Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France; University Paris Descartes, Paris, France.
Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France; INSERM, UMR1149, Centre de Recherche sur l'Inflammation, Paris, France; University Paris Diderot, Paris, France; Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France.
J Hepatol. 2019 Jun;70(6):1278-1291. doi: 10.1016/j.jhep.2019.02.012. Epub 2019 Feb 21.
Non-alcoholic fatty liver disease (NAFLD) and its complications are an expanding health problem associated with the metabolic syndrome. Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells localized at the interface between the blood derived from the gut and the adipose tissue on the one side, and other liver cells on the other side. In physiological conditions, LSECs are gatekeepers of liver homeostasis. LSECs display anti-inflammatory and anti-fibrogenic properties by preventing Kupffer cell and hepatic stellate cell activation and regulating intrahepatic vascular resistance and portal pressure. This review focusses on changes occurring in LSECs in NAFLD and on their consequences on NAFLD progression and complications. Capillarization, namely the loss of LSEC fenestrae, and LSEC dysfunction, namely the loss of the ability of LSECs to generate vasodilator agents in response to increased shear stress both occur early in NAFLD. These LSEC changes favour steatosis development and set the stage for NAFLD progression. At the stage of non-alcoholic steatohepatitis, altered LSECs release inflammatory mediators and contribute to the recruitment of inflammatory cells, thus promoting liver injury and inflammation. Altered LSECs also fail to maintain hepatic stellate cell quiescence and release fibrogenic mediators, including Hedgehog signalling molecules, promoting liver fibrosis. Liver angiogenesis is increased in NAFLD and contributes to liver inflammation and fibrosis, but also to hepatocellular carcinoma development. Thus, improving LSEC health appears to be a promising approach to prevent NAFLD progression and complications.
非酒精性脂肪性肝病（NAFLD）及其并发症是一种与代谢综合征相关的日益严重的健康问题。肝窦内皮细胞（LSEC）是定位于肠源性血液与脂肪组织一侧和其他肝细胞另一侧之间界面的高度特化的内皮细胞。在生理条件下，LSEC 是肝脏内稳态的守门员。LSEC 通过防止枯否细胞和肝星状细胞激活以及调节肝内血管阻力和门脉压来发挥抗炎和抗纤维化特性。本综述重点介绍了 NAFLD 中 LSEC 发生的变化及其对 NAFLD 进展和并发症的影响。毛细血管化，即 LSEC 窗孔的丧失，以及 LSEC 功能障碍，即 LSEC 丧失对增加的剪切力产生血管扩张剂的能力，这两种情况在 NAFLD 早期就会发生。这些 LSEC 变化有利于脂肪变性的发展，并为 NAFLD 进展奠定了基础。在非酒精性脂肪性肝炎阶段，改变的 LSEC 释放炎症介质并有助于炎症细胞的募集，从而促进肝损伤和炎症。改变的 LSEC 也不能维持肝星状细胞静止并释放纤维生成介质，包括 Hedgehog 信号分子，促进肝纤维化。NAFLD 中肝血管生成增加，有助于肝炎症和纤维化，但也有助于肝细胞癌的发展。因此，改善 LSEC 健康似乎是预防 NAFLD 进展和并发症的一种有前途的方法。
