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

Cristina Ortiz, Sabine Klein, Winfried H. Reul, Fernando Magdaleno, Stefanie Gröschl, Peter Dietrich, Robert Schierwagen, Frank E. Uschner, Sandra Torres, Christoph Hieber, Caroline Meier, Nico Kraus, Olaf Tyc, Maximilian Brol, Stefan Zeuzem, Christoph Welsch, Marco Poglitsch, Claus Hellerbrand, Mercedes Alfonso-Prieto, Fabio MiraUlrich auf dem Keller, Anja Tetzner, Andrew Moore, Thomas Walther, Jonel Trebicka*

*Corresponding author for this work

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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.

Original languageEnglish
Article number112059
JournalCell Reports
Issue number2
Number of pages21
Publication statusPublished - 28. Feb 2023

Bibliographical note

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  • cirrhosis
  • CP: Cell biology
  • hepatic stellate cell
  • neprilysin
  • neuropeptide Y
  • neuropeptide Y receptor 1
  • portal hypertension
  • renin-angiotensin system


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