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      Osteoprotegerin deficiency aggravates methionine–choline-deficient diet-induced nonalcoholic steatohepatitis in mice

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          Abstract

          Clinical studies have shown that osteoprotegerin (OPG) is reduced in patients with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms are unclear. The current study focuses on the role of OPG in the NASH pathogenesis. OPG knockout mice and wild-type control mice fed a methionine choline-deficient diet (MCD) for 4 weeks resulted in an animal model of NASH. Measurement of triglycerides (TG) in serum and liver to assess steatosis. Hematoxylin eosin (HE), Sirius Red and Masson staining were used to assess the liver damage. Transcriptome sequencing analysis, qPCR and western blot were to analyze changes in lipid metabolism and inflammation-related indicators in the liver. In vivo knockout of OPG resulted in a reduction of TG levels in the liver and a significant increase in serum ALT and AST. The expression of inflammatory factors and fibrosis genes was significantly upregulated in the livers of OPG knockout mice. Transcriptome sequencing analysis showed that OPG knockout significantly enhanced MCD diet-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Mechanistically, OPG may inhibit MAPK signaling pathway activity by upregulating the expression of dual specificity phosphatase 14 (DUSP14), thereby reducing inflammatory injury. OPG could regulate the activity of the MAPK signaling pathway via DUSP14, thus regulating the expression of some inflammatory factors in NASH, it may be a promising target for the treatment of NASH.

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          Most cited references45

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          TBtools - an integrative toolkit developed for interactive analyses of big biological data

          The rapid development of high-throughput sequencing techniques has led biology into the big-data era. Data analyses using various bioinformatics tools rely on programming and command-line environments, which are challenging and time-consuming for most wet-lab biologists. Here, we present TBtools (a Toolkit for Biologists integrating various biological data-handling tools), a stand-alone software with a user-friendly interface. The toolkit incorporates over 130 functions, which are designed to meet the increasing demand for big-data analyses, ranging from bulk sequence processing to interactive data visualization. A wide variety of graphs can be prepared in TBtools using a new plotting engine ("JIGplot") developed to maximize their interactive ability; this engine allows quick point-and-click modification of almost every graphic feature. TBtools is platform-independent software that can be run under all operating systems with Java Runtime Environment 1.6 or newer. It is freely available to non-commercial users at https://github.com/CJ-Chen/TBtools/releases.
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            Non-alcoholic fatty liver disease

            Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or without mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and related complications. Although the leading causes of death in people with NAFLD are cardiovascular disease and extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and overall mortality, and can be assessed with combinations of non-invasive tests. Patients with cirrhosis should be screened for hepatocellular carcinoma and oesophageal varices. There is currently no approved therapy for NAFLD, although several drugs are in advanced stages of development. Because of the complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is likely to be required for many patients with NAFLD. Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD.
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              Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention

              One quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC) in the USA, France and the UK. Globally, the prevalence of NAFLD-related HCC is likely to increase concomitantly with the growing obesity epidemic. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among patients with non-cirrhotic NAFLD is lower, approximately 0.1 to 1.3 per 1,000 patient-years. Although the incidence of NAFLD-related HCC is lower than that of HCC of other aetiologies such as hepatitis C, more people have NAFLD than other liver diseases. Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC. Emerging evidence indicates that reduced immune surveillance, increased gut inflammation and gut dysbiosis are potential key steps in tumorigenesis. In this Review, we discuss the global epidemiology, projections and risk factors for NAFLD-related HCC, and propose preventive strategies to tackle this growing problem.
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                Author and article information

                Contributors
                xianxiangzhangcqu@163.com
                xiaoheluo@163.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                23 February 2023
                23 February 2023
                2023
                : 13
                : 3194
                Affiliations
                [1 ]GRID grid.190737.b, ISNI 0000 0001 0154 0904, Department of Laboratory Medicine, Chongqing University Three Gorges Hospital, School of Medicine, , Chongqing University, ; No. 165, Xincheng Avenue, Wanzhou District, Chongqing, 404000 China
                [2 ]GRID grid.190737.b, ISNI 0000 0001 0154 0904, The Center of Clinical Research of Endocrinology and Metabolic Diseases in Chongqing, , Chongqing University Three Gorges Hospital, ; Chongqing, 404100 China
                [3 ]GRID grid.190737.b, ISNI 0000 0001 0154 0904, Department of Endocrinology, , Chongqing University Three Gorges Hospital, ; Chongqing, 404100 China
                [4 ]GRID grid.190737.b, ISNI 0000 0001 0154 0904, Chongqing Municipality Clinical Research Center for Geriatric Diseases, , Chongqing University Three Gorges Hospital, ; Chongqing, 404000 China
                Article
                30001
                10.1038/s41598-023-30001-7
                9950492
                36823220
                6dc31455-0368-40c9-8ffa-63e2d9d50df9
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 November 2022
                : 14 February 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005230, Natural Science Foundation of Chongqing;
                Award ID: cstc2020jcyj-msxmX0950
                Award ID: cstc2019jcyj-msxmX0823
                Award Recipient :
                Funded by: Wan Zhou District Science and Technology Planning Project
                Award ID: wzstc-2018008
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81900525
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2021M690178
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012226, Fundamental Research Funds for the Central Universities;
                Award ID: 2021CDJYGRH-008
                Award Recipient :
                Funded by: Doctoral Research Fund of Chongqing University Three Gorges Central Hospital
                Award ID: 2017BSKYQDJJ06
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2023

                Uncategorized
                endocrine system and metabolic diseases,gastrointestinal diseases
                Uncategorized
                endocrine system and metabolic diseases, gastrointestinal diseases

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