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

The function and regulation of amyloid-beta (A beta) in healthy and diseased liver remains unexplored. Because A beta reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. A beta 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 A beta more efficiently than astrocytes and HSC degraded A beta leading to suppressed expression of alpha-smooth muscle actin (alpha-SMA), collagen 1 and transforming growth factor beta (TGF beta). A beta also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGF beta in cultured human liver sinusoidal endothelial cells (hLSEC). Liver A beta 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 A beta in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.