In experimental rat liver perfusion we observed net production of free acet
ate accompanied by accelerated ketogenesis with long-chain fatty acids. Mit
ochondrial acetyl-CoA hydrolase, responsible for the production of free ace
tate, was found to be inhibited by the free form of CoA in a competitive ma
nner and activated by reduced nicotinamide adenine dinucleotide (NADH). The
conditions under which the ketogenesis was accelerated favored activation
of the hydrolase by dropping free CoA and elevating NADH levels. Free aceta
te was barely metabolized in the liver because of low affinity, high K,, of
acetyl coenzyme A (acetyl-CoA) synthetase for acetate. Therefore, infused
ethanol was oxidized only to acetate, which was entirely excreted into the
perfusate. The acetyl-CoA synthetase in the heart mitochondria was much low
er in K, than it was in the liver, thus the heart mitochondria was capable
of oxidizing free acetate as fast as other respiratory substrates, such as
succinate. These results indicate that rat liver produces free acetate as a
byproduct of ketogenesis and may supply free acetate, as in the case of ke
tone bodies, to extrahepatic tissues as fuel. (C) 2001 Elsevier Science B.V
. All rights reserved.