Retinoids stimulate ApoA-I synthesis by induction of gene transcription in primary hepatocyte cultures from cynomolgus monkey (Macaca fascicularis)
The influence of different retinoids on apolipoprotein A-I (apoA-I) synthesis and secretion was investigated in primary monolayer cultures of hepatocytes from cynomolgus monkeys. Addition of retinol (vitamin A) and retinoic acid to the culture medium resulted in a time- and dose-dependent increase in the secretion of apoA-I. No effect was observed during the first 24-hour incubation period; however, apoA-I secretion was enhanced 1.5-fold in the following 24-hour period in the presence of 10 mumol/L retinoic acid. Maximal stimulation (2.7-fold) was obtained at 10 mumol/L retinoic acid during a third 24-hour incubation. In these experiments apoB-100 secretion was unaffected. When [35S]methionine incorporation studies were performed de novo synthesis of apoA-I was increased, whereas total protein synthesis remained constant. These observations indicated that the induction of apoA-I synthesis is not part of a general effect of retinoic acid on hepatic protein synthesis. Among different natural and synthetic retinoids, retinoic acid and its 9-cis and 13-cis isomers were equally active and were the most potent inducers of apoA-I synthesis, whereas the maximal stimulation induced by retinol was lower (1.6-fold). ApoA-I mRNA abundance was increased threefold in hepatocytes exposed for 72 hours to 10 mumol/L retinoic acid, which was associated with a twofold increase in the transcriptional rate of the apoA-I gene. In contrast, no changes were found in the apoB-100 mRNA level and transcriptional activity of the apoB-100 gene. We conclude that retinoids enhance apoA-I synthesis in simian hepatocytes by transcriptional regulation.
Gaubius Laboratory IVVO-TNO, Leiden, The Netherlands.
A
A
Kaptein
E C
EC
de Wit
H M
HM
Princen
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology
D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D012333:RNA, Messenger; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin