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Articles in PresS, published online ahead of print June 13, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00244.2002
Submitted on March 20, 2002
Accepted on June 10, 2002
1 Biochemistry & Nutrition, University of Montreal, Montreal, Quebec, Canada
2 Nutrition, Case Western University, Cleveland, Ohio, USA
3 Physiology, George Washington University, Washington, DC, USA
* To whom correspondence should be addressed. E-mail: christine.des.rosiers{at}umontreal.ca.
Little is know about the sources of cytosolic acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of fatty acid oxidation in the heart. We tested the hypothesis that citrate provides acetyl-CoA for malonyl-CoA synthesis following its mitochondrial efflux and cleavage by cytosolic ATP-citrate lyase. We expand on a previous study where we characterized citrate release from perfused rat hearts (Vincent et al., Am. J. Physiol., 278: E846-E856, 2000). In the present study, we show that citrate release rates, ranging from 6 to 22 nmol/min, can support net increase in malonyl-CoA concentrations induced by changes in substrate supply, at most 0.7 nmol/min. In experiments with [U-13C](lactate + pyruvate) and [1-13C]oleate, we showed that the acetyl moiety of malonyl-CoA is derived from both pyruvate and long chain fatty acids. This 13C-labeling of malonyl-CoA occurred without any changes in its concentration. Hydroxycitrate, an inhibitor of ATP-citrate lyase, prevents increases in malonyl-CoA concentrations and decreases its labeling from [U-13C](lactate + pyruvate). Our data support an at least partial role of citrate in the transfer from mitochondria to cytosol of acetyl units for malonyl-CoA synthesis. In addition, they provide a dynamic picture of malonyl-CoA metabolism: even when malonyl-CoA concentration remains constant, there appears to be a constant need to supply acetyl-CoA from various carbon sources, both carbohydrates and lipids, for malonyl-CoA synthesis.
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