong-Tian Qi
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhao-Ling Qin
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| |
Collapse
|
|
15
|
Sobolewski C, Abegg D, Berthou F, Dolicka D, Calo N, Sempoux C, Fournier M, Maeder C, Ay AS, Clavien PA, Humar B, Dufour JF, Adibekian A, Foti M. S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development. Gut 2020; 69:1841-1854. [PMID: 31919231 DOI: 10.1136/gutjnl-2019-319019] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. DESIGN The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. RESULTS A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. CONCLUSION Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.
Collapse
Affiliation(s)
- Cyril Sobolewski
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Daniel Abegg
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA
| | - Flavien Berthou
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Dobrochna Dolicka
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Nicolas Calo
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Christine Sempoux
- Department of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Anne-Sophie Ay
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Pierre-Alain Clavien
- Visceral and Transplantation Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Bostjan Humar
- Department of Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Jean-François Dufour
- Department of Hepatology and Clinical Research, University of Bern, Bern, Switzerland
| | - Alexander Adibekian
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| |
Collapse
|
|
16
|
Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037366. [PMID: 31501266 DOI: 10.1101/cshperspect.a037366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.
Collapse
Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.,Institut Universitaire de France (IUF), 75231 Paris, France
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| |
Collapse
|
|
17
|
Clément S, Sobolewski C, Gomes D, Rojas A, Goossens N, Conzelmann S, Calo N, Negro F, Foti M. Activation of the oncogenic miR-21-5p promotes HCV replication and steatosis induced by the viral core 3a protein. Liver Int 2019; 39:1226-1236. [PMID: 30938910 DOI: 10.1111/liv.14112] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/11/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS miR-21-5p is a potent oncogenic microRNA targeting many key tumour suppressors including phosphatase and tensin homolog (PTEN). We recently identified PTEN as a key factor modulated by hepatitis C virus (HCV) to promote virion egress. In hepatocytes, expression of HCV-3a core protein was sufficient to downregulate PTEN and to trigger lipid droplet accumulation. Here, we investigated whether HCV controls PTEN expression through miR-21-5p-dependent mechanisms to trigger steatosis in hepatocytes and to promote HCV life cycle. METHODS MiR-21-5p expression in HCV-infected patients was evaluated by transcriptome meta-analysis. HCV replication and viral particle production were investigated in Jc1-infected Huh-7 cells after miR-21-5p inhibition. PTEN expression and steatosis were assessed in HCV-3a core protein-expressing Huh-7 cells and in mouse primary hepatocytes having miR-21-5p inhibited or genetically deleted respectively. HCV-3a core-induced steatosis was assessed in vivo in Mir21a knockout mice. RESULTS MiR-21-5p expression was significantly increased in hepatic tissues from HCV-infected patients. Infection by HCV-Jc1, or transduction with HCV-3a core, upregulated miR-21-5p expression and/or activity in Huh-7 cells. miR-21-5p inhibition decreased HCV replication and release of infectious virions by Huh-7 cells. HCV-3a core-induced PTEN downregulation and steatosis were further prevented in Huh-7 cells following miR-21-5p inhibition or in Mir21a knockout mouse primary hepatocytes. Finally, steatosis induction by AAV8-mediated HCV-3a core expression was reduced in vivo in Mir21a knockout mice. CONCLUSION MiR-21-5p activation by HCV is a key molecular step, promoting both HCV life cycle and HCV-3a core-induced steatosis and may be among the molecular changes induced by HCV-3a to promote carcinogenesis.
Collapse
Affiliation(s)
- Sophie Clément
- Division of Clinical Pathology, University Hospital, Geneva, Switzerland
| | - Cyril Sobolewski
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Diana Gomes
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Angela Rojas
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland
| | - Stéphanie Conzelmann
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nicolas Calo
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, University Hospital, Geneva, Switzerland.,Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.,Faculty of Medicine, Diabetes Center, University of Geneva, Geneva, Switzerland
| | - Michelangelo Foti
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.,Faculty of Medicine, Diabetes Center, University of Geneva, Geneva, Switzerland
| |
Collapse
|
|
18
|
Goossens N, de Vito C, Mangia A, Clément S, Cenderello G, Barrera F, D'Ambrosio R, Coppola N, Zampino R, Stanzione M, Adinolfi LE, Wedemeyer H, Semmo N, Müllhaupt B, Semela D, Malinverni R, Moradpour D, Heim M, Trincucci G, Rubbia-Brandt L, Negro F. Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review. J Viral Hepat 2018. [PMID: 29532619 DOI: 10.1111/jvh.12891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.
Collapse
Affiliation(s)
- N Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland
| | - C de Vito
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - A Mangia
- Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - S Clément
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - G Cenderello
- Division of Infectious Diseases, Galliera Hospital, Genova, Italy
| | - F Barrera
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, NSW, Australia
| | - R D'Ambrosio
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - N Coppola
- Department of Mental Health and Preventive Medicine, Second University of Naples, Napoli, Italy
| | - R Zampino
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, Italy
| | - M Stanzione
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Napoli, Italy
| | - L E Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, Italy
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research, Hannover-Braunschweig, Germany
| | - N Semmo
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
| | - B Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - D Semela
- Division of Gastroenterology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | | | - D Moradpour
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
| | - M Heim
- Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - G Trincucci
- Department of Pathology and Immunology, Geneva University, Geneva, Switzerland
| | - L Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - F Negro
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland.,Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | | |
Collapse
|
|
19
|
Glingston RS, Deb R, Kumar S, Nagotu S. Organelle dynamics and viral infections: at cross roads. Microbes Infect 2018; 21:20-32. [PMID: 29953921 PMCID: PMC7110583 DOI: 10.1016/j.micinf.2018.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/14/2018] [Accepted: 06/15/2018] [Indexed: 01/12/2023]
Abstract
Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.
Collapse
Affiliation(s)
- R Sahaya Glingston
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Rachayeeta Deb
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sachin Kumar
- Viral Immunology Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
| | - Shirisha Nagotu
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
| |
Collapse
|
|
20
|
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
|
|
21
|
Shubin AV, Demidyuk IV, Komissarov AA, Rafieva LM, Kostrov SV. Cytoplasmic vacuolization in cell death and survival. Oncotarget 2018; 7:55863-55889. [PMID: 27331412 PMCID: PMC5342458 DOI: 10.18632/oncotarget.10150] [Citation(s) in RCA: 236] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 06/06/2016] [Indexed: 12/15/2022] Open
Abstract
Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.
Collapse
Affiliation(s)
- Andrey V Shubin
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia.,Laboratory of Chemical Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.,Laboratory of Biologically Active Nanostructures, N.F. Gamaleya Institute of Epidemiology and Microbiology, Moscow, Russia
| | - Ilya V Demidyuk
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Alexey A Komissarov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Lola M Rafieva
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| | - Sergey V Kostrov
- Laboratory of Protein Engineering, Institute of Molecular Genetics, Moscow, Russia
| |
Collapse
|
|
22
|
Wang H, Feng Z, Xie J, Wen F, Jv M, Liang T, Li J, Wang Y, Zuo Y, Li S, Li R, Li Z, Zhang B, Liang X, Liu S, Shi W, Wang W. Podocyte-specific knockin of PTEN protects kidney from hyperglycemia. Am J Physiol Renal Physiol 2018; 314:F1096-F1107. [PMID: 29361670 DOI: 10.1152/ajprenal.00575.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.
Collapse
Affiliation(s)
- Huizhen Wang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Ziwei Feng
- Division of Urology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Jianteng Xie
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Feng Wen
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Menglei Jv
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Tiantian Liang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Jing Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Yanhui Wang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Yangyang Zuo
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Sheng Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Ruizhao Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Zhilian Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Bin Zhang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Xinling Liang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Shuangxin Liu
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Wei Shi
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| | - Wenjian Wang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , China
| |
Collapse
|
|
23
|
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
|
|
24
|
Khalid A, Hussain T, Manzoor S, Saalim M, Khaliq S. PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma. Tumour Biol 2017. [DOI: 10.1177/1010428317705754] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Ayesha Khalid
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Tabinda Hussain
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Sobia Manzoor
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Muhammad Saalim
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied BioSciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Saba Khaliq
- University of Health Sciences, Lahore, Pakistan
| |
Collapse
|
|
25
|
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
|
|
26
|
Awad A, Gassama-Diagne A. PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis. World J Hepatol 2017; 9:18-29. [PMID: 28105255 PMCID: PMC5220268 DOI: 10.4254/wjh.v9.i1.18] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/10/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.
Collapse
|
|
27
|
Meyers NL, Fontaine KA, Kumar GR, Ott M. Entangled in a membranous web: ER and lipid droplet reorganization during hepatitis C virus infection. Curr Opin Cell Biol 2016; 41:117-24. [PMID: 27240021 DOI: 10.1016/j.ceb.2016.05.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. To establish and maintain chronic infection, HCV extensively rearranges cellular organelles to generate distinct compartments for viral RNA replication and virion assembly. Here, we review our current knowledge of how HCV proliferates and remodels ER-derived membranes while preserving and expanding associated lipid droplets during viral infection. Unraveling the molecular mechanisms responsible for HCV-induced membrane reorganization will enhance our understanding of the HCV life-cycle, the associated liver pathology, and the biology of the ER:lipid droplet interface in general.
Collapse
Affiliation(s)
- Nathan L Meyers
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - Krystal A Fontaine
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - G Renuka Kumar
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - Melanie Ott
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States.
| |
Collapse
|
|
28
|
Sanchez-Pareja A, Clément S, Peyrou M, Spahr L, Negro F, Rubbia-Brandt L, Foti M. Phosphatase and tensin homolog is a differential diagnostic marker between nonalcoholic and alcoholic fatty liver disease. World J Gastroenterol 2016; 22:3735-3745. [PMID: 27076758 PMCID: PMC4814736 DOI: 10.3748/wjg.v22.i14.3735] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 01/28/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protein expression of phosphatase and tensin homolog (PTEN) in human liver biopsies of patients with alcoholic and non-alcoholic liver disease.
METHODS: PTEN protein expression was assessed by immunohistochemistry in formalin-fixed, paraffin-embedded liver sections of patients with non-alcoholic fatty liver disease (NAFLD) (n = 44) or alcoholic liver disease (ALD) (n = 25). Liver resections obtained from 3 healthy subjects candidate for partial liver donation served as controls. Histological evaluations were performed by two experienced pathologists, and diagnoses established based on international criteria. The intensity of the PTEN staining in nuclei was compared between steatotic and non-steatotic areas of each liver fragment analyzed. For each liver specimen, the antibody-stained sections were examined and scored blindly by three independent observers, who were unaware of the patients’ clinical history.
RESULTS: In healthy individuals, PTEN immunostaining was intense in both the cytoplasm and nuclei of all hepatocytes. However, PTEN was strongly downregulated in both the nucleus and the cytoplasm of hepatocytes from steatotic areas in patients with NAFLD, independently of the disease stage. In contrast, no changes in PTEN protein expression were observed in patients with ALD, regardless of the presence of steatosis or the stage of the disease. The degree of PTEN downregulation in hepatocytes of patients with NAFLD correlated with the percentage of steatosis (r = 0.3061, P = 0.0459) and the BMI (r = 0.4268, P = 0.0043). Hovewer, in patients with ALD, PTEN expression was not correlated with the percentage of steatosis with or without obesity as a confounding factor (P = 0.5574). Finally, PTEN expression level in steatotic areas of ALD patients was significantly different from that seen in steatotic areas of NAFLD patients (P < 0.0001).
CONCLUSION: PTEN protein expression is downregulated early in NAFLD, but not in ALD. PTEN immunohistochemical detection could help in the differential diagnosis of NAFLD and ALD.
Collapse
|
|
29
|
Morgan ML, Sigala B, Soeda J, Cordero P, Nguyen V, McKee C, Mouraliderane A, Vinciguerra M, Oben JA. Acetylcholine induces fibrogenic effects via M2/M3 acetylcholine receptors in non-alcoholic steatohepatitis and in primary human hepatic stellate cells. J Gastroenterol Hepatol 2016; 31:475-83. [PMID: 26270240 DOI: 10.1111/jgh.13085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 07/03/2015] [Accepted: 07/15/2015] [Indexed: 01/13/2023]
Abstract
BACKGROUND The parasympathetic nervous system (PNS), via neurotransmitter acetylcholine (ACh), modulates fibrogenesis in animal models. However, the role of ACh in human hepatic fibrogenesis is unclear. AIMS We aimed to determine the fibrogenic responses of human hepatic stellate cells (hHSC) to ACh and the relevance of the PNS in hepatic fibrosis in patients with non-alcoholic steatohepatitis (NASH). METHODS Primary hHSC were analyzed for synthesis of endogenous ACh and acetylcholinesterase and gene expression of choline acetyltransferase and muscarinic ACh receptors (mAChR). Cell proliferation and fibrogenic markers were analyzed in hHSC exposed to ACh, atropine, mecamylamine, methoctramine, and 4-diphenylacetoxy-N-methylpiperidine methiodide. mAChR expression was analyzed in human NASH scored for fibrosis. RESULTS We observed that hHSC synthesize ACh and acetylcholinesterase and express choline acetyltransferase and M1-M5 mAChR. We also show that M2 was increased during NASH progression, while both M2 and M3 were found upregulated in activated hHSC. Furthermore, endogenous ACh is required for hHSC basal growth. Exogenous ACh resulted in hHSC hyperproliferation via mAChR and phosphoinositide 3-kinase and Mitogen-activated protein kinase kinase (MEK) signaling pathways, as well as increased fibrogenic markers. CONCLUSION We show that ACh regulates hHSC activation via M2 and M3 mAChR involving the phosphoinositide 3-kinase and MEK pathways in vitro. Finally, we provide evidence that the PNS may be involved in human NASH fibrosis.
Collapse
Affiliation(s)
- Maelle L Morgan
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Barbara Sigala
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Junpei Soeda
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Paul Cordero
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Vi Nguyen
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Chad McKee
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Angelina Mouraliderane
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Manlio Vinciguerra
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.,Gastroenterology Unit, Department of Medical Sciences, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.,Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Jude A Oben
- University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.,Guy's and St Thomas' National Health Service Foundation Trust, London, UK
| |
Collapse
|
|
30
|
Brief Report: Coordinated Modulation of Circulating miR-21 in HIV, HIV-Associated Pulmonary Arterial Hypertension, and HIV/Hepatitis C Virus Coinfection. J Acquir Immune Defic Syndr 2016; 70:236-41. [PMID: 26473639 DOI: 10.1097/qai.0000000000000741] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Dysregulation of microRNA-21 (miR-21) is independently associated with HIV infection, pulmonary arterial hypertension (PAH), and hepatitis C virus (HCV) infection. To assess the expression of miR-21 in these overlapping comorbidities, we measured plasma miR-21 in HIV with and without PAH and then stratified by concomitant HCV infection. MiR-21 was increased in HIV and HIV-PAH versus uninfected subjects, but it did not differ between these groups. HIV/HCV coinfection correlated with even higher miR-21 levels within the HIV-infected population. These data reveal specific regulation of plasma miR-21 in HIV, HIV/HCV coinfection, and PAH and suggest that miR-21 may integrate complex disease-specific signaling in the setting of HIV infection.
Collapse
|
|
31
|
Blanco JR, Rivero-Juarez A. HCV genotype 3: a wolf in sheep's clothing. Expert Rev Anti Infect Ther 2016; 14:149-52. [PMID: 26635242 DOI: 10.1586/14787210.2016.1127757] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- José-R Blanco
- a Infectious Diseases Area , Hospital San Pedro - Center for Biomedical Research of La Rioja (CIBIR) , Logroño , Spain
| | - Antonio Rivero-Juarez
- b Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Córdoba , Spain
| |
Collapse
|
|
32
|
Saik OV, Ivanisenko TV, Demenkov PS, Ivanisenko VA. Interactome of the hepatitis C virus: Literature mining with ANDSystem. Virus Res 2015; 218:40-8. [PMID: 26673098 DOI: 10.1016/j.virusres.2015.12.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/22/2015] [Accepted: 12/03/2015] [Indexed: 12/19/2022]
Abstract
A study of the molecular genetics mechanisms of host-pathogen interactions is of paramount importance in developing drugs against viral diseases. Currently, the literature contains a huge amount of information that describes interactions between HCV and human proteins. In addition, there are many factual databases that contain experimentally verified data on HCV-host interactions. The sources of such data are the original data along with the data manually extracted from the literature. However, the manual analysis of scientific publications is time consuming and, because of this, databases created with such an approach often do not have complete information. One of the most promising methods to provide actualisation and completeness of information is text mining. Here, with the use of a previously developed method by the authors using ANDSystem, an automated extraction of information on the interactions between HCV and human proteins was conducted. As a data source for the text mining approach, PubMed abstracts and full text articles were used. Additionally, external factual databases were analyzed. On the basis of this analysis, a special version of ANDSystem, extended with the HCV interactome, was created. The HCV interactome contains information about the interactions between 969 human and 11 HCV proteins. Among the 969 proteins, 153 'new' proteins were found not previously referred to in any external databases of protein-protein interactions for HCV-host interactions. Thus, the extended ANDSystem possesses a more comprehensive detailing of HCV-host interactions versus other existing databases. It was interesting that HCV proteins more preferably interact with human proteins that were already involved in a large number of protein-protein interactions as well as those associated with many diseases. Among human proteins of the HCV interactome, there were a large number of proteins regulated by microRNAs. It turned out that the results obtained for protein-protein interactions and microRNA-regulation did not depend on how well the proteins were studied, while protein-disease interactions appeared to be dependent on the level of study. In particular, the mean number of diseases linked to well-studied proteins (proteins were considered well-studied if they were mentioned in 50 or more PubMed publications) from the HCV interactome was 20.8, significantly exceeding the mean number of associations with diseases (10.1) for the total set of well-studied human proteins present in ANDSystem. For proteins not highly poorly-studied investigated, proteins from the HCV interactome (each protein was referred to in less than 50 publications) distribution of the number of diseases associated with them had no statistically significant differences from the distribution of the number of diseases associated with poorly-studied proteins based on the total set of human proteins stored in ANDSystem. With this, the average number of associations with diseases for the HCV interactome and the total set of human proteins were 0.3 and 0.2, respectively. Thus, ANDSystem, extended with the HCV interactome, can be helpful in a wide range of issues related to analyzing HCV-host interactions in the search for anti-HCV drug targets. The demo version of the extended ANDSystem covered here containing only interactions between human proteins, genes, metabolites, diseases, miRNAs and molecular-genetic pathways, as well as interactions between human proteins/genes and HCV proteins, is freely available at the following web address: http://www-bionet.sscc.ru/psd/andhcv/.
Collapse
Affiliation(s)
- Olga V Saik
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia; PB-soft, LLC, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia.
| | - Timofey V Ivanisenko
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia; PB-soft, LLC, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova Str. 2, 630090 Novosibirsk, Russia.
| | - Pavel S Demenkov
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia; PB-soft, LLC, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia.
| | - Vladimir A Ivanisenko
- The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia; PB-soft, LLC, Prospekt Lavrentyeva 10, 630090 Novosibirsk, Russia.
| |
Collapse
|
|
33
|
Gondeau C, Pageaux GP, Larrey D. Hepatitis C virus infection: Are there still specific problems with genotype 3? World J Gastroenterol 2015; 21:12101-13. [PMID: 26576095 PMCID: PMC4641128 DOI: 10.3748/wjg.v21.i42.12101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/07/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease and the main indication for liver transplantation worldwide. As promising specific treatments have been introduced for genotype 1, clinicians and researchers are now focusing on patients infected by non-genotype 1 HCV, particularly genotype 3. Indeed, in the golden era of direct-acting antiviral drugs, genotype 3 infections are no longer considered as easy to treat and are associated with higher risk of developing severe liver injuries, such as cirrhosis and hepatocellular carcinoma. Moreover, HCV genotype 3 accounts for 40% of all HCV infections in Asia and is the most frequent genotype among HCV-positive injecting drug users in several countries. Here, we review recent data on HCV genotype 3 infection/treatment, including clinical aspects and the underlying genotype-specific molecular mechanisms.
Collapse
|
|
34
|
Cheng D, Zhang L, Yang G, Zhao L, Peng F, Tian Y, Xiao X, Chung RT, Gong G. Hepatitis C virus NS5A drives a PTEN-PI3K/Akt feedback loop to support cell survival. Liver Int 2015; 35:1682-91. [PMID: 25388655 DOI: 10.1111/liv.12733] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 11/06/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Decreased levels of phosphatase and tensin homologue (PTEN) are associated with hepatocellular carcinoma (HCC) pathogenesis and poor prognosis in hepatitis C virus (HCV)-infected HCC patients. The molecular processes governing the reduction in PTEN and outcome of PTEN dysfunction in hepatocytes are poorly understood. METHODS The levels of proteins and mRNA were assessed by real time PCR and immunoblot. PTEN promoter activity was measured by reporter assay. Signalling pathways were perturbed using siRNAs or pharmacological inhibitors. RESULTS Here, we report that HCV down-regulates PTEN expression at the transcriptional level by decreasing its promoter activity, mRNA transcription, and protein levels. We further identify NS5A protein as a key determinant of PTEN reduction among HCV proteins. NS5A-mediated down-regulation of PTEN occurs through a cooperation of reactive oxygen species (ROS)-dependent Nuclear Factor- kappa B (NF-κB) and ROS-independent phosphoinositol-3-kinase (PI3K) pathways. Moreover, NS5A protects cells against apoptosis. In addition, we found that down-regulation of PTEN relieves its inhibitory effect on PI3K-Akt pathway and triggers cumulative activation of Akt. This PTEN-PI3K/Akt feedback network mediates the suppression of cell apoptosis caused by NS5A. CONCLUSIONS These data demonstrate that HCV NS5A down-regulates PTEN expression through a cooperation of ROS-dependent and -independent pathways that subsequently drives a PTEN-PI3K/Akt feedback loop to support cell survival. Our findings provide new insights suggesting that NS5A contributes to HCV-related hepatocarcinogenesis.
Collapse
Affiliation(s)
- Du Cheng
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, China.,Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Liver Diseases Center, Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Leiliang Zhang
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Guangbo Yang
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei Zhao
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Feng Peng
- Liver Diseases Center, Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Tian
- Liver Diseases Center, Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xinqiang Xiao
- Liver Diseases Center, Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Raymond T Chung
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Guozhong Gong
- Liver Diseases Center, Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
35
|
Gao TT, Qin ZL, Ren H, Zhao P, Qi ZT. Inhibition of IRS-1 by hepatitis C virus infection leads to insulin resistance in a PTEN-dependent manner. Virol J 2015; 12:12. [PMID: 25645159 PMCID: PMC4323155 DOI: 10.1186/s12985-015-0241-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/15/2015] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection was recently recognized as an independent risk factor for insulin resistance (IR), the onset phase of type 2 diabetes mellitus (T2DM). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates PI3K/Akt signaling pathway, which is critical for IR development and progression of cirrhosis to hepatocellular carcinoma (HCC). Here, we investigate the role of PTEN in HCV-associated IR and explored the mechanisms by which HCV regulates PTEN. Methods Western blotting was used to detect the levels of insulin signaling pathway components, including insulin receptor substrate-1 (IRS-1), phosphorylated IRS-1 (pIRS-1) at serine 307 (Ser307), both phosphorylated Akt (pAkt) and total Akt. A time-course experiment measuring activation of the insulin signaling pathway was performed to assess the effect of HCV infection on insulin sensitivity by examining the phosphorylation levels of Akt and GSK3β, a downstream target of Akt. Huh7.5.1 cells were transduced with a lentiviral vector expressing PTEN or PTEN shRNA, and IRS-1 and pIRS-1 (Ser307) levels were determined in both HCV-infected and uninfected cells. The pc-JFH1-core plasmid was constructed to explore the underlying mechanisms by which HCV regulated PTEN and therefore IRS-1 levels. Results HCV infection inhibited the insulin signaling pathway by reducing the levels of IRS-1 and pAkt/Akt while increasing phosphorylation of IRS-1 Ser307. In addition, HCV infection decreased the sensitivity to insulin-induced stimulation by inhibiting Akt and GSK3β phosphorylation. Furthermore, PTEN mRNA and protein levels were reduced upon HCV infection as well as transfection with the pc-JFH1-core plasmid. The reduction in IRS-1 level observed in HCV-infected cells was rescued to a limited extent by overexpression of PTEN, which in turn slightly reduced pIRS-1 (Ser307) level. In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN-dependent manner. Conclusions HCV infection suppresses the insulin signaling pathway and promotes IR by repressing PTEN, subsequently leading to decreased levels of IRS-1 and increased levels of pIRS-1 at Ser307. The findings provide new insight on the mechanism of HCV-associated IR.
Collapse
Affiliation(s)
- Ting-ting Gao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhao-ling Qin
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| | - Zhong-tian Qi
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, 200433, China.
| |
Collapse
|
|
36
|
Peyrou M, Bourgoin L, Poher AL, Altirriba J, Maeder C, Caillon A, Fournier M, Montet X, Rohner-Jeanrenaud F, Foti M. Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice. J Hepatol 2015; 62:421-9. [PMID: 25234947 DOI: 10.1016/j.jhep.2014.09.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 09/03/2014] [Accepted: 09/09/2014] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. METHODS Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. RESULTS PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice. CONCLUSIONS Although steatosis develops in LPTEN KO mice, PTEN deficiency in hepatocytes promotes a crosstalk between liver and muscle, as well as adipose tissue, resulting in enhanced insulin sensitivity, improved glucose tolerance and decreased adiposity.
Collapse
Affiliation(s)
- Marion Peyrou
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland
| | - Anne-Laure Poher
- Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland
| | - Jordi Altirriba
- Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland
| | - Christine Maeder
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland
| | - Aurélie Caillon
- Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland
| | - Margot Fournier
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland
| | - Xavier Montet
- Department of Radiology, Faculty of Medicine, University of Geneva, Switzerland
| | - Françoise Rohner-Jeanrenaud
- Department of Internal Medicine Specialties, Division of Endocrinology, Diabetology, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland.
| |
Collapse
|
|
37
|
Boštjančič E, Bandelj E, Luzar B, Poljak M, Glavač D. Hepatic expression of miR-122, miR-126, miR-136 and miR-181a and their correlation to histopathological and clinical characteristics of patients with hepatitis C. J Viral Hepat 2015; 22:146-57. [PMID: 25065618 DOI: 10.1111/jvh.12266] [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: 08/19/2013] [Accepted: 04/03/2014] [Indexed: 12/13/2022]
Abstract
It has been shown for hepatitis C virus (HCV) infection that host miRNAs contribute to the replication of the viral RNA genome. However, the clinical impact of these and many other cellular miRNAs on HCV in humans is still largely unclear. We therefore analysed the expression of miR-122, miR-126, miR-181a and miR-136 in HCV-infected patients. The study included liver biopsies of 65 patients infected with HCV of different genotypes (gt 1, gt 1a, gt 1b, gt 3 and gt 4) and nine noninfected individuals. Expression analysis of miRNAs was performed by qPCR, and they were analysed for differences between patient gender and age, genotypes, stage of fibrosis, grade of inflammation, serum level of liver enzymes, serum viral load, the presence of steatosis and mode of transmission. Different target prediction algorithms were used to search for targets of analyzed miRNAs. Statistical analysis revealed significant up-regulation of miR-136 and down-regulation of miR-126 and miR-181a in patients infected with HCV of different genotypes compared with noninfected individuals. The same expression pattern was observed in different stages and grades of liver disease. miR-122 was up-regulated in women relative to men and associated to portal inflammation, miR-122 and miR-126 correlated with serum HCV load and miR-136 and miR-122 correlated with the presence of steatosis. miR-126 and miR-136 were differentially expressed between different modes of HCV transmission. There were approximately 2000 different targets predicted for all four miRNAs and each of the analyzed miRNAs could be involved in more than a 100 different biochemical pathways. miR-122, miR-126, miR-136 and miR-181a have been shown to be involved in HCV infection with different genotypes. Their expression has been associated with the gender, stage and grade of liver disease, mode of transmission, serum HCV load and the presence of steatosis. Numerous target genes and biochemical pathways are predicted for each of the analyzed miRNAs. All these results suggest their role in HCV-infected liver disease.
Collapse
Affiliation(s)
- E Boštjančič
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | | | | | | |
Collapse
|
|
38
|
Loizides-Mangold U, Clément S, Alfonso-Garcia A, Branche E, Conzelmann S, Parisot C, Potma EO, Riezman H, Negro F. HCV 3a core protein increases lipid droplet cholesteryl ester content via a mechanism dependent on sphingolipid biosynthesis. PLoS One 2014; 9:e115309. [PMID: 25522003 PMCID: PMC4270764 DOI: 10.1371/journal.pone.0115309] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 11/21/2014] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) infected patients often develop steatosis and the HCV core protein alone can induce this phenomenon. To gain new insights into the pathways leading to steatosis, we performed lipidomic profiling of HCV core protein expressing-Huh-7 cells and also assessed the lipid profile of purified lipid droplets isolated from HCV 3a core expressing cells. Cholesteryl esters, ceramides and glycosylceramides, but not triglycerides, increased specifically in cells expressing the steatogenic HCV 3a core protein. Accordingly, inhibitors of cholesteryl ester biosynthesis such as statins and acyl-CoA cholesterol acyl transferase inhibitors prevented the increase of cholesteryl ester production and the formation of large lipid droplets in HCV core 3a-expressing cells. Furthermore, inhibition of de novo sphingolipid biosynthesis by myriocin - but not of glycosphingolipid biosynthesis by miglustat - affected both lipid droplet size and cholesteryl ester level. The lipid profile of purified lipid droplets, isolated from HCV 3a core-expressing cells, confirmed the particular increase of cholesteryl ester. Thus, both sphingolipid and cholesteryl ester biosynthesis are affected by the steatogenic core protein of HCV genotype 3a. These results may explain the peculiar lipid profile of HCV-infected patients with steatosis.
Collapse
Affiliation(s)
- Ursula Loizides-Mangold
- Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Sophie Clément
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| | - Alba Alfonso-Garcia
- University of California Irvine, Beckman Laser Institute, Irvine, California, United States of America
| | - Emilie Branche
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| | - Stéphanie Conzelmann
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| | - Clotilde Parisot
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
| | - Eric O. Potma
- University of California Irvine, Beckman Laser Institute, Irvine, California, United States of America
| | - Howard Riezman
- Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
- Divisions of Gastroenterology and Hepatology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland
- * E-mail:
| |
Collapse
|
|
39
|
Hepatitis C virus and lipid droplets: finding a niche. Trends Mol Med 2014; 21:34-42. [PMID: 25496657 DOI: 10.1016/j.molmed.2014.11.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 11/11/2014] [Accepted: 11/17/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) causes serious liver disease in chronically infected individuals. Infectious virions are released from hepatocytes as lipoprotein complexes, indicating that the virus interacts with very low density lipoprotein (VLDL) assembly to propagate. The primary source of lipid for incorporation into VLDL is cytoplasmic lipid droplets (LDs). This organelle is targeted by two virus-encoded proteins as part of a process essential for virion morphogenesis. Moreover, LDs regulate infection. A common condition in HCV-infected individuals is steatosis, characterized by an accumulation of LDs. The mechanisms underlying development of steatosis include direct effects of the virus on lipid metabolism. This review reveals new insights into HCV infection and a further twist to the growing list of functions performed by LDs.
Collapse
|
|
40
|
Camus G, Schweiger M, Herker E, Harris C, Kondratowicz AS, Tsou CL, Farese RV, Herath K, Previs SF, Roddy TP, Pinto S, Zechner R, Ott M. The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem 2014; 289:35770-80. [PMID: 25381252 DOI: 10.1074/jbc.m114.587816] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Liver steatosis is a common health problem associated with hepatitis C virus (HCV) and an important risk factor for the development of liver fibrosis and cancer. Steatosis is caused by triglycerides (TG) accumulating in lipid droplets (LDs), cellular organelles composed of neutral lipids surrounded by a monolayer of phospholipids. The HCV nucleocapsid core localizes to the surface of LDs and induces steatosis in cultured cells and mouse livers by decreasing intracellular TG degradation (lipolysis). Here we report that core at the surface of LDs interferes with the activity of adipose triglyceride lipase (ATGL), the key lipolytic enzyme in the first step of TG breakdown. Expressing core in livers or mouse embryonic fibroblasts of ATGL(-/-) mice no longer decreases TG degradation as observed in LDs from wild-type mice, supporting the model that core reduces lipolysis by engaging ATGL. Core must localize at LDs to inhibit lipolysis, as ex vivo TG hydrolysis is impaired in purified LDs coated with core but not when free core is added to LDs. Coimmunoprecipitation experiments revealed that core does not directly interact with the ATGL complex but, unexpectedly, increased the interaction between ATGL and its activator CGI-58 as well as the recruitment of both proteins to LDs. These data link the anti-lipolytic activity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of both proteins with LDs.
Collapse
Affiliation(s)
- Gregory Camus
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Martina Schweiger
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Eva Herker
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany
| | - Charles Harris
- UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Division of Endocrinology Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Andrew S Kondratowicz
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Chia-Lin Tsou
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158
| | - Robert V Farese
- UCSF Liver Center, University of California, San Francisco, California 94158, Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, and
| | - Kithsiri Herath
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Stephen F Previs
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Thomas P Roddy
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Shirly Pinto
- Merck Research Laboratories, Merck and Co., Inc., Kenilworth, New Jersey 07065
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Melanie Ott
- From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, UCSF Liver Center, University of California, San Francisco, California 94158, Department of Medicine, University of California, San Francisco, California 94158,
| |
Collapse
|
|
41
|
Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014; 61:S69-78. [PMID: 25443347 DOI: 10.1016/j.jhep.2014.08.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
Collapse
Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
| |
Collapse
|
|
42
|
Bao W, Florea L, Wu N, Wang Z, Banaudha K, Qian J, Houzet L, Kumar R, Kumar A. Loss of nuclear PTEN in HCV-infected human hepatocytes. Infect Agent Cancer 2014; 9:23. [PMID: 25075209 PMCID: PMC4114100 DOI: 10.1186/1750-9378-9-23] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 06/26/2014] [Indexed: 02/04/2023] Open
Abstract
Background Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11. Methods The intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots of nuclear and cytoplasmic proteins. Effects of PTEN depletion were examined by comparing expression arrays of uninfected cells with either HCV-infected or vmr11-transfected cells. Target genes suggested by array analyses were validated by Western blot. The influence of nuclear PTEN deficiency on virus production was determined by quantitative analysis of HCV genomic RNA in culture media of infected hepatocytes. Results Import of PTEN to the nucleus relies on the interaction of Transportin-2 and PTEN proteins; we show that depletion of Transportin-2 by HCV infection or by the introduction of vmr11 in uninfected cells results in reduced nuclear PTEN. In turn, nuclear PTEN insufficiency correlates with increased virus production and the induction of γ-H2AX, a marker of DNA double-strand breaks and genomic instability. Conclusion An HCV-derived small non-coding RNA inhibits Transportin-2 and PTEN translocation to the nucleus, suggesting a direct viral role in hepatic oncogenesis.
Collapse
Affiliation(s)
- Wenjie Bao
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| | - Liliana Florea
- McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Ningbin Wu
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| | - Zhao Wang
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| | - Krishna Banaudha
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| | - Jason Qian
- Current address: Metabolism Branch, NIH, Bethesda, MD, USA
| | - Laurent Houzet
- Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, USA ; Current address: INSERM U1085-IRSET, Universite de Rennes1, Institut Federatif de Recherche 140, Rennes, France
| | - Rakesh Kumar
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| | - Ajit Kumar
- Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA
| |
Collapse
|
|
43
|
Li HC, Ma HC, Yang CH, Lo SY. Production and pathogenicity of hepatitis C virus core gene products. World J Gastroenterol 2014; 20:7104-7122. [PMID: 24966583 PMCID: PMC4064058 DOI: 10.3748/wjg.v20.i23.7104] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/05/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and its infection is also associated with insulin resistance and type 2 diabetes mellitus. HCV, belonging to the Flaviviridae family, is a small enveloped virus whose positive-stranded RNA genome encoding a polyprotein. The HCV core protein is cleaved first at residue 191 by the host signal peptidase and further cleaved by the host signal peptide peptidase at about residue 177 to generate the mature core protein (a.a. 1-177) and the cleaved peptide (a.a. 178-191). Core protein could induce insulin resistance, steatosis and even hepatocellular carcinoma through various mechanisms. The peptide (a.a. 178-191) may play a role in the immune response. The polymorphism of this peptide is associated with the cellular lipid drop accumulation, contributing to steatosis development. In addition to the conventional open reading frame (ORF), in the +1 frame, an ORF overlaps with the core protein-coding sequence and encodes the alternative reading frame proteins (ARFP or core+1). ARFP/core+1/F protein could enhance hepatocyte growth and may regulate iron metabolism. In this review, we briefly summarized the current knowledge regarding the production of different core gene products and their roles in viral pathogenesis.
Collapse
|
|
44
|
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] [Accepted: 04/03/2014] [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
|
|
45
|
Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology 2014; 59:2403-12. [PMID: 24155107 DOI: 10.1002/hep.26905] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 10/18/2013] [Indexed: 12/14/2022]
Abstract
UNLABELLED Genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to-treat infection, with higher cure rates (∼70%) than other viral genotypes with the standard combination of pegylated interferon-α and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. CONCLUSION Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments.
Collapse
Affiliation(s)
- Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | | |
Collapse
|
|
46
|
Rohwedder A, Zhang Q, Rudge SA, Wakelam MJO. Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. J Cell Sci 2014; 127:3104-15. [PMID: 24876224 DOI: 10.1242/jcs.145854] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
It is unclear how changes in lipid droplet size and number are regulated - for example, it is not known whether this involves a signalling pathway or is directed by cellular lipid uptake. Here, we show that oleic acid stimulates lipid droplet formation by activating the long-chain fatty acid receptor FFAR4, which signals through a pertussis-toxin-sensitive G-protein signalling pathway involving phosphoinositide 3-kinase (PI3-kinase), AKT (also known as protein kinase B) and phospholipase D (PLD) activities. This initial lipid droplet formation is not dependent upon exogenous lipid, whereas the subsequent more sustained increase in the number of lipid droplets is dependent upon lipid uptake. These two mechanisms of lipid droplet formation point to distinct potential intervention points.
Collapse
Affiliation(s)
- Arndt Rohwedder
- Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
| | - Qifeng Zhang
- Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
| | - Simon A Rudge
- Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
| | - Michael J O Wakelam
- Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
| |
Collapse
|
|
47
|
Abstract
The lifecycle of several viruses is intimately tied to the lipid metabolism of their host cells, and lipid droplets (LDs) have emerged as crucial organelles in the propagation of these viral infections. Investigating the roles of LDs in viral infection requires expertise in both virology and cell metabolism pertaining to LDs. In this review, we offer an updated list and review of the multiples methods we have used in our laboratory to study both the role of LDs in viral infection and the effect of viral infection on cellular LDs, with a special emphasis on hepatitis C virus and other RNA viruses.
Collapse
|
|
48
|
Hepatitis C virus and microRNAs: miRed in a host of possibilities. Curr Opin Virol 2014; 7:1-10. [PMID: 24721496 DOI: 10.1016/j.coviro.2014.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 12/17/2022]
Abstract
It is well-established that the host microRNA (miRNA) milieu has a significant influence on the etiology of disease. In the context of viruses, such as hepatitis C virus (HCV), microRNAs have been shown to influence viral life cycles both directly, through interactions with the viral genome, and indirectly, through regulation of critical virus-associated host pathways. Several miRNA profiling studies have demonstrated that HCV infection aberrantly regulates a significant number of human miRNA. However, the biological relevance of these modulations remains poorly understood. In this review, we summarize recent research that has shed light on the pro-viral and anti-viral roles of HCV-induced changes in human miRNA expression and their significance in the development of HCV related sequelae and response to therapy.
Collapse
|
|
49
|
Carter R, Mouralidarane A, Soeda J, Ray S, Pombo J, Saraswati R, Novelli M, Fusai G, Rappa F, Saracino C, Pazienza V, Poston L, Taylor PD, Vinciguerra M, Oben JA. Non-alcoholic fatty pancreas disease pathogenesis: a role for developmental programming and altered circadian rhythms. PLoS One 2014; 9:e89505. [PMID: 24657938 PMCID: PMC3962337 DOI: 10.1371/journal.pone.0089505] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/21/2014] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Emerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock--molecular core circadian genes (CCG) in the generation of NAFPD. DESIGN Female C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined. RESULTS Offspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (-4.818, p<0.01), REV-ERB-α (-1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (-0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG. CONCLUSIONS Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.
Collapse
Affiliation(s)
- Rebeca Carter
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
| | - Angelina Mouralidarane
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
| | - Junpei Soeda
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
| | - Shuvra Ray
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Joaquim Pombo
- Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom
| | - Ruma Saraswati
- Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom
- Department of Pathology, University College London, London, United Kingdom
| | - Marco Novelli
- Department of Pathology, University College London, London, United Kingdom
| | - Giuseppe Fusai
- Hepatobiliary and Liver Transplant Unit, Royal Free Hospital, University College London, London, United Kingdom
| | - Francesca Rappa
- Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
| | - Chiara Saracino
- Department of Medical Sciences, Gastroenterology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
| | - Valerio Pazienza
- Department of Medical Sciences, Gastroenterology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
| | - Lucilla Poston
- Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom
| | - Paul D. Taylor
- Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
- Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
- Department of Medical Sciences, Gastroenterology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
| | - Jude A. Oben
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
- * E-mail:
| |
Collapse
|
|
50
|
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
|