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- Gardmo, C, et al.
(author)
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In vivo transfection of rat liver discloses binding sites conveying GH-dependent and female-specific gene expression
- 2006
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In: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 37:3, s. 433-441
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Journal article (peer-reviewed)abstract
- The sexually dimorphic mode of GH secretion leads to a sex-differentiated expression of many hepatic target genes. Expression of the a1bg gene in rat liver is specifically induced by the female pattern of GH secretion. In this study, we have used the a1bg promoter in in vivo transfection experiments to investigate molecular mechanisms of GH-mediated female-specific hepatic gene regulation. Rat liver transfection was achieved by rapid tail vein injection of large volumes of plasmid solution. Expression of reporter constructs showed that the 160 bp proximal part of the a1bg promoter contained elements directing sex-specific expression. In vitro footprinting analysis and electromobility shift assays identified binding of hepatic nuclear factor 6 (HNF6), signal transducer and activator of transcriptions (Stat5) and nuclear factor 1 (NF1) in liver nuclear extracts to the 160 bp proximal promoter. Transfection of mutated and/or deletion constructs showed that HNF6 and NF1 binding markedly enhanced expression in female livers, whereas Stat5 reduces the sex difference by enhancing expression more strongly in male than in female rat liver. Based on our present results, we propose that adjacent binding sites for NF1 and HNF6 constitute a gene regulatory unit of importance for transducing the female-specific effect of GH in rat liver.
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- Kotokorpi, P, et al.
(author)
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Activation of the glucocorticoid receptor or liver X receptors interferes with growth hormone-induced akr1b7 gene expression in rat hepatocytes
- 2004
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:12, s. 5704-5713
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Journal article (peer-reviewed)abstract
- The akr1b7 gene encodes an aldo-keto reductase involved in detoxification of isocaproaldehyde, the product from side chain cleavage of cholesterol, and of 4-hydroxynonenal (4-HNE) formed by lipid peroxidation and cleavage. Here we show that the expression of akr1b7 mRNA in rat liver is sexually differentiated, expressed in females but not in males, and regulated by the sexually dimorphic secretion pattern of GH. A GH dose-dependent induction of akr1b7 was demonstrated in cultured primary rat hepatocytes, which was sensitive to cycloheximide. Activation of the glucocorticoid receptor (GR) or liver X receptors (LXR) by dexamethasone (Dex) and T1317, respectively, attenuated the GH-induced expression of akr1b7 and CYP2C12, the prototypical rat hepatic gene dependent on the female-characteristic secretion pattern of GH. In contrast, neither Dex nor T1317 had any repressive effect on the GH induction of IGF-I mRNA. A common mechanism for LXR- and GR-mediated repressive actions on gene transcription is inhibition of nuclear factor (NF)-κB; however, EMSAs and pharmacological interference with NF-κB signaling provided no evidence for the involvement of NF-κB in the repressive action of Dex and T1317 on GH-induced akr1b7 expression.
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