The effects of clofibrate on malonyl‐CoA inhibition of carnitine pamitoyltransferase I (CPT I) and fatty acid oxidation in liver of neonatal pigs

Abstract

Previous studies demonstrated that clofibrate increased CPT I activity and fatty acid oxidation in piglets, but the role of malonyl‐CoA, a physiological inhibitor of CPT I, has not been clearly elucidated. Thirty colostrum‐deprived newborn pigs were fed milk replacer and orally gavaged with either vehicle (2 % Tween 80) or clofibrate (75 mg /kg body weight) +/− etomoxir (5 mg/ kg body weight) once daily for up to 7 days, and the sensitivity of liver CPT I to malonyl‐CoA inhibition and fatty acid oxidation were determined using 1‐14C‐octanoic, oleic and erucic acids. Administration of clofibrate significantly increased liver CPT I activity (60%) and malonyl‐CoA IC50 values (56%). Addition of etomoxir potently inhibited CPT I activity, but malonyl‐CoA IC50 remained unchanged. Consistent with CPT I activity, clofibrate increased mitochondrial fatty acid oxidation by 53%, but did not affect the rate of peroxisomal beta‐oxidation. Etomoxir did not alter the rate of fatty acid oxidation despite a 30% reduction in CPT I activity. These results indicate that the increase in fatty acid oxidation induced by clofibrate is due to both an increase in CPT I activity and a decrease in sensitivity of CPT I to malonyl‐CoA inhibition, suggesting that malonyl‐CoA plays an important role in the induction of fatty acid oxidation by clofibrate. Supported by CSREES, USDA NRI program award 2007‐35206‐1 7897.