Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity
Olga Pivovarova-Ramich,
Jennifer Loske,
Silke Hornemann,
Mariya Markova,
Nicole Seebeck,
Anke Rosenthal,
Frederick Klauschen,
José Pedro Castro,
René Buschow,
Tilman Grune,
Volker Lange,
Natalia Rudovich,
D. Margriet Ouwens
Affiliations
Olga Pivovarova-Ramich
Research Group Molecular Nutritional Medicine, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
Jennifer Loske
Research Group Molecular Nutritional Medicine, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
Silke Hornemann
Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
Mariya Markova
Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
Nicole Seebeck
Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
Anke Rosenthal
Clinic for Nutritional Medicine, 10625 Berlin, Germany
Frederick Klauschen
Institute of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany
José Pedro Castro
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
René Buschow
Department of Microscopy & Cryo-Electron Microscopy, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Tilman Grune
German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany
Volker Lange
Centre for Obesity and Metabolic Surgery, Vivantes Hospital, 13509 Berlin, Germany
Natalia Rudovich
Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 14558 Nuthetal, Germany
D. Margriet Ouwens
German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany
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.
