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  Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis

Winther-Sorensen, M., Galsgaard, K. D., Santos, A., Trammell, S. A. J., Sulek, K., Kuhre, R. E., et al. (2020). Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis. Molecular Metabolism, 42: 101080. doi:10.1016/j.molmet.2020.101080.

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Genre: Journal Article
Subtitle : Original Article

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 Creators:
Winther-Sorensen, Marie1, Author
Galsgaard, Katrine D.1, Author
Santos, Alberto1, Author
Trammell, Samuel A. J.1, Author
Sulek, Karolina1, Author
Kuhre, Rune E.1, Author
Pedersen, Jens1, Author
Andersen, Daniel B.1, Author
Hassing, Anna S.1, Author
Dall, Morten1, Author
Treebak, Jonas T.1, Author
Gillum, Matthew P.1, Author
Torekov, Signe S.1, Author
Windelov, Johanne A.1, Author
Hunt, Jenna E.1, Author
Kjeldsen, Sasha A. S.1, Author
Jepsen, Sara L.1, Author
Vasilopoulou, Catherine G.2, Author              
Knop, Filip K.1, Author
Orskov, Cathrine1, Author
Werge, Mikkel P.1, AuthorBisgaard, Hanne Cathrine1, AuthorEriksen, Peter Lykke1, AuthorVilstrup, Hendrik1, AuthorGluud, Lise Lotte1, AuthorHolst, Jens J.1, AuthorAlbrechtsen, Nicolai J. Wewer1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: Endocrinology & Metabolism; Amino acids; Glucagon; Liver-alpha cell axis; Non-alcoholic fatty liver disease;
 Abstract: Objective: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. Methods: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). Results: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). Conclusions: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism. (C) 2020 The Author(s). Published by Elsevier GmbH.

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Language(s): eng - English
 Dates: 2020-092020-12
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: Molecular Metabolism
Source Genre: Journal
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Publ. Info: Amsterdam, Netherlands : Elsevier B.V.
Pages: - Volume / Issue: 42 Sequence Number: 101080 Start / End Page: - Identifier: ISSN: 2212-8778
CoNE: https://pure.mpg.de/cone/journals/resource/2212-8778