iScience (Nov 2023)
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
- Journal volume & issue
-
Vol. 26,
no. 11
p. 108190
Abstract
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.
