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) sy nthesis and secretion was investigated in primary monolayer cultures o f 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-1. No effect was observed during the first 24-hour incubation period; however, apoA-1 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 obtain ed at 10 mumol/L retinoic acid during a third 24-hour incubation. In t hese experiments apoB-100 secretion was unaffected. When [S-35]methion ine incorporation studies were performed de novo synthesis of apoA-1 w as increased, whereas total protein synthesis remained constant. These observations indicated that the induction of apoA-1 synthesis is not part of a general effect of retinoic acid on hepatic protein synthesis . Among different natural and synthetic retinoids, retinoic acid and i ts 9-cis and 13-cis isomers were equally active and were the most pote nt inducers of apoA-1 synthesis, whereas the maximal stimulation induc ed by retinol was lower (1.6-fold). ApoA-1 mRNA abundance was increase d threefold in hepatocytes exposed for 72 hours to 10 mumol/L retinoic acid, which was associated with a twofold increase in the transcripti onal rate of the apoA-1 gene. In contrast, no changes were found in th e apoB-100 mRNA level and transcriptional activity of the apoB-100 gen e. We conclude that retinoids enhance apoA-1 synthesis in simian hepat ocytes by transcriptional regulation.