Expression of hepatocyte nuclear factor 6 in rat liver is sex-dependent and regulated by growth hormone.
Growth hormone (GH) binding to its receptor modulates gene transcription by influencing the amount or activity of transcription factors. In the rat, GH exerts sexually dimorphic effects on liver gene transcription through its pattern of secretion which is intermittent in males and continuous in females. The expression of the CYP2C12 gene coding for the female-specific cytochrome P450 2C12 protein is dependent on the continuous exposure to GH. To identify the transcription factor(s) that mediate(s) this sex-dependent GH effect, we studied the interactions of the CYP2C12 promoter with liver nuclear proteins obtained from male and female rats and from hypophysectomized animals treated or not by continuous GH infusion. GH treatment induced the binding of a protein that we identified as hepatocyte nuclear factor (HNF) 6, the prototype of a novel class of homeodomain transcription factors. HNF-6 competed with HNF-3 for binding to the same site in the CYP2C12 promoter. This HNF-6/HNF-3 binding site conveyed both HNF-6- and HNF-3-stimulated transcription of a reporter gene construct in transient cotransfection experiments. Electrophoretic mobility shift assays showed more HNF-6 DNA-binding activity in female than in male liver nuclear extracts. Liver HNF-6 mRNA was barely detectable in the hypophysectomized rats and was restored to normal levels by GH treatment. This work provides an example of a homeodomain-containing transcription factor that is GH-regulated and also reports on the hormonal regulation of HNF-6.
Lahuna
O
O
Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology and Louvain University Medical School, 75 Avenue Hippocrate, B-1200 Brussels, Belgium. lahuna@horm.ucl.ac.be
Fernandez
L
L
Karlsson
H
H
Maiter
D
D
Lemaigre
F P
FP
Rousseau
G G
GG
Gustafsson
J
J
Mode
A
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001665:Binding Sites / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000008:administration & dosage*; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D007262:Infusions, Intravenous; D008099:Liver / Q000502:physiology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C496607:Onecut1 protein, rat; D015534:Trans-Activators; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C034694:steroid 15-beta-hydroxylase