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Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK ?1 isoforms.


ABSTRACT: Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules1. 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 ?-oxidation2-6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) ?1-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 ?-subunit kinase domain and the ?-subunit. ?1 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 ?1-selective activators and promote LCFA oxidation.

SUBMITTER: Pinkosky SL 

PROVIDER: S-EPMC7502547 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules<sup>1</sup>. 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<sup>2-6</sup>. Here we report a new level of regul  ...[more]

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