TY  - JOUR
AU  - Ortiz, Cristina
AU  - Klein, Sabine
AU  - Reul, Winfried H.
AU  - Magdaleno, Fernando
AU  - Gröschl, Stefanie
AU  - Dietrich, Peter
AU  - Schierwagen, Robert
AU  - Uschner, Frank E.
AU  - Torres, Sandra
AU  - Hieber, Christoph
AU  - Meier, Caroline
AU  - Kraus, Nico
AU  - Tyc, Olaf
AU  - Brol, Maximilian
AU  - Zeuzem, Stefan
AU  - Welsch, Christoph
AU  - Poglitsch, Marco
AU  - Hellerbrand, Claus
AU  - Alfonso-Prieto, Mercedes
AU  - Mira, Fabio
AU  - Keller, Ulrich auf dem
AU  - Tetzner, Anja
AU  - Moore, Andrew
AU  - Walther, Thomas
AU  - Trebicka, Jonel
TI  - Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1
JO  - Cell reports
VL  - 42
IS  - 2
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - FZJ-2023-01456
SP  - 112059
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 36729833
UR  - <Go to ISI:>//WOS:000927805600001
DO  - DOI:10.1016/j.celrep.2023.112059
UR  - https://juser.fz-juelich.de/record/1005353
ER  -