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 micromol/L at-RA. Apo B-100 synthesis remained constant, while apo A-I synthesis was increased by 112% after treatment with 10 micromol/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-prope nyl] 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 micromol/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.
Neele
D M
DM
Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
de Wit
E C
EC
Princen
H M
HM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001054:Apolipoproteins A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D000077610:Bexarotene; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008074:Lipoproteins / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008252:Macaca fascicularis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001054:Apolipoproteins A; D001565:Benzoates; D008024:Ligands; D008074:Lipoproteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D000077610:Bexarotene