Opposite in vitro and in vivo regulation of hepatic apolipoprotein A-I gene expression by retinoic acid. Absence of effects on apolipoprotein A-II gene expression.
We studied the pharmacological potential of retinoids to modulate apolipoprotein (apo) A-I and apoA-II gene expression and production in vitro in the human cell line HepG2 as well as in primary cultures of adult rat hepatocytes and in vivo in the rat. In HepG2 cells, addition of all-trans retinoic acid (RA) doubled apoA-I mRNA within 24 hours and protein secreted in the culture medium after 48 hours. The induction of apoA-I mRNA by RA was completely blocked by actinomycin D, suggesting that RA acts at the transcriptional level in HepG2 cells. In primary cultures of rat hepatocytes, addition of RA increased apoA-I mRNA in a dose- and time-dependent manner as well as the secretion of apoA-I protein. Similar changes in apoA-I mRNA were observed with 9-cis RA. However, in vivo, hepatic apoA-I mRNA levels decreased after a single administration of RA at 10 mg/kg and remained low after prolonged treatment or at a higher dose, and serum apoA-I concentrations did not change. Furthermore, RA treatment did not substantially affect apoA-II mRNA levels or protein secretion either in vitro or in vivo. As a control, RA receptor-beta mRNA levels increased after RA both in vitro and in vivo. In conclusion, RA treatment selectively induces apoA-I and not apoA-II expression in vitro but not in vivo. These results therefore show additional regulatory effects of RA on apoA-I gene expression in vivo and raise questions about the usefulness of RA in the treatment of atherosclerosis.
Berthou
L
L
Department of Biotechnology C.R.V.A. Rhône-Poulenc Rorer SA, Vitry sur Seine, France.
Staels
B
B
Saldicco
I
I
Berthelot
K
K
Casey
J
J
Fruchart
J C
JC
Denèfle
P
P
Branellec
D
D
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000235:genetics; D013237:Stereoisomerism; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin