Journal Article

FZJ-2023-01456

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1

Ortiz, C. ; Klein, S. ; Reul, W. H. ; Magdaleno, F. ; Gröschl, S. ; Dietrich, P. ; Schierwagen, R. ; Uschner, F. E. ; Torres, S. ; Hieber, C. ; Meier, C. ; Kraus, N. ; Tyc, O. ; Brol, M. ; Zeuzem, S. ; Welsch, C. ; Poglitsch, M. ; Hellerbrand, C. ; Alfonso-Prieto, M.FZJ* ; Mira, F. ; Keller, U. a. d. ; Tetzner, A. ; Moore, A. ; Walther, T. ; Trebicka, J. (Corresponding author)

2023
Elsevier [New York, NY]

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Please use a persistent id in citations: http://hdl.handle.net/2128/34128  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 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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)

Appears in the scientific report 2023

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Database coverage:
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