Mechanism of increased hepatic concentration of carnitine by clofibrate

Our previous studies have shown that treatment of rats with clofibrate, a hypolipidemic drug, greatly increases the total concentration of carnitine in the liver (H. S. Paul and S. A. Adibi, J. Clin. Invest. 64: 405-412, 1979). In the present experiment we have investigated some possible mechanisms to account for this increase. Clofibrate treatment (30 mg/100 g rat/day for 2 wk) increased significantly the concentration (nmol/g, mean +/- SE, 6 rats) of both free (289 +/- 21 vs. 1,747 +/- 131) and acylcarnitine (87 +/- 11 vs. 412 +/- 42). These increases were not the result of redistribution of carnitine among tissues or due to a decrease in urinary excretion. In view of previous observations that thyroid hormones increase the hepatic concentrations of carnitine, and clofibrate treatment causes a hyperthyroid state in the liver, we investigated the effect of clofibrate in thyroidectomized rats. Clofibrate treatment of thyroidectomized rats also increased the concentration of free (423 +/- 25 vs. 1,460 +/- 123) and acylcarnitine (35 +/- 6 vs. 305 +/- 31) in the liver. Finally, clofibrate treatment significantly increased the urinary excretion of trimethyllysine, a precursor of carnitine (31 +/- 3 vs. 47 +/- 4 nmol/mg creatinine, mean +/- SE, 5 rats). Our data suggest that clofibrate treatment stimulates hepatic synthesis of carnitine by increasing the availability of its precursor, trimethyllysine. This effect of clofibrate is independent of thyroid hormone.