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

Ortiz C, Klein S, Reul WH, Magdaleno F, Groeschl S, Dietrich P, Schierwagen R, Uschner FE, Torres S, Hieber C, Meier C, Kraus N, Tyc O, Brol M, Zeuzem S, Welsch C, Poglitsch M, Hellerbrand C, Alfonso-Prieto M, Mira F, Keller UAD, Tetzner A, Moore A, Walther T, Trebicka J (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 42

Journal Issue: 2

DOI: 10.1016/j.celrep.2023.112059

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 termi-nate 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 addi-tion 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.

Authors with CRIS profile

Peter Dietrich Lehrstuhl für Biochemie und Molekulare Medizin Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

D040: The role of the DEAD-box RNA helicase DDX46 in liver cancer March 1, 2023 - Aug. 31, 2025

Involved external institutions

Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Attoquant Diagnostics GmbH DE Germany (DE) Forschungszentrum Jülich / Research Centre Jülich (FZJ) DE Germany (DE) Technical University of Denmark / Danmarks Tekniske Universitet (DTU) DK Denmark (DK) University College Cork (UCC) IE Ireland (IE)

How to cite

APA:

Ortiz, C., Klein, S., Reul, W.H., Magdaleno, F., Groeschl, S., Dietrich, P.,... Trebicka, J. (2023). Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1. Cell Reports, 42(2). https://dx.doi.org/10.1016/j.celrep.2023.112059

MLA:

Ortiz, Cristina, et al. "Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1." Cell Reports 42.2 (2023).

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