Growth hormone inhibits rat liver alpha-1-acid glycoprotein gene expression in vivo and in vitro.
The gene encoding alpha-1-acid glycoprotein (AGP), one of the major acute-phase proteins, is positively controlled at the transcriptional level by cytokines (interleukin-1 [IL-1], IL-6, and tumor necrosis factor alpha) and glucocorticoids. Here, we show that growth hormone (GH) treatment of isolated rat hepatocytes in vitro reduces AGP messenger RNA (mRNA) expression. AGP gene expression remained inducible by IL-1, IL-6, and phenobarbital (PB) in GH-treated hepatocytes. Interestingly, the repressive effect of GH on AGP gene expression was also observed in vivo: liver AGP mRNA content was strongly increased in hypophysectomized rats, and GH treatment of these animals led to a decrease in mRNA to levels lower than those in untreated control animals. Moreover, the inhibitory effect of GH mainly occurs at the transcriptional level and can be observed as little as 0.5 hours after GH adding in vitro to isolated hepatocytes. These results show negative regulation of AGP gene expression and strongly suggest that GH is a major endogenous regulator of constitutive AGP gene expression. Moreover, transfection assays showed that the region of the AGP promoter located at position -147 to -123 is involved in AGP gene regulation by GH. Furthermore, GH deeply modifies the pattern of nuclear protein binding to this region. GH treatment of hypophysectomized rats led to the release of proteins of 42 to 45 and 80 kd and to the binding of proteins of 48 to 50 and 90 kd.
Mejdoubi
N
N
Laboratoire de Biochimie Générale, Faculté de Pharmacie, Chatenay-Malabry, France.
Henriques
C
C
Bui
E
E
Durand
G
G
Lardeux
B
B
Porquet
D
D
D000818:Animals; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D013006:Growth Hormone / Q000502:physiology*; D019382:Human Growth Hormone / Q000494:pharmacology; D007016:Hypophysectomy; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D009961:Orosomucoid / Q000096:biosynthesis* / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D003432:Cross-Linking Reagents; D007375:Interleukin-1; D015850:Interleukin-6; D009687:Nuclear Proteins; D009961:Orosomucoid; D012333:RNA, Messenger; D019382:Human Growth Hormone; D003907:Dexamethasone; D013006:Growth Hormone; D010634:Phenobarbital