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      Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis

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          Abstract

          Aim

          We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk.

          Methods

          Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed.

          Results

          A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels.

          Conclusions

          Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.

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          Most cited references38

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          The lipid droplet is an important organelle for hepatitis C virus production.

          The lipid droplet (LD) is an organelle that is used for the storage of neutral lipids. It dynamically moves through the cytoplasm, interacting with other organelles, including the endoplasmic reticulum (ER). These interactions are thought to facilitate the transport of lipids and proteins to other organelles. The hepatitis C virus (HCV) is a causative agent of chronic liver diseases. HCV capsid protein (Core) associates with the LD, envelope proteins E1 and E2 reside in the ER lumen, and the viral replicase is assumed to localize on ER-derived membranes. How and where HCV particles are assembled, however, is poorly understood. Here, we show that the LD is involved in the production of infectious virus particles. We demonstrate that Core recruits nonstructural (NS) proteins and replication complexes to LD-associated membranes, and that this recruitment is critical for producing infectious viruses. Furthermore, virus particles were observed in close proximity to LDs, indicating that some steps of virus assembly take place around LDs. This study reveals a novel function of LDs in the assembly of infectious HCV and provides a new perspective on how viruses usurp cellular functions.
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            Is Open Access

            Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases

            Low-density lipoprotein (LDL) plays a key role in the development and progression of atherosclerosis and cardiovascular disease. LDL consists of several subclasses of particles with different sizes and densities, including large buoyant (lb) and intermediate and small dense (sd) LDLs. It has been well documented that sdLDL has a greater atherogenic potential than that of other LDL subfractions and that sdLDL cholesterol (sdLDL-C) proportion is a better marker for prediction of cardiovascular disease than that of total LDL-C. Circulating sdLDL readily undergoes multiple atherogenic modifications in blood plasma, such as desialylation, glycation, and oxidation, that further increase its atherogenicity. Modified sdLDL is a potent inductor of inflammatory processes associated with cardiovascular disease. Several laboratory methods have been developed for separation of LDL subclasses, and the results obtained by different methods can not be directly compared in most cases. Recently, the development of homogeneous assays facilitated the LDL subfraction analysis making possible large clinical studies evaluating the significance of sdLDL in the development of cardiovascular disease. Further studies are needed to establish guidelines for sdLDL evaluation and correction in clinical practice.
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              Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version.

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: Supervision
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: MethodologyRole: Supervision
                Role: MethodologyRole: Supervision
                Role: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: Supervision
                Role: MethodologyRole: Supervision
                Role: Data curation
                Role: Data curation
                Role: MethodologyRole: Supervision
                Role: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 December 2018
                2018
                : 13
                : 12
                : e0209615
                Affiliations
                [1 ] Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
                [2 ] Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
                [3 ] Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
                [4 ] Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine Hokkaido University, Sapporo, Hokkaido, Japan
                Policlinico Universitario Campus Bio-Medico, ITALY
                Author notes

                Competing Interests: Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K, grants and endowments from MSD K. K and Chugai Pharmaceutical Co., Ltd, and a research grant from Gilead Sciences Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb. The other authors have nothing to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-2953-6242
                Article
                PONE-D-18-25038
                10.1371/journal.pone.0209615
                6303061
                30576386
                4747c57b-74a4-4fd6-b15e-7ee8e82edf61
                © 2018 Kawagishi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 September 2018
                : 28 November 2018
                Page count
                Figures: 5, Tables: 3, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 16fk0210102h0001, and 17fk0210106h0501
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 16K09334
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 17fk0210102h0001
                Award Recipient :
                Goki Suda received the following fundings: The Japan Agency for Medical Research and Development (AMED), Grant Number 16fk0210102h0001, 17fk0210106h0501, URL https://www.amed.go.jp/; and Japan Society for the Promotion of Science (JSPS) KAKENHI, Grant number 16K09334, URL https://www.jsps.go.jp/. Naoya Skamoto received funding from the Japan Agency for Medical Research and Development (AMED). Grant number is 17fk0210102h0001. URL is https://www.amed.go.jp/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Fatty Liver
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Anatomical Pathology
                Cytopathology
                Steatosis
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
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                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Organisms
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                Viral pathogens
                Flaviviruses
                Hepacivirus
                Hepatitis C virus
                Biology and life sciences
                Microbiology
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                Microbial pathogens
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                Hepatitis viruses
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                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
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                Hepatitis viruses
                Hepatitis C virus
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Hepatitis viruses
                Hepatitis C virus
                Medicine and Health Sciences
                Metabolic Disorders
                Dyslipidemia
                Medicine and Health Sciences
                Vascular Medicine
                Atherosclerosis
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Liver Fibrosis
                Medicine and Health Sciences
                Cardiovascular Medicine
                Cardiovascular Diseases
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Medicine and Health Sciences
                Physiology
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                All relevant data are within the manuscript and its Supporting Information files.

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