Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1
Cristina Ortiz, Sabine Klein, Winfried Reul, Fernando Magdaleno, Stefanie Gröschl, Peter Dietrich, Robert Schierwagen, Frank Erhard Uschner, Sandra Torres, Christoph Hieber, Caroline Meier, Nico Kraus, Olaf Tyc, Maximilian Joseph Brol, Stefan Zeuzem, Christoph Welsch, Marco Poglitsch, Claus Hellerbrand, Mercedes Alfonso‐Prieto, Fabio Mira, Ulrich auf dem Keller, Anja Tetzner, Andrew G. Moore, Thomas Walther, Jonel Trebicka
Abstract
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.