Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1

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. [Display omitted] •Proteolysis of NPY by NEP promotes liver fibrosis via NPY1 receptor blockade in HSCs•In the liver, NPY enhances contraction induced by AT1R stimulation•Administration of Entresto decreases liver fibrosis and portal pressure Neprilysin is upregulated in fibrosis and activated hepatic stellate cells (HSCs). Nep−/− reduced fibrosis due to increased levels of neuropeptide Y. Ortiz et al. describe a new player in fibrosis and deliver the molecular rationale for combined neprilysin and angiotensin inhibition as treatment of human liver fibrosis with portal hypertension.