Inhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle.
High concentrations of lactate and oxfenicine inhibit fatty acid oxidation in cardiac muscle. The site of this inhibition was investigated in isolated perfused rat hearts. In hearts perfused with glucose (11 mM) and [U-14 C]palmitate (1.0 mM), addition of 5 mM lactate caused a 38% reduction in 14CO2 production. Tissue levels of long-chain acyl carnitine decreased suggesting that inhibition occurred at either fatty acyl CoA synthetase or carnitine-acyl CoA transferase. Cytosolic levels of acyl-CoA are low compared with mitochondrial levels and changes in acyl-CoA within the cytosolic compartment cannot be estimated directly. Consequently, the rate of conversion of 14C-palmitate to neutral lipids was used as an indicator of cytosolic acyl CoA levels. Lactate caused a 100% increase in 14C-fatty acid conversion to triglycerides suggesting that cytosolic levels of acyl-CoA increased in association with decreased acyl-carnitine. This indicates that lactate inhibited FFA oxidation at the level of carnitine-acyl CoA transferase. Oxfenicine (2 mM) reduced fatty acid oxidation by 45%, decreased acyl-carnitine levels by 80%, and increased conversion of 14C-palmitate to neutral lipids by 44%, suggesting that oxfenicine also inhibits fatty acid oxidation at the level of carnitine-acyl CoA transferase. These data further indicate that carnitine-acyl CoA transferase is an important site of control in the pathway of fatty acid oxidation.
D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007773:Lactates / Q000494:pharmacology*; D019344:Lactic Acid; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000378:metabolism
D000214:Acyl Coenzyme A; D007773:Lactates; D010168:Palmitates; D014280:Triglycerides; D002245:Carbon Dioxide; D019344:Lactic Acid; C023010:4-hydroxyphenylglycine; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine; D005998:Glycine