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. Svane,
Kirstine N. Bojsen-Møller,
Nicolai J. Wewer Albrechtsen
Affiliations
Sasha A.S. Kjeldsen
Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Lise L. Gluud
Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Mikkel P. Werge
Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
Julie S. Pedersen
Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
Flemming Bendtsen
Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Kleopatra Alexiadou
Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2BX, UK
Tricia Tan
Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2BX, UK
Signe S. Torekov
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Eva W. Iepsen
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Nicole J. Jensen
Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark; Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
Michael M. Richter
Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark
Jens P. Goetze
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark
Jørgen Rungby
Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark; Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
Bolette Hartmann
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Jens J. Holst
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Birgitte Holst
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Joachim Holt
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Finn Gustafsson
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Cardiology, Rigshospitalet, 2100 Copenhagen, Denmark
Sten Madsbad
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
Maria S. Svane
Gastro Unit, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark; Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
Kirstine N. Bojsen-Møller
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital - Hvidovre, 2650 Hvidovre, Denmark
Nicolai J. Wewer Albrechtsen
Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, 2400 Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Corresponding author
Summary: 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.
