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