Inhibition of apolipoprotein(a) synthesis in cynomolgus monkey hepatocytes by retinoids via involvement of the retinoic acid receptor

We have shown previously that retinoids induce apolipoprotein (apo) A-I gene expression in cultured cynomolgus hepatocytes and do not have an effect on apo B-100 synthesis. In the present study, the effect of retinoids on apolipoprotein(a) (apo(a)) synthesis in cultured hepatocytes was investigated. The addition of all-trans retinoic acid (at-RA) to the medium of the hepatocytes resulted in a dose- and time-dependent decrease in apo(a) synthesis. Maximal inhibition was 54% after 72 hr of incubation with 10 mu mol/L at-RA. Apo B-100 synthesis remained constant, while apo A-1 synthesis was increased by 112% after treatment with 10 mu mol/L at-RA for 72 hr, indicating that at-RA does not have a general effect on apolipoprotein synthesis in hepatocytes. 9-cis-RA (-36%) and 13-cis-RA (-20%) also inhibited apo(a) synthesis, whereas retinol was not active. To investigate which retinoid receptors are involved in the inhibition of apo(a) synthesis, specific retinoid X receptor (RXR) and retinoic acid receptor (RAR) ligands were used. 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-ethenyl] benzoic acid (3-methyl-TTNEB), a specific RXR agonist, did not have ;an effect on apo(a) synthesis, whereas incubation with (E)-4-[2-(5,5,8,8 tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl] benzoic acid (TTNPB), a specific RAR agonist, resulted in a decrease of 34%. Steady-state apo(a) mRNA levels were decreased by 42% and 33% after the cells were incubated for 48 hr with 10 mu mol/L at RA and TTNPB, respectively, indicating that the decreased synthesis is regulated at the (post) transcriptional level. We conclude that retinoids down regulate apo(a) synthesis and mRNA via involvement of RAR and not the RXR homodimer in cynomolgus hepatocytes. (C) 1999 Elsevier Science Inc.