Retinoids inhibit primary cynomolgus monkey hepatocyte lipoprotein(a) levels.
Elevated plasma lipoprotein(a) [Lp(a)] independently contributes to a variety of vascular diseases; consequentially, factors that modulate its levels are of interest. Since Lp(a) is produced by a disulfide linkage between apolipoprotein(a) [apo(a)] and apolipoproteinB-100 (apoB-100) of low density lipoprotein (LDL) on the hepatocyte surface, modulation of either particle may be useful in lowering Lp(a). Using primary cynomolgus monkey hepatocyte cultures that endogenously express apo(a) and apoB-100, we showed that all-trans (retinol, retinal, retinoic acid) and 9-cis (retinal, retinoic acid) retinoids lower Lp(a) accumulation in the cell media, with the 9-cis derivatives being > 10-fold more potent than the all-trans stereoisomers. Lp(a) Towering was related to decreases in apo(a) and its cognate transcript, but not to apoB-100. These results demonstrate that retinoids lower Lp(a) levels by decreasing apo(a) through its cognate mRNA.
Ramharack
R
R
Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105, USA. ramharr@aa.wl.com
Spahr
M A
MA
Sekerke
C S
CS
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D017270:Lipoprotein(a) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008252:Macaca fascicularis; D012333:RNA, Messenger / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D012333:RNA, Messenger; D012176:Retinoids