TY - JOUR
T1 - Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy
AU - Kjeldsen, Sasha A.S.
AU - Gluud, Lise L.
AU - Werge, Mikkel P.
AU - Pedersen, Julie S.
AU - Bendtsen, Flemming
AU - Alexiadou, Kleopatra
AU - Tan, Tricia
AU - Torekov, Signe S.
AU - Iepsen, Eva W.
AU - Jensen, Nicole J.
AU - Richter, Michael M.
AU - Goetze, Jens P.
AU - Rungby, Jørgen
AU - Hartmann, Bolette
AU - Holst, Jens J.
AU - Holst, Birgitte
AU - Holt, Joachim
AU - Gustafsson, Finn
AU - Madsbad, Sten
AU - Svane, Maria S.
AU - Bojsen-Møller, Kirstine N.
AU - Wewer Albrechtsen, Nicolai J.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023
Y1 - 2023
N2 - Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
AB - Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.
KW - Diabetology
KW - Health sciences
KW - Obesity medicine
UR - http://www.scopus.com/inward/record.url?scp=85175342309&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2023.108190
DO - 10.1016/j.isci.2023.108190
M3 - Journal article
C2 - 37953952
AN - SCOPUS:85175342309
VL - 26
JO - iScience
JF - iScience
SN - 2589-0042
IS - 11
M1 - 108190
ER -