Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1.

Cell Rep

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. Electronic address:

Published: February 2023

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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9989826PMC
http://dx.doi.org/10.1016/j.celrep.2023.112059DOI Listing

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