Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany.
Cell Rep. 2023 Feb 28;42(2):112059. doi: 10.1016/j.celrep.2023.112059. Epub 2023 Jan 31.
Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.
肝纤维化的发展伴随着肝星状细胞（HSCs）的收缩，HSCs 是主要的致纤维化肝细胞。然而，关于 Neprilysin（NEP）及其底物神经肽 Y（NPY）在肝纤维化中的相互作用知之甚少，NPY 是收缩的有力增强剂。我们证明 HSCs 是 NEP 的来源。重要的是，NPY 主要来源于内脏区域，并被 NEP 切割以终止收缩。有趣的是，在两种不同的小鼠纤维化模型中，NEP 缺乏（Nep）在肝损伤时表现出较少的纤维化但门静脉高压。我们证明了 Nep 在加上 AT1R 阻滞剂（ARB）或 ACE 抑制剂治疗纤维化和门静脉高压方面的附加益处。最后，ARB 和 NEP 抑制剂的组合 Entresto 的口服给药可减少小鼠的肝纤维化和门静脉压。这些结果为将 NEP-AT1R 阻断转化为人类肝纤维化和门静脉高压提供了机制依据。
