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1 Department of Biochemistry, Universite de Montreal, Montreal, Quebec, Canada; Centre de recherche, CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada
2 Centre de recherche, CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada
3 Department of Biochemistry, Universite de Montreal, Montreal, Quebec, Canada; Department of Nutrition, Universite de Montreal, Montreal, Quebec, Canada; Centre de recherche, CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: Christine.Des.Rosiers{at}umontreal.ca.
The objective of this study was to test the effect of increasing fatty acid concentrations on substrate fluxes through pathways leading to citrate synthesis and release in the heart. This was accomplished using semi-recirculating work-performing rat hearts perfused with substrate mixtures mimicking the in situ milieu (5.5 mM glucose, 8 nM insulin, 1 mM lactate, 0.2 mM pyruvate and 0.4 mM oleate-albumin) and 13C-methods. Raising the fatty acid concentration from 0.4 to 1 mM with long-chain oleate or medium-chain octanoate resulted in a lowering (~20%) of cardiac output and efficiency with unaltered O2 consumption. At the metabolic level, beyond the expected effects of high fatty acid levels on the contribution of pyruvate decarboxylation (reduced > 3-fold) and 
-oxidation (enhanced ~ 3-fold) to citrate synthesis, there was also a 2.4-fold lowering of anaplerotic pyruvate carboxylation. Despite the duel inhibitory effect of high fatty acids on pyruvate decarboxylation and carboxylation, tissue citrate levels were 2-fold higher, but citrate release rates remained unchanged at 11-14 nmol/min, representing < 0.5% of citric acid cycle flux. A similar trend was observed for most metabolic parameters following oleate or octanoate addition. Altogether, these results emphasize a differential modulation of anaplerotic pyruvate carboxylation and citrate release in the heart by fatty acids. We interpret the lack of effects of high fatty acid concentrations on citrate release rates as suggesting that under physiological conditions, this process is maximal, probably limited by the activity of its mitochondrial or plasma membrane transporter. Limited citrate release at high fatty acid concentrations may have important consequences for the heart's fuel metabolism and function.
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