Inhibition of apolipoprotein(a) synthesis in cynomolgus monkey hepatocytes by retinoids via involvement of the retinoic acid receptor
article
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 μmol/L at-RA. Apo B-100 synthesis remained constant, while apo A-I synthesis was increased by 112% after treatment with 10 μmol/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 μmol/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. Copyright (C) 1999 Elsevier Science Inc.
Topics
Apolipoprotein(a)Cynomolgus monkey hepatocytesRARRetinoidsRXRalitretinoinapolipoprotein Aisotretinoinretinoic acidretinoic acid receptorretinoidretinoid X receptorretinolanimal cellarticleconcentration responsecontrolled studydose time effect relationdrug effectenzyme linked immunosorbent assaygene expressionlipoprotein synthesisliver cellmonkeynonhumanpriority journalAnimalsAntineoplastic AgentsApolipoproteins ABenzoatesDose-Response Relationship, DrugLigandsLipoproteinsLiverMacaca fascicularisReceptors, Retinoic AcidRetinoid X ReceptorsRetinoidsRNA, MessengerTetrahydronaphthalenesTime FactorsTranscription Factors
TNO Identifier
235088
ISSN
00062952
Source
Biochemical Pharmacology, 58(2), pp. 263-271.
Pages
263-271
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