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Article

Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity

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Research Group Molecular Nutritional Medicine, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
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Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
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Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany
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German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany
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Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
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Clinic for Nutritional Medicine, 10625 Berlin, Germany
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Institute of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany
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German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
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i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
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Department of Microscopy & Cryo-Electron Microscopy, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
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German Center for Cardiovascular Research (DZHK), 13347 Berlin, Germany
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Centre for Obesity and Metabolic Surgery, Vivantes Hospital, 13509 Berlin, Germany
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Helios Klinikum Berlin-Buch, 13125 Berlin, Germany
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Division of Endocrinology and Diabetology, Department of Internal Medicine, Spital Bülach, 8180 Bülach, Switzerland
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German Diabetes Center, 40225 Duesseldorf, Germany
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Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium
*
Author to whom correspondence should be addressed.
Academic Editors: Tommy Nilsson, Peter Metrakos and Anthoula Lazaris
Cells 2021, 10(5), 1048; https://doi.org/10.3390/cells10051048
Received: 8 February 2021 / Revised: 14 April 2021 / Accepted: 27 April 2021 / Published: 29 April 2021
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of NAFLD and HCC)
Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis. View Full-Text
Keywords: WISP-1/CCN4; CCN proteins; adipokine; obesity; liver; fibrosis; inflammation; hepatic stellate cells WISP-1/CCN4; CCN proteins; adipokine; obesity; liver; fibrosis; inflammation; hepatic stellate cells
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MDPI and ACS Style

Pivovarova-Ramich, O.; Loske, J.; Hornemann, S.; Markova, M.; Seebeck, N.; Rosenthal, A.; Klauschen, F.; Castro, J.P.; Buschow, R.; Grune, T.; Lange, V.; Rudovich, N.; Ouwens, D.M. Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity. Cells 2021, 10, 1048. https://doi.org/10.3390/cells10051048

AMA Style

Pivovarova-Ramich O, Loske J, Hornemann S, Markova M, Seebeck N, Rosenthal A, Klauschen F, Castro JP, Buschow R, Grune T, Lange V, Rudovich N, Ouwens DM. Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity. Cells. 2021; 10(5):1048. https://doi.org/10.3390/cells10051048

Chicago/Turabian Style

Pivovarova-Ramich, Olga, Jennifer Loske, Silke Hornemann, Mariya Markova, Nicole Seebeck, Anke Rosenthal, Frederick Klauschen, José P. Castro, René Buschow, Tilman Grune, Volker Lange, Natalia Rudovich, and D. M. Ouwens. 2021. "Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity" Cells 10, no. 5: 1048. https://doi.org/10.3390/cells10051048

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