Retinoic acid increases insulin-like growth factor-binding protein-4 expression in cultured rat hepatocytes.
Hepatic insulin-like growth factor binding protein (IGFBP) expression is controlled by diverse factors including thyroid hormone, which enhances IGFBP-4 production in hepatocytes. In the present work, we have investigated whether hepatic IGFBP-4 expression is regulated by retinoic acid (RA), which acts via nuclear receptors belonging to the steroid/thyroid hormone receptor superfamily. Primary cultures of adult rat hepatocytes were incubated with two natural stereoisomers of RA, all-trans RA and 9-cis RA (atRA and 9cRA), and with the synthetic RA receptor (RAR)-selective agonist TTNPB. IGFBP-4 mRNA abundance was measured by Northern blot and protein production was evaluated by Ligand blot on hepatocyte-conditioned culture media. Our results indicate that atRA, 9cRA, and TTNPB increase IGFBP-4 expression by cultured hepatocytes, both at the mRNA and protein level. The RARs play a definite role in this regulation, which is independent from ongoing protein synthesis but dependent on active transcription. AtRA and thyroid hormone act synergistically in increasing hepatic IGFBP-4 expression. Our data establish a role for hormonal factors such as thyronines and retinoids in regulating the hepatic IGF system directly at the IGFBP-4 level.
Dipartimento di Biologia Sperimentale, Ambientale ed Applicata, Sezione di Fisiologia Generale e Comparata, Università degli Studi di Genova, Genoa, Italy.
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D000077556:Alitretinoin; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015152:Blotting, Northern; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000502:physiology; D012176:Retinoids / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
D001565:Benzoates; D017077:Culture Media, Conditioned; D018974:Insulin-Like Growth Factor Binding Protein 4; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D000077556:Alitretinoin; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid