Cell Reports (Feb 2023)
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 Mira,
- Ulrich auf dem Keller,
- Anja Tetzner,
- Andrew Moore,
- Thomas Walther,
- Jonel Trebicka
Affiliations
- Cristina Ortiz
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Sabine Klein
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany
- Winfried H. Reul
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Fernando Magdaleno
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Stefanie Gröschl
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Peter Dietrich
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Department of Internal Medicine 1, FAU Erlangen-Nuremberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
- Robert Schierwagen
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Frank E. Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Sandra Torres
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Christoph Hieber
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Caroline Meier
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Nico Kraus
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Olaf Tyc
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Maximilian Brol
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Christoph Welsch
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Marco Poglitsch
- Attoquant Diagnostics GmbH, Vienna, Austria
- Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Mercedes Alfonso-Prieto
- Institute for Neuroscience and Medicine INM-9 and Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, Jülich, Germany; Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Fabio Mira
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
- Ulrich auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
- Anja Tetzner
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
- Andrew Moore
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
- Thomas Walther
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland; Department of Pediatric Surgery, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany; Department of Obstetrics, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany
- Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Institute for Bioengineering of Catalonia, Barcelona, Spain; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 2
p. 112059
Abstract
Summary: 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.
