The effect of propionate on the regulation of the pyruvate dehydrogenase complex in the rat liver

doi:10.1016/0003-9861(83)90430-7

Archives of Biochemistry and Biophysics

Volume 220, Issue 2, 1 February 1983, Pages 405-414

https://doi.org/10.1016/0003-9861(83)90430-7 Get rights and content

Abstract

Propionate inhibited the metabolic flux through the pyruvate dehydrogenase reaction in the perfused rat liver when the perfusate concentration of propionate was below 10 mm and the perfusate pyruvate concentration was held within the physiological range. At higher propionate concentrations (e.g., 20 mm) the inhibition of pyruvate dehydrogenase was alleviated and the activation state of the pyruvate dehydrogenase complex was nearly doubled. In livers perfused with a high pyruvate concentration (e.g., 5 mm), propionate coinfusion at all concentrations inhibited the rate of pyruvate decarboxylation. Additional studies were performed in liver mitochondria maintained in State 3 where the $ATP ADP$ and the $NADH NAD^{+}$ ratios were held constant. Low propionate concentrations (e.g., 0.5 mm) inactivated the mitochondrial pyruvate dehydrogenase complex, whereas propionate levels in excess of 1 mm activated the enzyme complex. CoA distribution analyses of the mitochondrial incubations indicated that the presence of either 0.5 or 10 mm propionate caused a substantial accumulation of propionyl-CoA and methylmalonyl-CoA at the expense of free CoASH. Experiments were performed in which the ratios of various acyl-CoA derivatives to CoASH were varied by sequentially increasing the l-carnitine concentrations in the incubation. An inverse relationship between the propionyl-CoA/CoASH and methylmalonyl-CoA/CoASH ratios and the activity of the pyruvate dehydrogenase complex was observed. Experiments using freeze-thawed liver mitochondrial membranes indicated that propionate protected the pyruvate dehydrogenase complex from ATP-mediated inactivation by the pyruvate dehydrogenase kinase. It is our contention that the inactivation of pyruvate dehydrogenase complex at low propionate levels may be due to an increase in the mitochondrial $acyl- CoA CoASH$ ratios, whereas the activation of the enzyme complex demonstrated at high propionate levels is due to the inhibition of the pyruvate dehydrogenase kinase in a manner similar to that caused by pyruvate or dichloroacetic acid.

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^☆: This work was supported by grants from the NIH, AM-19473 and HL-24654, and the Robert A. Welch Foundation, AQ-728.

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The effect of propionate on the regulation of the pyruvate dehydrogenase complex in the rat liver☆

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