No Effect of Fibrates on Synthesis of Apolipoprotein(a) in Primary Cultures of Cynomolgus Monkey and Human Hepatocytes: Apolipoprotein A-I Synthesis Increased

Abstract

Fibrates have been shown to decrease plasma levels of triglyceride-rich lipoproteins and LDL and to increase HDL. Data on the effect of fibrates on lipoprotein(a) levels in man are not consistent. Because lp(a) levelsin vivoare mainly regulated at synthesis level, we studied the effect of fibrates on the synthesis of apolipoprotein(a) (apo(a)) in primary cultures of cynomolgus monkey and human hepatocytes. Furthermore, we assessed the effect of fibrates on apolipoprotein A-I (apo A-I) synthesis and investigated whether different fibrates have different effects on the apo(a) and apo A-I synthesis. The addition of gemfibrozil to cultures of monkey and human hepatocytes had no effect on apo(a) synthesis, but resulted in a dose- and time-dependent increase of apo A-I synthesis and mRNA. In simian hepatocytes maximal stimulation was 2.5-fold after incubation for 72 h with 1.0 mM gemfibrozil, whereas apo A-I synthesis was induced 1.8- and 2.0-fold by using 0.1 mM and 0.3 mM, respectively. Similar results were obtained by using human hepatocytes; apo(a) synthesis remained unchanged, while apo A-I secretion was 2.0-fold increased at 1 mM gemfibozil. Other fibrates like bezafibrate, clofibrate and clofibric acid did not change apo(a) synthesis either. In contrast, they enhanced the synthesis of apo A-I (1.5-, 1.8- and 1.8-fold, respectively), although less potently than gemfibrozil. We conclude that fibrates have no effect on apolipoprotein(a) synthesis in monkey and human hepatocytes and that these drugs induce apo A-I synthesis.