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Rani A, Stadler JT, Marsche G. HDL-based therapeutics: A promising frontier in combating viral and bacterial infections. Pharmacol Ther 2024; 260:108684. [PMID: 38964560 DOI: 10.1016/j.pharmthera.2024.108684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/03/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
Low levels of high-density lipoprotein (HDL) and impaired HDL functionality have been consistently associated with increased susceptibility to infection and its serious consequences. This has been attributed to the critical role of HDL in maintaining cellular lipid homeostasis, which is essential for the proper functioning of immune and structural cells. HDL, a multifunctional particle, exerts pleiotropic effects in host defense against pathogens. It functions as a natural nanoparticle, capable of sequestering and neutralizing potentially harmful substances like bacterial lipopolysaccharides. HDL possesses antiviral activity, preventing viruses from entering or fusing with host cells, thereby halting their replication cycle. Understanding the complex relationship between HDL and the immune system may reveal innovative targets for developing new treatments to combat infectious diseases and improve patient outcomes. This review aims to emphasize the role of HDL in influencing the course of bacterial and viral infections and its and its therapeutic potential.
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Affiliation(s)
- Alankrita Rani
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria
| | - Julia T Stadler
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria
| | - Gunther Marsche
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Styria, Austria; BioTechMed-Graz, Mozartgasse 12/II, 8010 Graz, Styria, Austria.
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2
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Duan S, Qin N, Pi J, Sun P, Gao Y, Liu L, Li Z, Li Y, Shi L, Gao Q, Qiu Y, Tang S, Wang CH, Chen TY, Wang ST, Young KC, Sun HY. Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition. Hepatology 2023; 78:1182-1199. [PMID: 37013405 DOI: 10.1097/hep.0000000000000185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/26/2022] [Indexed: 04/05/2023]
Abstract
BACKGROUND AND AIMS Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis. APPROACH AND RESULTS By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus. CONCLUSIONS ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.
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Affiliation(s)
- Shuangdi Duan
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Nong Qin
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Jiayi Pi
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Pei Sun
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Yating Gao
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Lamei Liu
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
| | - Zenghui Li
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Ya Li
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
| | - Liyang Shi
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
| | - Qiang Gao
- School of Biomedical Sciences, Hunan University, Changsha, China
| | - Ye Qiu
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Songqing Tang
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China
| | - Chun-Hsiang Wang
- Division of Gastroenterology, Tainan Municipal Hospital, Tainan, Taiwan
| | - Tzu-Ying Chen
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sin-Tian Wang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Yu Sun
- Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Zhang L, Liu X, Mao J, Sun Y, Gao Y, Bai J, Jiang P. Porcine reproductive and respiratory syndrome virus-mediated lactate facilitates virus replication by targeting MAVS. Vet Microbiol 2023; 284:109846. [PMID: 37586149 DOI: 10.1016/j.vetmic.2023.109846] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/06/2023] [Accepted: 08/07/2023] [Indexed: 08/18/2023]
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important causative agents in the pig industry worldwide, causing reproductive failure in sows and respiratory problems in growing pigs. Glucose metabolism is a major pathway for energy production and interacts with many cellular processes, such as innate immunity response. It is unclear whether PRRSV infection can use the glucose metabolic pathway to generate immune escape in favor of viral replication. Here, we found that high glucose promotes PRRSV replication and glycolysis, and inhibits poly(I:C)-induced RLR signaling. Conversely, inhibition of the glycolysis pathway significantly promoted poly(I:C)-induced RLR signaling and inhibited PRRSV replication, suggesting that glycolysis promotes PRRSV replication by inhibiting interferon signaling. Furthermore, PRRSV promotes glycolysis to produce lactate, which acts as a key metabolite to promote viral replication by inhibiting RLR signaling by targeting MAVS. And the glycolytic inhibitors targeting HK2 and LDHA in glycolysis could inhibit PRRSV replication. Taken together, these findings suggested that PRRSV infection promotes glycolysis to produce lactate, which targets MAVS to inhibit RLR signaling and thus promote viral replication. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.
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Affiliation(s)
- Lujie Zhang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xing Liu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Jian Mao
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yangyang Sun
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yanni Gao
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Juan Bai
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou 225009, PR China
| | - Ping Jiang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou 225009, PR China.
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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.
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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
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Demirbas S, Yerlikaya FH, Yosunkaya S, Can U, Celalettin K. The investigation of levels of endothelial cell-specific molecule, progranuline, clusterin, and human epididymis protein 4 in the differential diagnosis of malignant pleural effusions. Medicine (Baltimore) 2022; 101:e32471. [PMID: 36595996 PMCID: PMC9803442 DOI: 10.1097/md.0000000000032471] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Progranulin (PGRN), endothelial cell-specific molecule-1, clusterin (CLU), and human epididymis protein 4 (HE-4) are novel proteins reported to have diagnostic and prognostic potential in lung cancer. Here, we aimed to identify the markers with high sensitivity and specificity in distinguishing malignant pleural fluids from other pleural fluids. METHODS This prospective, descriptive study was conducted at a medical faculty hospital between 2016 and 2019. The study population consisted of 90 patients <18 years of age with pleural effusion (PE). Levels of pleural fluids of PGRN, endothelial cell-specific molecule-1, CLU, and HE-4 were measured with enzyme-linked immunosorbent assay kits under the manufacturer's manual. RESULTS Of 90 patients, 54 were men, and 36 were women (mean age 65 ± 16 years). Of pleural fluids investigated, 23 (25%) and 67 (74%) were transudates and exudates, respectively. Of exudates, while 27 (40%) and 19 (28%) were parapneumonic PE and tuberculous PE, respectively, 20 (29%) were malignant pleural effusion (MPE). Levels of all biomarkers in exudate fluids were found significantly higher than those of transudate fluids. CLU, HE-4, and PGRN levels in MPE were also found significantly higher than benign fluids (P < .05). Cutoff values were achieved by receiver operating characteristics analysis for CLU, HE-4, and PGRN to distinguish between malignant and benign groups. For diagnosis of MPE, the sensitivity and specificity values were found as 0.66 and 0.67 for a cutoff value of CLU of 18.29 mg/L (P = .00), as 0.76 and 0.76 for a cutoff value of HE-4 of 9.33 mg/L (P = .00), and as 0.66 and 0.67 for a cutoff value of PGRN of 105.91 mg/L (P = .001). CONCLUSION HE-4 having high sensitivity and specificity can be a potential diagnostic marker in distinguishing between malignant and benign effusions, and these findings can constitute a basis for future research.
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Affiliation(s)
- Soner Demirbas
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
- * Correspondence: Soner Demirbas, Meram Faculty of Medicine, Department of Chest Diseases, Necmetin Erbakan University, Selçuklu, Konya 42080, Turkey (e-mail: )
| | - Fatma Hümeyra Yerlikaya
- Department of Biochemistry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Sebnem Yosunkaya
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
| | - Ummugulsum Can
- Department of Biochemistry, Konya Training and Research Hospital, Konya, Turkey
| | - Korkmaz Celalettin
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
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Naryzhny S, Ronzhina N, Zorina E, Kabachenko F, Klopov N, Zgoda V. Construction of 2DE Patterns of Plasma Proteins: Aspect of Potential Tumor Markers. Int J Mol Sci 2022; 23:ijms231911113. [PMID: 36232415 PMCID: PMC9569744 DOI: 10.3390/ijms231911113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
The use of tumor markers aids in the early detection of cancer recurrence and prognosis. There is a hope that they might also be useful in screening tests for the early detection of cancer. Here, the question of finding ideal tumor markers, which should be sensitive, specific, and reliable, is an acute issue. Human plasma is one of the most popular samples as it is commonly collected in the clinic and provides noninvasive, rapid analysis for any type of disease including cancer. Many efforts have been applied in searching for “ideal” tumor markers, digging very deep into plasma proteomes. The situation in this area can be improved in two ways—by attempting to find an ideal single tumor marker or by generating panels of different markers. In both cases, proteomics certainly plays a major role. There is a line of evidence that the most abundant, so-called “classical plasma proteins”, may be used to generate a tumor biomarker profile. To be comprehensive these profiles should have information not only about protein levels but also proteoform distribution for each protein. Initially, the profile of these proteins in norm should be generated. In our work, we collected bibliographic information about the connection of cancers with levels of “classical plasma proteins”. Additionally, we presented the proteoform profiles (2DE patterns) of these proteins in norm generated by two-dimensional electrophoresis with mass spectrometry and immunodetection. As a next step, similar profiles representing protein perturbations in plasma produced in the case of different cancers will be generated. Additionally, based on this information, different test systems can be developed.
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Affiliation(s)
- Stanislav Naryzhny
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
- Correspondence: ; Tel.: +7-911-176-4453
| | - Natalia Ronzhina
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
| | - Elena Zorina
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
| | - Fedor Kabachenko
- Institute of Biomedical Systems and Biotechnology, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia
| | - Nikolay Klopov
- Petersburg Institute of Nuclear Physics (PNPI) of National Research Center “Kurchatov Institute”, 188300 Gatchina, Russia
| | - Victor Zgoda
- Institute of Biomedical Chemistry, Pogodinskaya, 10, 119121 Moscow, Russia
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Andújar-Vera F, García-Fontana C, Sanabria-de la Torre R, González-Salvatierra S, Martínez-Heredia L, Iglesias-Baena I, Muñoz-Torres M, García-Fontana B. Identification of Potential Targets Linked to the Cardiovascular/Alzheimer's Axis through Bioinformatics Approaches. Biomedicines 2022; 10:389. [PMID: 35203598 PMCID: PMC8962298 DOI: 10.3390/biomedicines10020389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 12/23/2022] Open
Abstract
The identification of common targets in Alzheimer's disease (AD) and cardiovascular disease (CVD) in recent years makes the study of the CVD/AD axis a research topic of great interest. Besides aging, other links between CVD and AD have been described, suggesting the existence of common molecular mechanisms. Our study aimed to identify common targets in the CVD/AD axis. For this purpose, genomic data from calcified and healthy femoral artery samples were used to identify differentially expressed genes (DEGs), which were used to generate a protein-protein interaction network, where a module related to AD was identified. This module was enriched with the functionally closest proteins and analyzed using different centrality algorithms to determine the main targets in the CVD/AD axis. Validation was performed by proteomic and data mining analyses. The proteins identified with an important role in both pathologies were apolipoprotein E and haptoglobin as DEGs, with a fold change about +2 and -2, in calcified femoral artery vs healthy artery, respectively, and clusterin and alpha-2-macroglobulin as close interactors that matched in our proteomic analysis. However, further studies are needed to elucidate the specific role of these proteins, and to evaluate its function as biomarkers or therapeutic targets.
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Affiliation(s)
- Francisco Andújar-Vera
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Department of Computer Science and Artificial Intelligence, University of Granada, 18071 Granada, Spain
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), 18014 Granada, Spain
| | - Cristina García-Fontana
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio of Granada, 18016 Granada, Spain
- CIBERFES, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Raquel Sanabria-de la Torre
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Department of Medicine, University of Granada, 18016 Granada, Spain
| | - Sheila González-Salvatierra
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio of Granada, 18016 Granada, Spain
- Department of Medicine, University of Granada, 18016 Granada, Spain
| | - Luis Martínez-Heredia
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Department of Medicine, University of Granada, 18016 Granada, Spain
| | - Iván Iglesias-Baena
- Fundación para la Investigación Biosanitaria de Andalucía Oriental-Alejandro Otero (FIBAO), 18012 Granada, Spain;
| | - Manuel Muñoz-Torres
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio of Granada, 18016 Granada, Spain
- CIBERFES, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Medicine, University of Granada, 18016 Granada, Spain
| | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada, 18012 Granada, Spain; (R.S.-d.l.T.); (S.G.-S.); (L.M.-H.); (B.G.-F.)
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio of Granada, 18016 Granada, Spain
- CIBERFES, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Sun HY, Chen TY, Tan YC, Wang CH, Young KC. Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses. Commun Biol 2021; 4:564. [PMID: 33980978 PMCID: PMC8115332 DOI: 10.1038/s42003-021-02093-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/06/2021] [Indexed: 11/08/2022] Open
Abstract
The risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.
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Affiliation(s)
- Hung-Yu Sun
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China
- Institute of Pathogen Biology and Immunology of College of Biology, Hunan Provincial Key Laboratory of Medical Virology, Hunan University, Changsha, China
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tzu-Ying Chen
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ching Tan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hsiang Wang
- Division of Gastroenterology, Tainan Municipal Hospital, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Zhang J, Shen Y, Xu X, Dai Y, Li J. Transcriptome Analysis of the Liver and Muscle Tissues of Black Carp (Mylopharyngodon piceus) of Different Growth Rates. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2020; 22:706-716. [PMID: 32914204 DOI: 10.1007/s10126-020-09994-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/25/2020] [Indexed: 06/11/2023]
Abstract
In this study, we used RNA-seq to analyze the muscle and liver tissues of black carps (Mylopharyngodon piceus) of different growth rates from the same batch to evaluate their growth traits. We have two groups; they are the black carp group with fast-growth rate and the slow-growth rate. A total of 23,132 genes were enriched in the Gene Ontology analysis, and 285 related pathways were found in the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The KEGG pathway analysis showed significant differences in the expression of some genes involved in growth- and development-related metabolic pathways such as the FoxO signaling pathway, p53 signaling pathway, PI3K-Akt signaling pathway, apoptosis, TGF-β signaling pathway, and insulin signaling pathway. The numbers of differentially expressed genes in muscle and liver are 1913 and 1775. Nine of the differently expressed genes involved in the different growth traits and accuracy of the transcriptome data were validated using quantitative real-time PCR. We found that the expression levels of some growth-related genes were significantly higher in the fast-growth rate black carps than in the slow-growth rate black carps. The large number of transcriptome sequences obtained in this study has enriched the black carp gene resources, and the obtained differentially expressed genes and related pathway analysis provide valuable information for understanding the growth traits of the black carp.
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Affiliation(s)
- Jiahua Zhang
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rual Affairs, Shanghai Ocean University, Shanghai, China
| | - Yubang Shen
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rual Affairs, Shanghai Ocean University, Shanghai, China.
- Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China.
- College of Aquaculture and Life science, Shanghai Ocean University, Shanghai, 201306, China.
| | - Xiaoyan Xu
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rual Affairs, Shanghai Ocean University, Shanghai, China
- Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Yafan Dai
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rual Affairs, Shanghai Ocean University, Shanghai, China
| | - Jiale Li
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rual Affairs, Shanghai Ocean University, Shanghai, China.
- Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China.
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China.
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10
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Chen Z, Fan Z, Dou X, Zhou Q, Zeng G, Liu L, Chen W, Lan R, Liu W, Ru G, Yu L, He QY, Chen L. Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity. Am J Cancer Res 2020; 10:11520-11534. [PMID: 33052230 PMCID: PMC7545994 DOI: 10.7150/thno.44829] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 09/04/2020] [Indexed: 12/31/2022] Open
Abstract
Purpose: Clinical success of precision medicine is severely limited by de novo or acquired drug resistance. It remains a clinically unmet need to treat these patients. Tumor suppressor genes (TSGs) play a critical role in tumorigenesis and impact the therapeutic effect of various treatments. Experimental Design: Using clinical data, in vitro cell line data and in vivo mouse model data, we revealed the tumor suppressive role of Clusterin in lung cancer. We also delineated the signaling cascade elicited by loss of function of CLU in NSCLC cells and tested precision medicine for CLU deficient lung cancers. Results: CLU is a potent and clinically relevant TSG in lung cancer. Mechanistically, CLU inhibits TGFBR1 to recruit TRAF6/TAB2/TAK1 complex and thus inhibits activation of TAK1- NF-κB signaling axis. Lung cancer cells with loss of function of CLU show exquisite sensitivity to TAK1 inhibitors. Importantly, we show that a significant portion of Kras mutation positive NSCLC patients are concurrently deficient of CLU and that TAK1 kinase inhibitor synergizes with existing drugs to treat this portion of lung cancers patients. Conclusions: Combinational treatment with TAK1 inhibitor and MEK1/2 inhibitor effectively shrank Kras mutation positive and CLU deficient NSCLC tumors. Moreover, we put forward a concept that loss of function of a TSG rewires signaling network and thereby creates an Achilles' heel in tumor cells which could be exploited in precision medicine.
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11
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Fu N, Du H, Li D, Lu Y, Li W, Wang Y, Kong L, Du J, Zhao S, Ren W, Han F, Wang R, Zhang Y, Nan Y. Clusterin contributes to hepatitis C virus-related hepatocellular carcinoma by regulating autophagy. Life Sci 2020; 256:117911. [DOI: 10.1016/j.lfs.2020.117911] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/24/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
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12
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Silva BSC, DiGiovanni L, Kumar R, Carmichael RE, Kim PK, Schrader M. Maintaining social contacts: The physiological relevance of organelle interactions. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118800. [PMID: 32712071 PMCID: PMC7377706 DOI: 10.1016/j.bbamcr.2020.118800] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/12/2020] [Accepted: 07/19/2020] [Indexed: 02/07/2023]
Abstract
Membrane-bound organelles in eukaryotic cells form an interactive network to coordinate and facilitate cellular functions. The formation of close contacts, termed "membrane contact sites" (MCSs), represents an intriguing strategy for organelle interaction and coordinated interplay. Emerging research is rapidly revealing new details of MCSs. They represent ubiquitous and diverse structures, which are important for many aspects of cell physiology and homeostasis. Here, we provide a comprehensive overview of the physiological relevance of organelle contacts. We focus on mitochondria, peroxisomes, the Golgi complex and the plasma membrane, and discuss the most recent findings on their interactions with other subcellular organelles and their multiple functions, including membrane contacts with the ER, lipid droplets and the endosomal/lysosomal compartment.
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Affiliation(s)
- Beatriz S C Silva
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK
| | - Laura DiGiovanni
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Rechal Kumar
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK
| | - Ruth E Carmichael
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK.
| | - Peter K Kim
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.
| | - Michael Schrader
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK.
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13
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Cai H, Yao W, Huang J, Xiao J, Chen W, Hu L, Mai R, Liang M, Chen D, Jiang N, Zhou L, Peng T. Apolipoprotein M, identified as a novel hepatitis C virus (HCV) particle associated protein, contributes to HCV assembly and interacts with E2 protein. Antiviral Res 2020; 177:104756. [PMID: 32119870 DOI: 10.1016/j.antiviral.2020.104756] [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: 08/19/2019] [Revised: 01/18/2020] [Accepted: 02/25/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases such as steatosis, cirrhosis, and hepatocellular carcinoma. HCV particles have been found to associate with apolipoproteins, and apolipoproteins not only participate in the HCV life cycle, but also help HCV escape recognition by the host immune system, which pose challenges for the development of both HCV treatments and vaccines. However, no study has reported on the comprehensive identification of apolipoprotein associations with HCV particles. In the present study, we performed proteome analysis by affinity purification coupled with mass spectrometry (AP-MS) to comprehensively identify the apolipoprotein associations with HCV particles, and ApoM was first identified by AP-MS besides the previously reported ApoE, ApoB, ApoA-I and ApoC-I. Additionally, three assays further confirmed that ApoM was a novel virus particle associated protein. We also showed that ApoM was required for HCV production, especially for the assembly/release step of HCV life cycle. Furthermore, ApoM interacted with the HCV E2 protein. Finally, HCV infection reduced ApoM expression both in vitro and in vivo. Collectively, our study demonstrates that ApoM, identified as a novel HCV particle associated protein, contributes to HCV assembly/release and interacts with HCV E2 protein. It provides new insights on how HCV and the host apolipoproteins are reciprocally influenced and lays a basis for research in developing innovative antiviral strategies.
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Affiliation(s)
- Hua Cai
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Wenxia Yao
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
| | - Jingxian Huang
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Jing Xiao
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Wenli Chen
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Longbo Hu
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Runming Mai
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Mengdi Liang
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Di Chen
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Nan Jiang
- The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Zhou
- The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tao Peng
- Guangzhou Hoffmann Institute of Immunology, College of Basic Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
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14
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Su F, GM A, Palgunachari MN, White CR, Stessman H, Wu Y, Vadgama J, Pietras R, Nguyen D, Reddy ST, Farias-Eisner R. Bovine HDL and Dual Domain HDL-Mimetic Peptides Inhibit Tumor Development in Mice. JOURNAL OF CANCER RESEARCH AND THERAPEUTIC ONCOLOGY 2020; 8:101. [PMID: 32462055 PMCID: PMC7252215 DOI: 10.17303/jcrto.2020.8.101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
A growing body of literature supports the role of apolipoproteins present in HDL in the treatment of pro-inflammatory diseases including cancer. We examined whether bovine HDL (bHDL) and three dual-domain peptides, namely AEM-28 and its analog AEM-28-2, and HM-10/10, affect tumor growth and development in mouse models of ovarian and colon cancer. We demonstrate that bHDL inhibits mouse colorectal cancer cell line CT26-mediated lung tumor development, and mouse ovarian cancer cell line ID8-mediated tumor burden. We also demonstrate that, although to different degrees, dual-domain peptides inhibit cell viability of mouse and human ovarian and colon cancer cell lines, but not that of normal human colonic epithelial cells or NIH3T3 mouse fibroblasts. Dual-domain peptides administered subcutaneously or in a chow diet decrease CT26 cell-mediated tumor burden, tumor growth, and tumor dissemination in BALB/c mice. Plasma levels of lysophosphatidic acid (LPA) are significantly reduced in mice that received bHDL and the dual-domain peptides, suggesting that reduction by effecting accumulation and/or synthesis of pro-inflammatory lipids may be one of the mechanisms for the inhibition of tumor development by bHDL and the dual-domain peptides. Our studies suggest that therapeutics based on apolipoproteins present in HDL may be novel agents for the treatment of epithelial adenocarcinomas of the ovary and colon.
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Affiliation(s)
- Feng Su
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Anantharamaiah GM
- Department of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | - C. Roger White
- Department of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Holly Stessman
- Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA
| | - Yanyuan Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Department of Internal Medicine, Charles Drew University, Los Angeles, CA 90059, USA
| | - Jay Vadgama
- Department of Internal Medicine, Charles Drew University, Los Angeles, CA 90059, USA
- Jonsson Comprehensive Cancer Center, the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Richard Pietras
- Jonsson Comprehensive Cancer Center, the University of California at Los Angeles, Los Angeles, CA 90095, USA
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Dorothy Nguyen
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Srinivasa T. Reddy
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, the University of California at Los Angeles, Los Angeles, CA 90095, USA
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Robin Farias-Eisner
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, the University of California at Los Angeles, Los Angeles, CA 90095, USA
- Department of Obstetrics, Gynecology, School of Medicine, Creighton University, Omaha, NE 68178, USA
- Hereditary Cancer Center, School of Medicine, Creighton University, Omaha, NE 68178, USA
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15
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New Diagnostic Approaches to Viral Sexually Transmitted Infections. Sex Transm Infect 2020. [DOI: 10.1007/978-3-030-02200-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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16
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Prinz WA, Toulmay A, Balla T. The functional universe of membrane contact sites. Nat Rev Mol Cell Biol 2020; 21:7-24. [PMID: 31732717 PMCID: PMC10619483 DOI: 10.1038/s41580-019-0180-9] [Citation(s) in RCA: 425] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2019] [Indexed: 12/13/2022]
Abstract
Organelles compartmentalize eukaryotic cells, enhancing their ability to respond to environmental and developmental changes. One way in which organelles communicate and integrate their activities is by forming close contacts, often called 'membrane contact sites' (MCSs). Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of critical roles in cells than was initially thought. Indeed, functions for MCSs in intracellular signalling (particularly calcium signalling, reactive oxygen species signalling and lipid signalling), autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have now been reported.
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Affiliation(s)
- William A Prinz
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Alexandre Toulmay
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Tamas Balla
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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17
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Etifoxine, a TSPO Ligand, Worsens Hepatitis C-Related Insulin Resistance but Relieves Lipid Accumulation. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3102414. [PMID: 30984779 PMCID: PMC6432734 DOI: 10.1155/2019/3102414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/22/2018] [Accepted: 01/23/2019] [Indexed: 11/17/2022]
Abstract
Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.
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18
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Li C, Ming Y, Wang Z, Xu Q, Yao L, Xu D, Tang Y, Lei X, Li X, Mao Y. GADD45α alleviates acetaminophen-induced hepatotoxicity by promoting AMPK activation. Cell Mol Life Sci 2019; 76:129-145. [PMID: 30151693 PMCID: PMC11105285 DOI: 10.1007/s00018-018-2912-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 07/31/2018] [Accepted: 08/22/2018] [Indexed: 02/08/2023]
Abstract
As an analgesic and antipyretic drug, acetaminophen (APAP) is commonly used and known to be safe at therapeutic doses. In many countries, the overuse of APAP provokes acute liver injury and even liver failure. APAP-induced liver injury (AILI) is the most used experimental model of drug-induced liver injury (DILI). Here, we have demonstrated elevated levels of growth arrest and DNA damage-inducible 45α (GADD45α) in the livers of patients with DILI/AILI, in APAP-injured mouse livers and in APAP-treated hepatocytes. GADD45α exhibited a protective effect against APAP-induced liver injury and alleviated the accumulation of small lipid droplets in vitro and in vivo. We found that GADD45α promoted the activation of AMP-activated protein kinase α and induced fatty acid beta-oxidation, tricarboxylic acid cycle (TCA) and glycogenolysis-related gene expression after APAP exposure. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that GADD45α increased the levels of TCA cycle metabolites. Co-immunoprecipitation analysis showed that Ppp2cb, a catalytic subunit of protein phosphatase 2A, could interact directly with GADD45α. Our results indicate that hepatocyte GADD45α might represent a therapeutic target to prevent and rescue liver injury caused by APAP.
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Affiliation(s)
- Chunmin Li
- Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanan Ming
- Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhengyang Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Qingling Xu
- Department of Hepatology, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Lvfeng Yao
- Department of Hepatology, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Dongke Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Yingyue Tang
- Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaohong Lei
- Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaobo Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
| | - Yimin Mao
- Division of Gastroenterology and Hepatology, School of Medicine, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
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19
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Kanannejad Z, Gharesi-Fard B. Difference in the seminal plasma protein expression in unexplained infertile men with successful and unsuccessful in vitro fertilisation outcome. Andrologia 2018; 51:e13158. [DOI: 10.1111/and.13158] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 08/13/2018] [Accepted: 08/22/2018] [Indexed: 12/19/2022] Open
Affiliation(s)
- Zahra Kanannejad
- Department of Immunology; Shiraz University of Medical Sciences; Shiraz Iran
| | - Behrouz Gharesi-Fard
- Department of Immunology; Shiraz University of Medical Sciences; Shiraz Iran
- Infertility Research Center; Shiraz University of Medical Sciences; Shiraz Iran
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20
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Martins AS, Martins IC, Santos NC. Methods for Lipid Droplet Biophysical Characterization in Flaviviridae Infections. Front Microbiol 2018; 9:1951. [PMID: 30186265 PMCID: PMC6110928 DOI: 10.3389/fmicb.2018.01951] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 08/02/2018] [Indexed: 01/14/2023] Open
Abstract
Lipid droplets (LDs) are intracellular organelles for neutral lipid storage, originated from the endoplasmic reticulum. They play an essential role in lipid metabolism and cellular homeostasis. In fact, LDs are complex organelles, involved in many more cellular processes than those initially proposed. They have been extensively studied in the context of LD-associated pathologies. In particular, LDs have emerged as critical for virus replication and assembly. Viruses from the Flaviviridae family, namely dengue virus (DENV), hepatitis C virus (HCV), West Nile virus (WNV), and Zika virus (ZIKV), interact with LDs to usurp the host lipid metabolism for their own viral replication and pathogenesis. In general, during Flaviviridae infections it is observed an increasing number of host intracellular LDs. Several viral proteins interact with LDs during different steps of the viral life cycle. The HCV core protein and DENV capsid protein, extensively interact with LDs to regulate their replication and assembly. Detailed studies of LDs in viral infections may contribute for the development of possible inhibitors of key steps of viral replication. Here, we reviewed different techniques that can be used to characterize LDs isolated from infected or non-infected cells. Microscopy studies have been commonly used to observe LDs accumulation and localization in infected cell cultures. Fluorescent dyes, which may affect LDs directly, are widely used to probe LDs but there are also approaches that do not require the use of fluorescence, namely stimulated Raman scattering, electron and atomic force microscopy-based approaches. These three are powerful techniques to characterize LDs morphology. Raman scattering microscopy allows studying LDs in a single cell. Electron and atomic force microscopies enable a better characterization of LDs in terms of structure and interaction with other organelles. Other biophysical techniques, such as dynamic light scattering and zeta potential are also excellent to characterize LDs in terms of size in a simple and fast way and test possible LDs interaction with viral proteins. These methodologies are reviewed in detail, in the context of viral studies.
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Affiliation(s)
- Ana S Martins
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Ivo C Martins
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Nuno C Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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21
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Viral dynamics of persistent hepatitis C virus infection in high-sensitive reporter cells resemble patient's viremia. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2018; 51:446-455. [DOI: 10.1016/j.jmii.2016.11.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 10/08/2016] [Accepted: 11/07/2016] [Indexed: 01/06/2023]
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22
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Odun-Ayo F, Moodley J, Naicker T. Urinary clusterin and glutathione-s-transferase levels in HIV positive normotensive and preeclamptic pregnancies. Hypertens Pregnancy 2018; 37:160-167. [PMID: 30024772 DOI: 10.1080/10641955.2018.1498881] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
OBJECTIVE To determine the level and effect of urinary clusterin (CLU) and glutathione-s-transferase (GST) proteins in normotensive and preeclamptic pregnant women with HIV infection. METHODS The urine concentration of CLU and GST in normotensive (n = 38) and preeclamptic pregnant (n = 38) women stratified by HIV status were estimated using the Bio-Plex® ProTM immunoassay. RESULTS Across the group, a significant down-regulation of CLU (p = 0.039) with a reduced trend in GST was shown in HIV positive preeclampsia. CONCLUSION HIV infection affects the activity of urinary CLU protein in HIV positive preeclampsia. However, the cytoprotective role of these proteins neutralizes the oxidative radicals associated with preeclampsia development through complement response in HIV infection.
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Affiliation(s)
- Frederick Odun-Ayo
- a Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences , University of KwaZulu-Natal , Durban , South Africa
| | - Jagidesa Moodley
- b Women's Health and HIV Research Unit, Nelson R Mandela School of Medicine , University of KwaZulu-Natal , Durban , South Africa
| | - Thajasvarie Naicker
- a Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences , University of KwaZulu-Natal , Durban , South Africa
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23
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Sun HY, Cheng PN, Tseng CY, Tsai WJ, Chiu YC, Young KC. Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection. Gut 2018; 67:1342-1350. [PMID: 28615303 DOI: 10.1136/gutjnl-2017-313832] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/28/2017] [Accepted: 04/30/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Lipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment. DESIGN Twenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unit RESULTS: DAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism. CONCLUSION The DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.
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Affiliation(s)
- Hung-Yu Sun
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chiung-Ying Tseng
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Jen Tsai
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Lin YM, Sun HY, Chiu WT, Su HC, Chien YC, Chong LW, Chang HC, Bai CH, Young KC, Tsao CW. Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation. Viruses 2018; 10:v10020057. [PMID: 29385741 PMCID: PMC5850364 DOI: 10.3390/v10020057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/17/2018] [Accepted: 01/26/2018] [Indexed: 02/06/2023] Open
Abstract
Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-α (Wy14643) and -γ (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/β/γ blocked the activation of VDR. PPAR-β (linoleic acid) reversed the inhibition of NO release, whereas PPAR-γ (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.
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Affiliation(s)
- Yu-Min Lin
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Hung-Yu Sun
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Hui-Chen Su
- Department of Pharmacy, Chi-Mei Medical Center, Tainan 71004, Taiwan.
| | - Yu-Chieh Chien
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
- Department of Long Term Care, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.
| | - Lee-Won Chong
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Hung-Chuen Chang
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Chyi-Huey Bai
- Department of Public Health, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Chiung-Wen Tsao
- Department of Long Term Care, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.
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25
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Zhang J, Lan Y, Sanyal S. Modulation of Lipid Droplet Metabolism-A Potential Target for Therapeutic Intervention in Flaviviridae Infections. Front Microbiol 2017; 8:2286. [PMID: 29234310 PMCID: PMC5712332 DOI: 10.3389/fmicb.2017.02286] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 11/06/2017] [Indexed: 12/21/2022] Open
Abstract
Lipid droplets (LDs) are endoplasmic reticulum (ER)-related dynamic organelles that store and regulate fatty acids and neutral lipids. They play a central role in cellular energy storage, lipid metabolism and cellular homeostasis. It has become evident that viruses have co-evolved in order to exploit host lipid metabolic pathways. This is especially characteristic of the Flaviviridae family, including hepatitis C virus (HCV) and several flaviviruses. Devoid of an appropriate lipid biosynthetic machinery of their own, these single-strand positive-sense RNA viruses can induce dramatic changes in host metabolic pathways to establish a favorable environment for viral multiplication and acquire essential components to facilitate their assembly and traffic. Here we have reviewed the current knowledge on the intracellular life cycle of those from the Flaviviridae family, with particular emphasis on HCV and dengue virus (DENV), and their association with the biosynthesis and metabolism of LDs, with the aim to identify potential antiviral targets for development of novel therapeutic interventions.
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Affiliation(s)
- Jingshu Zhang
- HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Yun Lan
- HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Sumana Sanyal
- HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
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26
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Hinkelbein J, Jansen S, Iovino I, Kruse S, Meyer M, Cirillo F, Drinhaus H, Hohn A, Klein C, Robertis ED, Beutner D. Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum. Int J Mol Sci 2017; 18:E1882. [PMID: 28858246 PMCID: PMC5618531 DOI: 10.3390/ijms18091882] [Citation(s) in RCA: 12] [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: 07/27/2017] [Revised: 08/21/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
Hypobaric hypoxia (HH) during airline travel induces several (patho-) physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min) in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE) and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF). Biological functions of regulated proteins were identified using functional network analysis (GeneMania®, STRING®, and Perseus® software). In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU) was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades "regulation of haemostasis" (four proteins), "metabolism" (five proteins), and "leukocyte mediated immune response" (five proteins). Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight), analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis.
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Affiliation(s)
- Jochen Hinkelbein
- Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, 50937 Cologne, Germany.
| | - Stefanie Jansen
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50937 Cologne, Germany.
| | - Ivan Iovino
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Via S. Pansini, 5-80131 Napoli, Italy.
| | - Silvia Kruse
- Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, 50937 Cologne, Germany.
| | - Moritz Meyer
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50937 Cologne, Germany.
| | - Fabrizio Cirillo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Via S. Pansini, 5-80131 Napoli, Italy.
| | - Hendrik Drinhaus
- Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, 50937 Cologne, Germany.
| | - Andreas Hohn
- Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, 50937 Cologne, Germany.
| | - Corinna Klein
- CECAD Lipidomics & Proteomics Facilities, CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
| | - Edoardo De Robertis
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Via S. Pansini, 5-80131 Napoli, Italy.
| | - Dirk Beutner
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, 50937 Cologne, Germany.
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27
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Lavie M, Dubuisson J. Interplay between hepatitis C virus and lipid metabolism during virus entry and assembly. Biochimie 2017. [PMID: 28630011 DOI: 10.1016/j.biochi.2017.06.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a major public health problem worldwide. In most cases, HCV infection becomes chronic, leading to the development of liver diseases that range from fibrosis to cirrhosis and hepatocellular carcinoma. Due to its medical importance, the HCV life cycle has been deeply characterized, and a unique feature of this virus is its interplay with lipids. Accordingly, all the steps of the virus life cycle are influenced by the host lipid metabolism. Indeed, due to their association with host lipoproteins, HCV particles have a unique lipid composition. Furthermore, the biogenesis pathway of very low density lipoproteins has been shown to be involved in HCV morphogenesis with apolipoprotein E being an essential element for the production of infectious HCV particles. Association of viral components with host cytoplasmic lipid droplets is also central to the HCV morphogenesis process. Finally, due to its close connection with host lipoproteins, HCV particle also uses several lipoprotein receptors to initiate its infectious cycle. In this review, we outline the way host lipoproteins participate to HCV particle composition, entry and assembly.
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Affiliation(s)
- Muriel Lavie
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection & Immunity of Lille, F-59000, Lille, France
| | - Jean Dubuisson
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection & Immunity of Lille, F-59000, Lille, France.
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28
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Karaca I, Wagner H, Ramirez A. Suche nach Risikogenen bei der Alzheimer-Erkrankung. DER NERVENARZT 2017; 88:744-750. [DOI: 10.1007/s00115-017-0354-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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29
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Falcón V, Acosta-Rivero N, González S, Dueñas-Carrera S, Martinez-Donato G, Menéndez I, Garateix R, Silva JA, Acosta E, Kourı J. Ultrastructural and biochemical basis for hepatitis C virus morphogenesis. Virus Genes 2017; 53:151-164. [PMID: 28233195 DOI: 10.1007/s11262-017-1426-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 01/06/2017] [Indexed: 12/16/2022]
Abstract
Chronic infection with HCV is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. One of the least understood steps in the HCV life cycle is the morphogenesis of new viral particles. HCV infection alters the lipid metabolism and generates a variety of microenvironments in the cell cytoplasm that protect viral proteins and RNA promoting viral replication and assembly. Lipid droplets (LDs) have been proposed to link viral RNA synthesis and virion assembly by physically associating these viral processes. HCV assembly, envelopment, and maturation have been shown to take place at specialized detergent-resistant membranes in the ER, rich in cholesterol and sphingolipids, supporting the synthesis of luminal LDs-containing ApoE. HCV assembly involves a regulated allocation of viral and host factors to viral assembly sites. Then, virus budding takes place through encapsidation of the HCV genome and viral envelopment in the ER. Interaction of ApoE with envelope proteins supports the viral particle acquisition of lipids and maturation. HCV secretion has been suggested to entail the ion channel activity of viral p7, several components of the classical trafficking and autophagy pathways, ESCRT, and exosome-mediated export of viral RNA. Here, we review the most recent advances in virus morphogenesis and the interplay between viral and host factors required for the formation of HCV virions.
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Affiliation(s)
- Viviana Falcón
- Centro de Ingeniería Genética y Biotecnología, P.O. Box 6162, C.P. 10600, Havana, Cuba.
| | - Nelson Acosta-Rivero
- National Center for Scientific Research, P.O. Box 6414, 10600, Havana, Cuba.
- Centre for Protein Studies, Faculty of Biology, University of Havana, 10400, Havana, Cuba.
| | | | | | | | - Ivon Menéndez
- Centro de Ingeniería Genética y Biotecnología, P.O. Box 6162, C.P. 10600, Havana, Cuba
| | - Rocio Garateix
- Centro de Ingeniería Genética y Biotecnología, P.O. Box 6162, C.P. 10600, Havana, Cuba
| | - José A Silva
- Centro de Ingeniería Genética y Biotecnología, P.O. Box 6162, C.P. 10600, Havana, Cuba
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30
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Balena-Borneman J, Ambalavanan N, Tiwari HK, Griffin RL, Halloran B, Askenazi D. Biomarkers associated with bronchopulmonary dysplasia/mortality in premature infants. Pediatr Res 2017; 81:519-525. [PMID: 27893721 PMCID: PMC5373977 DOI: 10.1038/pr.2016.259] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 10/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) portends lifelong organ impairment and death. Our ability to predict BPD in first days of life is limited, but could be enhanced using novel biomarkers. METHODS Using an available clinical and urine biomarker database obtained from a prospective 113 infant cohort (birth weight ≤1,200 g and/or gestational age ≤31 wk), we evaluated the independent association of 14 urine biomarkers with BPD/mortality. RESULTS Two of the 14 urine biomarkers were independently associated with BPD/mortality after controlling for gestational age (GA), small for gestational age (SGA), and intubation status. The best performing protein was clusterin, a ubiquitously expressed protein and potential sensor of oxidative stress associated with lung function in asthma patients. When modeling for BPD/mortality, the independent odds ratio for maximum adjusted urine clusterin was 9.2 (95% CI: 3.3-32.8, P < 0.0001). In this model, clinical variables (GA, intubation status, and SGA) explained 38.3% of variance; clusterin explained an additional 9.2%, while albumin explained an additional 3.4%. The area under the curve incorporating clinical factors and biomarkers was 0.941. CONCLUSION Urine clusterin and albumin may improve our ability to predict BPD/mortality. Future studies are needed to validate these findings and determine their clinical usefulness.
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Affiliation(s)
| | | | - Hemant K. Tiwari
- Department of Biostatistics, University of Alabama at Birmingham,
Birmingham, AL, USA
| | - Russell L. Griffin
- Department of Epidemiology, University of Alabama at Birmingham,
Birmingham, AL, USA
| | - Brian Halloran
- Department of Pediatrics, University of Alabama at Birmingham,
Birmingham, AL, USA
| | - David Askenazi
- Department of Pediatrics, University of Alabama at Birmingham,
Birmingham, AL, USA,Corresponding author: David Askenazi MD, MSPH,
Department of Pediatrics, Division of Pediatric Nephrology, University of
Alabama at Birmingham, ACC 516, 1600 7th Avenue South, Birmingham, AL 35233,
United States. Phone: (+1) 205-638-9781. Fax: (+1) 205-975-7051.
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31
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Sun HY, Lin CC, Tsai PJ, Tsai WJ, Lee JC, Tsao CW, Cheng PN, Wu IC, Chiu YC, Chang TT, Young KC. Lipoprotein lipase liberates free fatty acids to inhibit HCV infection and prevent hepatic lipid accumulation. Cell Microbiol 2016; 19. [PMID: 27665576 DOI: 10.1111/cmi.12673] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 09/15/2016] [Accepted: 09/20/2016] [Indexed: 02/06/2023]
Abstract
Lipoprotein lipase (LPL) has been identified as an anti-hepatitis C virus (HCV) host factor, but the cellular mechanism remains elusive. Here, we investigated the cellular mechanism of LPL involving in anti-HCV. The functional activation of peroxisome proliferator-activated receptor (PPAR) α signal by LPL transducing into hepatocytes was investigated in HCV-infected cells, primary human hepatocytes, and in HCV-core transgenic mice. The result showed that the levels of transcriptional transactivity and nuclear translocation of PPARα in Huh7 cells and primary human hepatocytes were elevated by physiologically ranged LPL treatment of either very-low density lipoprotein or HCV particles. The LPL-induced hepatic PPARα activation was weakened by blocking the LPL enzymatic activity, and by preventing the cellular uptake of free unsaturated fatty acids with either albumin chelator or silencing of CD36 translocase. The knockdowns of PPARα and CD36 reversed the LPL-mediated suppression of HCV infection. Furthermore, treatment with LPL, like the direct activation of PPARα, not only reduced the levels of apolipoproteins B, E, and J, which are involved in assembly and release of HCV virions, but also alleviated hepatic lipid accumulation induced by core protein. HCV-core transgenic mice exhibited more hepatic miR-27b, which negatively regulates PPARα expression, than did the wild-type controls. The induction of LPL activity by fasting in the core transgenic mice activated PPARα downstream target genes that are involved in fatty acid β-oxidation. Taken together, our study reveals dual beneficial outcomes of LPL in anti-HCV and anti-steatosis and shed light on the control of chronic hepatitis C in relation to LPL modulators.
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Affiliation(s)
- Hung-Yu Sun
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Chieh Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Ju Tsai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Jen Tsai
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiung-Wen Tsao
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Chin Wu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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32
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Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection. J Virol 2016; 90:9632-9643. [PMID: 27535051 DOI: 10.1128/jvi.01353-16] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 08/03/2016] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting approximately 170 million people worldwide. HCV assembly is tightly associated with the lipoprotein pathway. Exchangeable apolipoprotein E (apoE) is incorporated on infectious HCV virions and is important for infectious HCV virion morphogenesis and entry. Moreover, the virion apoE level is positively correlated with its ability to escape E2 antibody neutralization. However, the role of apoE exchange in the HCV life cycle is unclear. In this study, the relationship between apoE expression and cell permissiveness to HCV infection was assessed by infecting apoE knockdown and derived apoE rescue cell lines with HCV. Exchange of apoE between lipoproteins and HCV lipoviral particles (LVPs) was evaluated by immunoprecipitation, infectivity testing, and viral genome quantification. Cell and heparin column binding assays were applied to determine the attachment efficiency of LVPs with different levels of incorporated apoE. The results showed that cell permissiveness for HCV infection was determined by exogenous apoE-associated lipoproteins. Furthermore, apoE exchange did occur between HCV LVPs and lipoproteins, which was important to maintain a high apoE level on LVPs. Lipid-free apoE was capable of enhancing HCV infectivity for apoE knockdown cells but not apoE rescue cells. A higher apoE level on LVPs conferred more efficient LVP attachment to both the cell surface and heparin beads. This study revealed that exogenous apoE-incorporating lipoproteins from uninfected hepatocytes safeguarded the apoE level of LVPs for more efficient attachment during HCV infection. IMPORTANCE In this study, a neglected but important role of apoE exchange in HCV LVP infectivity after virus assembly and release was identified. The data indicated that apoE expression level in uninfected cells is important for high permissiveness to HCV infection. Secreted apoE-associated lipoprotein specifically enhances infection of HCV LVPs. apoE exchange between HCV LVP and lipoproteins is important to maintain an adequate apoE level on LVPs for their efficient attachment to cell surface. These data defined for the first time an extracellular role of exchangeable apoE in HCV infection and suggested that exchangeable apolipoproteins reach a natural equilibrium between HCV LVPs and lipoprotein particles, which provides a new perspective to the understanding of the heterogeneity of HCV LVPs in composition.
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33
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Human Choline Kinase-α Promotes Hepatitis C Virus RNA Replication through Modulation of Membranous Viral Replication Complex Formation. J Virol 2016; 90:9075-95. [PMID: 27489281 PMCID: PMC5044849 DOI: 10.1128/jvi.00960-16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/20/2016] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) infection reorganizes cellular membranes to create an active viral replication site named the membranous web (MW). The role that human choline kinase-α (hCKα) plays in HCV replication remains elusive. Here, we first showed that hCKα activity, not the CDP-choline pathway, promoted viral RNA replication. Confocal microscopy and subcellular fractionation of HCV-infected cells revealed that a small fraction of hCKα colocalized with the viral replication complex (RC) on the endoplasmic reticulum (ER) and that HCV infection increased hCKα localization to the ER. In the pTM-NS3-NS5B model, NS3-NS5B expression increased the localization of the wild-type, not the inactive D288A mutant, hCKα on the ER, and hCKα activity was required for effective trafficking of hCKα and NS5A to the ER. Coimmunoprecipitation showed that hCKα was recruited onto the viral RC presumably through its binding to NS5A domain 1 (D1). hCKα silencing or treatment with CK37, an hCKα activity inhibitor, abolished HCV-induced MW formation. In addition, hCKα depletion hindered NS5A localization on the ER, interfered with NS5A and NS5B colocalization, and mitigated NS5A-NS5B interactions but had no apparent effect on NS5A-NS4B and NS4B-NS5B interactions. Nevertheless, hCKα activity was not essential for the binding of NS5A to hCKα or NS5B. These findings demonstrate that hCKα forms a complex with NS5A and that hCKα activity enhances the targeting of the complex to the ER, where hCKα protein, not activity, mediates NS5A binding to NS5B, thereby promoting functional membranous viral RC assembly and viral RNA replication. IMPORTANCE HCV infection reorganizes the cellular membrane to create an active viral replication site named the membranous web (MW). Here, we report that human choline kinase-α (hCKα) acts as an essential host factor for HCV RNA replication. A fraction of hCKα colocalizes with the viral replication complex (RC) on the endoplasmic reticulum (ER) in HCV-infected cells. NS3-NS5B expression increases ER localization of wild-type, but not D288A mutant, hCKα, and hCKα activity facilitates the transport of itself and NS5A to the ER. Silencing or inactivation of hCKα abrogates MW formation. Moreover, hCKα is recruited by NS5A independent of hCKα activity, presumably through binding to NS5A D1. hCKα activity then mediates the ER targeting of the hCKα-NS5A complex. On the ER membrane, hCKα protein, per se, induces NS5A binding to NS5B, thereby promoting membranous RC formation and viral RNA replication. Our study may benefit the development of hCKα-targeted anti-HCV therapeutics.
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34
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Zhang J, Miao C, Xu A, Zhao K, Qin Z, Li X, Liang C, Hua Y, Chen W, Zhang C, Liu Y, Su S, Wang Z, Liu B. Prognostic Role of Secretory Clusterin in Multiple Human Malignant Neoplasms: A Meta-Analysis of 26 Immunohistochemistry Studies. PLoS One 2016; 11:e0161150. [PMID: 27532124 PMCID: PMC4988765 DOI: 10.1371/journal.pone.0161150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 08/01/2016] [Indexed: 01/11/2023] Open
Abstract
Secretory clusterin (sCLU) is a potential prognostic tumour biomarker, but results of different sCLU studies are inconsistent. We conducted this meta-analysis to evaluate the precise predictive value of sCLU. Qualified studies were identified by performing online searches in PubMed, EMBASE, and Web of Science. The selected articles were divided into three groups based on scoring method for clusterin detection. Pooled hazard ratios (HRs) with 95% confidence interval (CI) for patient survival and disease recurrence were calculated to determine the correlation between sCLU expression and cancer prognosis. Heterogeneity was assessed using I2 statistics, and specific heterogeneity in different groups was analysed. Elevated sCLU was significantly associated with recurrence-free survival in groups 1 and 3 (group 1: pooled HR = 1.35, 95% CI = 1.01 to 1.79; group 3: pooled HR = 1.80, 95% CI = 1.22 to 2.65). However, clusterin expression was not associated with overall survival in all three groups. Results showed that only the heterogeneity of group 2 was very strong (p = 0.013, I2 = 76.3%), in which the specimens were scored through sCLU staining intensity only. sCLU is a potential biomarker for tumour prognosis, and IHC methods can be more standardised if both intensity and staining proportion are considered.
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Affiliation(s)
- Jianzhong Zhang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Chenkui Miao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Aiming Xu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Kai Zhao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Zhiqiang Qin
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Xiao Li
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Chao Liang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Yibo Hua
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Wei Chen
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Chao Zhang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Yiyang Liu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Shifeng Su
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Zengjun Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
| | - Bianjiang Liu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China
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35
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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.
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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.
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36
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Fukuhara T, Ono C, Puig-Basagoiti F, Matsuura Y. Roles of Lipoproteins and Apolipoproteins in Particle Formation of Hepatitis C Virus. Trends Microbiol 2016; 23:618-629. [PMID: 26433694 DOI: 10.1016/j.tim.2015.07.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/07/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
More than 160 million people worldwide are infected with hepatitis C virus (HCV), and cirrhosis and hepatocellular carcinoma induced by HCV infection are life-threatening diseases. HCV takes advantage of many aspects of lipid metabolism for an efficient propagation in hepatocytes. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Recent analyses have revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we summarize the roles of lipid metabolism in the life cycle of HCV.
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Affiliation(s)
- Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Chikako Ono
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Francesc Puig-Basagoiti
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
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37
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Grassi G, Di Caprio G, Fimia GM, Ippolito G, Tripodi M, Alonzi T. Hepatitis C virus relies on lipoproteins for its life cycle. World J Gastroenterol 2016; 22:1953-1965. [PMID: 26877603 PMCID: PMC4726671 DOI: 10.3748/wjg.v22.i6.1953] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 10/19/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects over 150 million people worldwide. In most cases, HCV infection becomes chronic causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. Viral persistence and pathogenesis are due to the ability of HCV to deregulate specific host processes, mainly lipid metabolism and innate immunity. In particular, HCV exploits the lipoprotein machineries for almost all steps of its life cycle. The aim of this review is to summarize current knowledge concerning the interplay between HCV and lipoprotein metabolism. We discuss the role played by members of lipoproteins in HCV entry, replication and virion production.
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38
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Khachatoorian R, French SW. Chaperones in hepatitis C virus infection. World J Hepatol 2016; 8:9-35. [PMID: 26783419 PMCID: PMC4705456 DOI: 10.4254/wjh.v8.i1.9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 10/01/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases: (1) binding and internalization; (2) cytoplasmic release and uncoating; (3) viral polyprotein translation and processing; (4) RNA genome replication; (5) encapsidation (packaging) and assembly; and (6) virus morphogenesis (maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.
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Cellular stress responses in hepatitis C virus infection: Mastering a two-edged sword. Virus Res 2015; 209:100-17. [PMID: 25836277 DOI: 10.1016/j.virusres.2015.03.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 03/21/2015] [Accepted: 03/23/2015] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) infection affects chronically more than 150 million humans worldwide. Chronic HCV infection causes severe liver disease and hepatocellular carcinoma. While immune response-mediated events are major players in HCV pathogenesis, the impact that viral replication has on cellular homeostasis is increasingly recognized as a necessary contributor to pathological manifestations of HCV infection such as steatosis, insulin-resistance or liver cancer. In this review, we will briefly overview the different cellular stress pathways that are induced by hepatitis C virus infection, the response that the cell promotes to attempt regaining homeostasis or to induce dysfunctional cell death, and how the virus co-opts these response mechanisms to promote both viral replication and survival of the infected cell. We will review the role of unfolded protein and oxidative stress responses as well as the role of auto- and mitophagy in HCV infection. Finally, we will discuss the recent discovery of a cellular chaperone involved in stress responses, the sigma-1 receptor, as a cellular factor required at the onset of HCV infection and the potential molecular events underlying the proviral role of this cellular factor in HCV infection.
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40
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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: 79] [Impact Index Per Article: 7.2] [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.
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