The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu
Autor: | Felix Stickel, Gunther Hartmann, Christian P. Strassburg, Philipp Lutz, Jochen Hampe, Jacob Nattermann, Stephan Buch, Christian Datz, Bettina Langhans, Benjamin Krämer, Hans Dieter Nischalke, Ulrich Spengler, Eva Bartok, Thomas Berg, Regina Frizler |
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Přispěvatelé: | University of Zurich, Nischalke, Hans Dieter |
Rok vydání: | 2019 |
Předmět: |
2716 Genetics (clinical)
Chemokine CXCL5 Alcoholic liver disease Carcinoma Hepatocellular Angiogenesis Chemokine CXCL1 medicine.medical_treatment 610 Medicine & health Platelet Factor 4 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Humans Genetic Predisposition to Disease Secretion Interleukin 8 Genetics (clinical) Tube formation Chemistry 3002 Drug Discovery Interleukin-8 Liver Neoplasms Membrane Proteins Lipase medicine.disease CXCL1 10219 Clinic for Gastroenterology and Hepatology Cytokine medicine.anatomical_structure 1313 Molecular Medicine Hepatocyte Hepatocytes Cancer research Molecular Medicine Chemokines CXC 030215 immunology |
Zdroj: | Journal of Molecular Medicine. 97:1589-1600 |
ISSN: | 1432-1440 0946-2716 |
Popis: | The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte®) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1. |
Databáze: | OpenAIRE |
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