Cells (Feb 2020)
Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver
- Gayane Hrachia Buniatian,
- Ralf Weiskirchen,
- Thomas S. Weiss,
- Ute Schwinghammer,
- Martin Fritz,
- Torgom Seferyan,
- Barbara Proksch,
- Michael Glaser,
- Ali Lourhmati,
- Marine Buadze,
- Erawan Borkham-Kamphorst,
- Frank Gaunitz,
- Christoph H. Gleiter,
- Thomas Lang,
- Elke Schaeffeler,
- Roman Tremmel,
- Holger Cynis,
- William H. Frey,
- Rolf Gebhardt,
- Scott L. Friedman,
- Wolfgang Mikulits,
- Matthias Schwab,
- Lusine Danielyan
Affiliations
- Gayane Hrachia Buniatian
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany
- Thomas S. Weiss
- Children’s University Hospital (KUNO), University of Regensburg, 93053 Regensburg, Germany
- Ute Schwinghammer
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Martin Fritz
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Torgom Seferyan
- H. Buniatian Institute of Biochemistry, National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan 0014, Armenia
- Barbara Proksch
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Michael Glaser
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Ali Lourhmati
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Marine Buadze
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Erawan Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany
- Frank Gaunitz
- Department of Neurosurgery, University Hospital of Leipzig, 04103 Leipzig, Germany
- Christoph H. Gleiter
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Thomas Lang
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany, and University of Tuebingen, 72076 Tuebingen, Germany
- Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany, and University of Tuebingen, 72076 Tuebingen, Germany
- Roman Tremmel
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany, and University of Tuebingen, 72076 Tuebingen, Germany
- Holger Cynis
- Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle, Germany
- William H. Frey
- Center for Memory & Aging, HealthPartners Neuroscience Center, St. Paul, MN 55130, USA
- Rolf Gebhardt
- Rudolf-Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
- Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
- Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria
- Matthias Schwab
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- Lusine Danielyan
- Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany
- DOI
- https://doi.org/10.3390/cells9020452
- Journal volume & issue
-
Vol. 9,
no. 2
p. 452
Abstract
The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer’s disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.
Keywords
- liver cirrhosis
- liver sinusoidal permeability
- liver sinusoidal endothelial cells
- hepatic stellate cells
- beta secretase
- presenilin
- endothelial nitric oxide synthase
- myelin basic protein
- alzheimer’s disease
- neprilysin
- astrocytes
