Interaction of carnitine and propionate with pyruvate oxidation by hepatocytes from clofibrate-treated rats: importance of coenzyme A availability.
Propionate interferes with normal hepatic metabolic regulation secondary to accumulation of propionyl- and methylmalonyl-CoA. Clofibrate-treatment increases hepatic CoA content and carnitine acetyltransferase activity, both of which may modulate propionate toxicity. Therefore, inhibition of pyruvate oxidation by propionate was studied in hepatocytes isolated from rats maintained on a control or 0.5% clofibrate diet for 7-9 d. Propionate (10 mmol/L) inhibited 14CO2 formation from [1-14C]pyruvate (10 mmol/L) by 60 +/- 2% in hepatocytes from control rats, but by only 46 +/- 3% in cells from clofibrate-treated rats (P less than 0.05). The smaller inhibitory effect of propionate in hepatocytes from clofibrate-treated rats occurred despite increased cellular propionyl-CoA content as compared with controls, but was associated with increased CoASH and total CoA contents. Despite greater carnitine acetyltransferase activity (20-fold) and propionylcarnitine production (2.5-fold) in hepatocytes from clofibrate-treated rats, reversal of propionate's inhibition of pyruvate oxidation by 10 mmol/L carnitine was small (8.7 +/- 3.9%) and not different from that observed in cells from control animals (6.7 +/- 2.4%). Carnitine (10 mmol/L) decreased hepatocyte total acid-soluble CoA content by 20-30% in cells from both control and clofibrate-treated rats. This carnitine-induced decrease in CoA content may limit the efficacy of carnitine under conditions of acyl-CoA accumulation. Clofibrate-induced increased CoA content provides partial protection against propionate toxicity. Metabolic toxicity of propionate is the result of both the increased cellular propionyl-CoA content and the depletion of cellular unesterified CoA.
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Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.
D000818:Animals; D002331:Carnitine / Q000378:metabolism*; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology*; D003065:Coenzyme A / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011422:Propionates / Q000378:metabolism*; D011773:Pyruvates / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D011422:Propionates; D011773:Pyruvates; D002332:Carnitine O-Acetyltransferase; D002994:Clofibrate; D002331:Carnitine; D003065:Coenzyme A