A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance

• Published in: Nature chemical biology Vol. 17; no. 3; pp. 298 - 306
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2021; Nature Publishing Group
• Subjects: 631/92/1643; 631/92/458; 631/92/613; Adenosine monophosphate; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Autophagy; Bioactive compounds; Biochemical Engineering; Biochemistry; Biological activity; Bioorganic Chemistry; Cell Biology; Cell Line, Transformed; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Degradation; Diet, High-Fat; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; F-Box Proteins; High fat diet; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Insulin; Insulin Resistance; Kinases; Metabolic pathways; Metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Mitochondrial Dynamics - drug effects; Obesity - drug therapy; Obesity - etiology; Obesity - genetics; Obesity - metabolism; Phagocytosis; Phosphates; Phosphorylation; Polyubiquitin - genetics; Polyubiquitin - metabolism; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein kinase; Protein Processing, Post-Translational - drug effects; Protein Stability - drug effects; Proteins; Proteolysis - drug effects; Ribonucleotides - pharmacology; Sensitivity; Target recognition; Therapeutic targets; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-020-00723-0

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. E3 ligase subunit protein Fbxo48 interacts with phosphorylated Ampkα and mediates its proteasomal degradation. Interruption of the pAmpkα/Fbxo48 interaction by a small-molecule BC1618 promoted Ampkα activation and improved insulin sensitivity.