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A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

The AMP-activated protein kinase (Ampk) is a central regulator of metabolic pathways and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmp...

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Autores principales: Liu, Yuan, Jurczak, Michael J., Lear, Travis B., Lin, Bo, Larsen, Mads B., Kennerdell, Jason R., Chen, Yanwen, Huckestein, Brydie R., Nguyen, Matthew K., Tuncer, Ferhan, Jiang, Yu, Monga, Satdarshan P., O’Donnell, Christopher P., Finkel, Toren, Chen, Bill B., Mallampalli, Rama K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529588/
https://www.ncbi.nlm.nih.gov/pubmed/33495648
http://dx.doi.org/10.1038/s41589-020-00723-0
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author Liu, Yuan
Jurczak, Michael J.
Lear, Travis B.
Lin, Bo
Larsen, Mads B.
Kennerdell, Jason R.
Chen, Yanwen
Huckestein, Brydie R.
Nguyen, Matthew K.
Tuncer, Ferhan
Jiang, Yu
Monga, Satdarshan P.
O’Donnell, Christopher P.
Finkel, Toren
Chen, Bill B.
Mallampalli, Rama K.
author_facet Liu, Yuan
Jurczak, Michael J.
Lear, Travis B.
Lin, Bo
Larsen, Mads B.
Kennerdell, Jason R.
Chen, Yanwen
Huckestein, Brydie R.
Nguyen, Matthew K.
Tuncer, Ferhan
Jiang, Yu
Monga, Satdarshan P.
O’Donnell, Christopher P.
Finkel, Toren
Chen, Bill B.
Mallampalli, Rama K.
author_sort Liu, Yuan
collection PubMed
description The AMP-activated protein kinase (Ampk) is a central regulator of metabolic pathways and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds AICAR or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy, and improves hepatic insulin sensitivity in high fat diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.
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spelling pubmed-85295882021-10-21 A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance Liu, Yuan Jurczak, Michael J. Lear, Travis B. Lin, Bo Larsen, Mads B. Kennerdell, Jason R. Chen, Yanwen Huckestein, Brydie R. Nguyen, Matthew K. Tuncer, Ferhan Jiang, Yu Monga, Satdarshan P. O’Donnell, Christopher P. Finkel, Toren Chen, Bill B. Mallampalli, Rama K. Nat Chem Biol Article The AMP-activated protein kinase (Ampk) is a central regulator of metabolic pathways and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds AICAR or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy, and improves hepatic insulin sensitivity in high fat diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit. 2021-01-25 2021-03 /pmc/articles/PMC8529588/ /pubmed/33495648 http://dx.doi.org/10.1038/s41589-020-00723-0 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Liu, Yuan
Jurczak, Michael J.
Lear, Travis B.
Lin, Bo
Larsen, Mads B.
Kennerdell, Jason R.
Chen, Yanwen
Huckestein, Brydie R.
Nguyen, Matthew K.
Tuncer, Ferhan
Jiang, Yu
Monga, Satdarshan P.
O’Donnell, Christopher P.
Finkel, Toren
Chen, Bill B.
Mallampalli, Rama K.
A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title_full A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title_fullStr A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title_full_unstemmed A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title_short A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance
title_sort fbxo48 inhibitor prevents pampkα degradation and ameliorates insulin resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529588/
https://www.ncbi.nlm.nih.gov/pubmed/33495648
http://dx.doi.org/10.1038/s41589-020-00723-0
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