Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

• Published in: Nature metabolism Vol. 2; no. 9; p. 873
• Main Authors: Pinkosky, Stephen L, Scott, John W, Desjardins, Eric M, Smith, Brennan K, Day, Emily A, Ford, Rebecca J, Langendorf, Christopher G, Ling, Naomi X Y, Nero, Tracy L, Loh, Kim, Galic, Sandra, Hoque, Ashfaqul, Smiles, William J, Ngoei, Kevin R W, Parker, Michael W, Yan, Yan, Melcher, Karsten, Kemp, Bruce E, Oakhill, Jonathan S, Steinberg, Gregory R
• Format: Journal Article
• Language: English
• Published: Germany 01.09.2020
• Subjects: Acyl Coenzyme A - physiology; Allosteric Regulation - physiology; AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Catalytic Domain; Esters; Isoenzymes - chemistry; Isoenzymes - metabolism; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Mutation - genetics; Oxidation-Reduction; Palmitoyl Coenzyme A - metabolism; Phosphorylation; Pyrones - pharmacology; Thiophenes - pharmacology
• ISSN: 2522-5812
• DOI: 10.1038/s42255-020-0245-2

Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules . LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation . Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1-selective activators and promote LCFA oxidation.