Evidence that acyl-CoAs are functionally channeled in liver
Activation of fatty acids by acyl-CoA synthetase (ACS) provides acyl-CoA for β-oxidation and for the synthesis of triacylglycerol (TAG), phospholipids (PL) and cholesterol esters (CE). Partitioning of acyl-CoAs towards these different metabolic fates is critical in the pathobiology of obesity, diabetes and hyperlipidemia. We used Triacsin C, a competitive inhibitor of long-chain ACS, to determine whether limited acyl-CoAs would be preferentially used for β-oxidation or complex lipid synthesis. Incubating cultured rat hepatocytes with 5 μM Triacsin for 24 hr decreased [14C]oleate incorporation into cellular TAG and CE by 76% and 26%, respectively (p<0.01), and acid soluble metabolites (ASM) (a measure of β-oxidation) by 42% (p<0.01), but did not affect incorporation into PL. Thus, acyl-CoAs were preferentially channeled into specific metabolic pathways. When cells were prelabeled for 24 hr with [14C]oleate, then chased for an additional 24 hr without label, Triacsin in the chase media did not inhibit labeling of ASM, indicating that Triacsin did not block oxidation of fatty acids hydrolyzed from endogenous acylglycerols. During 1 hr incubations, Triacsin decreased [14C]oleate incorporation into TAG by 36% (p<0.01), whereas it decreased [3H]glycerol incorporation into TAG by 58% (p<0.01), suggesting that Triacsin had a greater effect on de novo synthesis of TAG than on TAG synthesized from recycled acylglycerols. These data suggest that acyl-CoAs are actively channeled from targeted sources (exogenous compared to endogenous) towards specific metabolic pathways, possibly by multiple ACSs with distinct sensitivities to Triacsin.
Muoio, DM; Schmalz, P; Coleman, RA
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