NO EFFECT OF FIBRATES ON SYNTHESIS OF APOLIPOPROTEIN(A) IN PRIMARY CULTURES OF CYNOMOLGUS MONKEY AND HUMAN HEPATOCYTES - APOLIPOPROTEIN-A-ISYNTHESIS INCREASED

Fibrates have been shown to decrease plasma levels of triglyceride-ric h lipoproteins and LDL and to increase HDL. Data on the effect of fibr ates on lipoprotein(a) levels in man are not consistent, Because Ip(a) levels in vivo are mainly regulated at synthesis level, we studied th e effect of fibrates on the synthesis of apolipoprotein(a) (apo(a)) in primary cultures of cynomolgus monkey and human hepatocytes. Furtherm ore, we assessed the effect of fibrates on apolipoprotein A-I (ape A-I ) synthesis and investigated whether different fibrates have different effects on the apo(a) and apo A-I synthesis. The addition of gemfibro zil to cultures of monkey and human hepatocytes had no effect on apo(a ) synthesis, but resulted in a dose- and time-dependent increase of ap o A-I synthesis and mRNA. In simian hepatocytes maximal stimulation wa s 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 hepat ocytes; apo(a) synthesis remained unchanged, while apo A-I secretion w as 2.0-fold increased at 1 mM gemfibozil. Other fibrates like bezafibr ate, clofibrate and clofibric acid did not change apo(a) synthesis eit her. In contrast, they enhanced the synthesis of apo A-I (1.5-, 1.8- a nd 1.8-fold, respectively), although less potently than gemfibrozil. W e conclude that fibrates have no effect on apolipoprotein(a) synthesis in monkey and human hepatocytes and that these drugs induce apo A-I s ynthesis. (C) 1998 Academic Press.