2. Academic Validation
  3. A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

  • Nat Chem Biol. 2021 Mar;17(3):298-306. doi: 10.1038/s41589-020-00723-0.
Yuan Liu  # 1 2 3,  Michael J Jurczak 4,  Travis B Lear 5 6 7,  Bo Lin 5,  Mads B Larsen 5,  Jason R Kennerdell 5,  Yanwen Chen 5,  Brydie R Huckestein 4,  Matthew K Nguyen 5,  Ferhan Tuncer 5,  Yu Jiang 8,  Satdarshan P Monga 9,  Christopher P O'Donnell 6,  Toren Finkel 5 7,  Bill B Chen  # 10 11 12,  Rama K Mallampalli  # 13
Affiliations

Affiliations

  • 1 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA. [email protected].
  • 2 Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 3 The McGowan Institute for Regenerative Medicine, Pittsburgh, PA, USA. [email protected].
  • 4 Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA.
  • 6 Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • 8 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 9 Department of Pathology and Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 10 Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, USA. [email protected].
  • 11 Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 12 Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • 13 Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA. [email protected].
  • # Contributed equally.
PMID: 33495648 DOI: 10.1038/s41589-020-00723-0
Abstract

The adenosine monophosphate (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 have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside (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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