Neprilysin-Dependent Neuropeptide Y Cleavage in the Liver Promotes Fibrosis by Blocking Npy-Receptor 1
| Autor: | Maximilian J. Brol, Claus Hellerbrand, Caroline Meier, Fernando Magdaleno, Stefanie Gröschl, Ulrich Keller, Cristina Ortiz, Marko Poglitsch, Andrew S. Moore, Nico Kraus, Mercedes Alfonso-Prieto, Jonel Trebicka, Christoph Hieber, Peter Dietrich, Fabio Mira, Frank Erhard Uschner, Stefan Zeuzem, Robert Schierwagen, Sandra Torres, Winfried Reul, Sabine D. Klein, Christoph Welsch, Anja Tetzner, Olaf Tyc |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Liver injury
History medicine.medical_specialty Polymers and Plastics business.industry Portal venous pressure fungi Neuropeptide Y receptor medicine.disease Industrial and Manufacturing Engineering Endocrinology Fibrosis Internal medicine Hepatic stellate cell Medicine Portal hypertension Business and International Management business Hepatic fibrosis Neprilysin |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 |
| Popis: | Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSC), 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 HSC 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|