Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis
| Autor: | Ulrich Beuers, Veronika Kanitz, Ralf Wimmer, Coen C. Paulusma, Andreas E. Kremer, Simon Hohenester, David Horst, Gerald Denk, Helen Kuehn, Ronald P.J. Oude Elferink |
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| Přispěvatelé: | Graduate School, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Liver fibrosis Cell Inbred C57BL Mice 0302 clinical medicine Liver Cirrhosis/complications Fibrosis Medizinische Fakultät Phospholipid Transfer Proteins lcsh:QH301-705.5 Cells Cultured liver fibrosis hepatic stellate cell Adenosine Triphosphatases Cultured Chemistry General Medicine 3. Good health Hepatocytes/pathology medicine.anatomical_structure Liver 030211 gastroenterology & hepatology Collagen Myofibroblast Hydrophobic and Hydrophilic Interactions Liver/metabolism medicine.medical_specialty Mitogen-Activated Protein Kinase Kinases/metabolism MAP Kinase Signaling System EGFR Cells Cholestasis/complications Article 03 medical and health sciences Cholestasis Glycochenodeoxycholic Acid Internal medicine Collagen/metabolism medicine Hepatic Stellate Cells Animals Humans bile salts ddc:610 Cell Proliferation Mitogen-Activated Protein Kinase Kinases Messenger RNA Adenosine Triphosphatases/metabolism Feeding Behavior medicine.disease In vitro Hepatic Stellate Cells/metabolism Mice Inbred C57BL 030104 developmental biology Endocrinology lcsh:Biology (General) Gene Expression Regulation Chronic Disease Hepatic stellate cell Hepatocytes Phospholipid Transfer Proteins/metabolism cholestasis |
| Zdroj: | Cells, 9(2):281. MDPI Multidisciplinary Digital Publishing Institute Cells Volume 9 Issue 2 Cells, Vol 9, Iss 2, p 281 (2020) |
| ISSN: | 2073-4409 |
| Popis: | Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of &alpha SMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling. |
| Databáze: | OpenAIRE |
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