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

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.

Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice

“…Astrocytes have been suggested to be potent metabolizers of Aβ [ 27 , 46 ], and thus valuable therapeutic targets for enhancing Aβ-clearance in AD. However, whether a general enhancement of astroglial motility will lead to more effective targeting of Aβ plaques in vivo remains a matter for future investigations.…”

Role of ellagic acid for the prevention and treatment of liver diseases

“…This liver fibrosis process is further enhanced by the consecutive upregulation of growth factors (PDGF BB, TGF-β, VEGF) from activated HSCs and myofibroblasts. Interestingly, researchers also suggest that migratory HSCs can revert to their quiescent stage if the cytokines and inflammatory mediators could be curtailed, and thereby liver fibrogenesis could be resolved (Buniatian, 2020). The connecting triad between the inflammatory responses and the response cell (HSCs and myofibroblasts) and the soluble mediators of ECM proteins are an appealing target for intervention.…”

“…EA avoids this by negatively regulating the expression of Smad 2/3 phosphorylation by controlling the cytokine levels at the site of hepatic injury and thereby prevents fibrogenesis (Ramachandran & Iredale, 2015;Yoshida, Murata, Yamaguchi, Matsuzaki, & Okazaki, 2016). Targeting TGF-β-mediated molecular pathways in the regulatory network controlling inflammatory mediators, or HSC activation is adequate for developing anti-fibrotic drugs (Friedman, 2012;Gressner & Weiskirchen, 2006 (Buniatian, 2020). Therefore, a promising future can be foreseen for EA or its derivatives in the treatment and management of liver fibrosis, thereby preventing further progression to cirrhosis and liver cancer.…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

“…As the authors mentioned, early recognition of clinical signs and symptoms of simultaneous heart and liver injury has led to important benefits in terms of reduction of morbidity and mortality [50]. Similarly, Buniatian et al points to a close connection of the brain in the pathogenesis of liver fibrosis [51]. The authors report that amyloid-β is not only crucial in forming amyloid plaques during Alzheimer's disease, but has also antifibrotic activities during pathogenesis of liver fibrosis.…”

“…These findings conclusively suggest that this short peptide exerts antifibrotic functions by both autocrine and paracrine effects on HSC and sinusoidal endothelial cells. Moreover, clinically more importantly, it is likely that efforts to lower its accumulation in the brain could have adverse effects on the liver [51]. The same group investigated aspects of α 2 -adrenergic receptor signaling [52].…”