Department of Clinical Pharmacology, University Hospital of Tübingen, 72076 Tübingen, Germany.
H. Buniatian Institute of Biochemistry, National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan 0014, Armenia.
Cells. 2020 Feb 17;9(2):452. 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.
淀粉样蛋白-β（Aβ）在健康和患病肝脏中的功能和调节作用仍未被探索。由于 Aβ 降低了血脑屏障的完整性，我们研究了它在调节正常和肝硬化肝脏窦状隙通透性中的潜在作用。在人类肝硬化肝脏中，Aβ 及其产生的关键蛋白（β-分泌酶 1 和早老素 1）和降解它的蛋白（神经肽酶和髓鞘碱性蛋白）减少了。在培养中，活化的肝星状细胞（HSC）比星形胶质细胞更有效地内化 Aβ，并且 HSC 降解 Aβ，导致α-平滑肌肌动蛋白（α-SMA）、胶原 1 和转化生长因子β（TGFβ）的表达受到抑制。Aβ 还在上皮型一氧化氮合酶（eNOS）上调窦状隙通透性标志物，并降低培养的人肝窦内皮细胞（hLSEC）中的 TGFβ。肝 Aβ 水平也与转阿尔茨海默病小鼠以及人和啮齿动物肝硬化/纤维化中 eNOS 的表达相关。这些发现提示了 Aβ 在维持肝窦状隙通透性以及通过抑制 HSC 活化来防止肝硬化/纤维化方面的一个以前未被探索的作用。
