Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy

Sasha A.S. Kjeldsen, Lise L. Gluud, Mikkel P. Werge, Julie S. Pedersen, Flemming Bendtsen, Kleopatra Alexiadou, Tricia Tan, Signe S. Torekov, Eva W. Iepsen, Nicole J. Jensen, Michael M. Richter, Jens P. Goetze, Jørgen Rungby, Bolette Hartmann, Jens J. Holst, Birgitte Holst, Joachim Holt, Finn Gustafsson, Sten Madsbad, Maria S. SvaneKirstine N. Bojsen-Møller, Nicolai J. Wewer Albrechtsen*

*Corresponding author for this work

Abstract

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.

Original languageEnglish
Article number108190
JournaliScience
Volume26
Issue number11
ISSN2589-0042
DOIs
Publication statusPublished - 17 Nov 2023

Keywords

  • Diabetology
  • Health sciences
  • Obesity medicine

Fingerprint

Dive into the research topics of 'Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy'. Together they form a unique fingerprint.

Cite this