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*

*Kontaktforfatter

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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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.

OriginalsprogEngelsk
Artikelnummer112059
TidsskriftCell Reports
Vol/bind42
Udgave nummer2
Antal sider21
ISSN2211-1247
DOI
StatusUdgivet - 28. feb. 2023

Bibliografisk note

Funding Information:
All the authors are very grateful to Gudrun Hack, Silke Bellinghausen, Christiane Esch, Dikra Zouiten, and Evelyn Süß for their excellent technical assistance and to Sabine Dentler for critical reading. The authors were supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382) and Eurostars (ID 12350). The MICROB-PREDICT, GALAXY, and LIVERHOPE projects have received funding from the European Union's Horizon 2020 research and innovation program under grant agreements numbers 825694, 668031, and 731875, respectively. The manuscript reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. F.M. C.O. and J.T. drafted the manuscript. W.R. S.K. C.O. F.M. S.G. and M.A.-P. acquired, analyzed, and interpreted the data. C.O. R.S. F.U. C.S. T.W. P.D. and C.H. provided substantial material and methods and interpreted data. J.T. designed the original study, interpreted the data, supervised the study, and obtained financial support for the study. All authors reviewed the draft for important intellectual content and approved the final article for submission. The authors have no conflict of interest.

Funding Information:
All the authors are very grateful to Gudrun Hack, Silke Bellinghausen, Christiane Esch, Dikra Zouiten, and Evelyn Süß for their excellent technical assistance and to Sabine Dentler for critical reading. The authors were supported by grants from the Deutsche Forschungsgemeinschaft ( SFB TRR57 , CRC1382 ) and Eurostars (ID 12350 ). The MICROB-PREDICT, GALAXY, and LIVERHOPE projects have received funding from the European Union’s Horizon 2020 research and innovation program under grant agreements numbers 825694 , 668031 , and 731875 , respectively. The manuscript reflects only the authors’ views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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