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Neprilysin-Dependent Neuropeptide Y Cleavage in the Liver Promotes Fibrosis by Blocking Npy-Receptor 1
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi...........81e3215a289150cf3dbcdcad22826c77