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J. Biol. Chem., Vol. 276, Issue 27, 24674-24679, July 6, 2001
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From the Inhibition studies have suggested that acyl-CoA
synthetase (ACS, EC 6.2.1.3) isoforms might regulate the use of
acyl-CoAs by different metabolic pathways. In order to determine
whether the subcellular locations differed for each of the three ACSs present in liver and whether these isoforms were regulated
independently, non-cross-reacting peptide antibodies were raised
against ACS1, ACS4, and ACS5. ACS1 was identified in endoplasmic
reticulum, mitochondria-associated membrane (MAM), and cytosol, but not
in mitochondria. ACS4 was present primarily in MAM, and the 76-kDa ACS5
protein was located in mitochondrial membrane. Consistent with these
locations, N-ethylmaleimide, an inhibitor of ACS4, inhibited ACS activity 47% in MAM and 28% in endoplasmic reticulum. Troglitazone, a second ACS4 inhibitor, inhibited ACS activity <10% in
microsomes and mitochondria and 45% in MAM. Triacsin C, a competitive
inhibitor of both ACS1 and ACS4, inhibited ACS activity similarly in
endoplasmic reticulum, MAM, and mitochondria, suggesting that a
hitherto unidentified triacsin-sensitive ACS is present in
mitochondria. ACS1, ACS4, and ACS5 were regulated independently by
fasting and re-feeding. Fasting rats for 48 h resulted in a decrease in ACS4 protein, and an increase in ACS5. Re-feeding normal
chow or a high sucrose diet for 24 h after a 48-h fast increased
both ACS1 and ACS4 protein expression 1.5-2.0-fold, consistent with
inhibition studies. These results suggest that ACS1 and ACS4 may be
linked to triacylglycerol synthesis. Taken together, the data suggest
that acyl-CoAs may be functionally channeled to specific metabolic
pathways through different ACS isoforms in unique subcellular locations.
Acyl-CoA Synthetase Isoforms 1, 4, and 5 Are Present in Different
Subcellular Membranes in Rat Liver and Can Be Inhibited
Independently*
,,,¶
Departments of Nutrition and Pediatrics,
University of North Carolina, Chapel Hill, North Carolina 27599 and the
§ Department of Medicine and Canadian Institutes for Health
Research Group on Molecular and Cell Biology of Lipids, University of
Alberta, Edmonton, Alberta T6G 2S2, Canada
*
This work was supported by GlaxoSmithKline, by Grants HD
56598 (to R. A. C.) and HD 08431 (to T. M. L.) from
the National Institutes of Health, and by a grant from the North
Carolina Institute of Nutrition.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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