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

doi:10.1016/j.isci.2023.108190

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 af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Artikelnummer	108190
Tidsskrift	iScience
Vol/bind	26
Udgave nummer	11
Antal sider	13
ISSN	2589-0042
DOI	https://doi.org/10.1016/j.isci.2023.108190
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
This study was supported by Novo Nordisk Foundation, Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001 ), Future Leader Award European Foundation for the Study of Diabetes ( NNF21SA0072746 ) and Sapere Aude Independent Research Fund Denmark ( 1052-00003B ). Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001 ). We thank Christine Rasmussen, Department of Clinical Biochemistry, Bispebjerg University Hospital, Denmark for excellent technical assistance in the biochemical analyses.

Funding Information:
This study was supported by Novo Nordisk Foundation, Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001), Future Leader Award European Foundation for the Study of Diabetes (NNF21SA0072746) and Sapere Aude Independent Research Fund Denmark (1052-00003B). Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001). We thank Christine Rasmussen, Department of Clinical Biochemistry, Bispebjerg University Hospital, Denmark for excellent technical assistance in the biochemical analyses. SASK and NJWA conceived the idea of investigating systemic NEPa and NEP protein levels in metabolic disease and following the surgical and pharmaceutical modulation of metabolism. SASK wrote the first draft of the article. LLG, MW, JSP, FB, KA, TT, SST, EWI, NJJ, MMR, JPG, JR, BH, JJH, BH, JH, FG, SM, MSS, and KNB-M contributed with samples, and all authors revised and approved the final version of the article. The authors declare no competing interests.

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© 2023 The Authors

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Citationsformater

Kjeldsen, S. A. S., Gluud, L. L., Werge, M. P., Pedersen, J. S., Bendtsen, F., Alexiadou, K., Tan, T., Torekov, S. S., Iepsen, E. W., Jensen, N. J., Richter, M. M., Goetze, J. P., Rungby, J., Hartmann, B., Holst, J. J., Holst, B., Holt, J., Gustafsson, F., Madsbad, S., ... Wewer Albrechtsen, N. J. (2023). Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy. iScience, 26(11), [108190]. https://doi.org/10.1016/j.isci.2023.108190

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy. / Kjeldsen, Sasha A.S.; Gluud, Lise L.; Werge, Mikkel P.; Pedersen, Julie S.; Bendtsen, Flemming; Alexiadou, Kleopatra; Tan, Tricia; Torekov, Signe S.; Iepsen, Eva W.; Jensen, Nicole J.; Richter, Michael M.; Goetze, Jens P.; Rungby, Jørgen ; Hartmann, Bolette ; Holst, Jens J.; Holst, Birgitte ; Holt, Joachim ; Gustafsson, Finn ; Madsbad, Sten; Svane, Maria S.; Bojsen-Møller, Kirstine N.; Wewer Albrechtsen, Nicolai J.

I: iScience, Bind 26, Nr. 11, 108190, 2023.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Kjeldsen, SAS , Gluud, LL, Werge, MP, Pedersen, JS, Bendtsen, F, Alexiadou, K, Tan, T, Torekov, SS, Iepsen, EW, Jensen, NJ, Richter, MM , Goetze, JP , Rungby, J , Hartmann, B , Holst, JJ , Holst, B , Holt, J , Gustafsson, F , Madsbad, S, Svane, MS, Bojsen-Møller, KN & Wewer Albrechtsen, NJ 2023, 'Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy', iScience, bind 26, nr. 11, 108190. https://doi.org/10.1016/j.isci.2023.108190

Kjeldsen, Sasha A.S. ; Gluud, Lise L. ; Werge, Mikkel P. ; Pedersen, Julie S. ; Bendtsen, Flemming ; Alexiadou, Kleopatra ; Tan, Tricia ; Torekov, Signe S. ; Iepsen, Eva W. ; Jensen, Nicole J. ; Richter, Michael M. ; Goetze, Jens P. ; Rungby, Jørgen ; Hartmann, Bolette ; Holst, Jens J. ; Holst, Birgitte ; Holt, Joachim ; Gustafsson, Finn ; Madsbad, Sten ; Svane, Maria S. ; Bojsen-Møller, Kirstine N. ; Wewer Albrechtsen, Nicolai J. / Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy. I: iScience. 2023 ; Bind 26, Nr. 11.

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

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.",

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author = "Kjeldsen, {Sasha A.S.} and Gluud, {Lise L.} and Werge, {Mikkel P.} and Pedersen, {Julie S.} and Flemming Bendtsen and Kleopatra Alexiadou and Tricia Tan and Torekov, {Signe S.} and Iepsen, {Eva W.} and Jensen, {Nicole J.} and Richter, {Michael M.} and Goetze, {Jens P.} and J{\o}rgen Rungby and Bolette Hartmann and Holst, {Jens J.} and Birgitte Holst and Joachim Holt and Finn Gustafsson and Sten Madsbad and Svane, {Maria S.} and Bojsen-M{\o}ller, {Kirstine N.} and {Wewer Albrechtsen}, {Nicolai J.}",

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year = "2023",

doi = "10.1016/j.isci.2023.108190",

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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.

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.

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