Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 2; p. 452
• Main Authors: Buniatian, Gayane Hrachia, Weiskirchen, Ralf, Weiss, Thomas S, Schwinghammer, Ute, Fritz, Martin, Seferyan, Torgom, Proksch, Barbara, Glaser, Michael, Lourhmati, Ali, Buadze, Marine, Borkham-Kamphorst, Erawan, Gaunitz, Frank, Gleiter, Christoph H, Lang, Thomas, Schaeffeler, Elke, Tremmel, Roman, Cynis, Holger, Frey, 2nd, William H, Gebhardt, Rolf, Friedman, Scott L, Mikulits, Wolfgang, Schwab, Matthias, Danielyan, Lusine
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 17.02.2020; MDPI AG
• Subjects: alzheimer’s disease; Amyloid beta-Peptides - pharmacology; Amyloid beta-Peptides - therapeutic use; Animals; astrocytes; beta secretase; Disease Models, Animal; endothelial nitric oxide synthase; Fibrosis - drug therapy; Gene Expression - genetics; hepatic stellate cells; Humans; liver cirrhosis; Liver Cirrhosis - physiopathology; Liver Cirrhosis - therapy; liver sinusoidal endothelial cells; liver sinusoidal permeability; Male; Mice; Mice, Transgenic; Middle Aged; myelin basic protein; neprilysin; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; presenilin; Rats; Rats, Sprague-Dawley; hepatic stellate cells; Alzheimer’s disease; neprilysin; presenilin; liver sinusoidal permeability; endothelial nitric oxide synthase; liver sinusoidal endothelial cells; astrocytes; beta secretase; myelin basic protein; liver cirrhosis
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9020452

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.