Amino acid and growth hormone dependent regulation of insulin-like growth factor-I gene expression in ovine hepatocytes
This study was designed to assess the effects of amino acid supply and growth hormone (GH) treatment on IGF-I gene expression of ovine hepatocytes and to determine the possible mechanism(s) involved. Using a riboprobe that detect both type 1 and type 2 mRNA transcripts, GH and amino acid were shown to have separate and interactive effects on the regulation of IGF-I gene expression and these effects were similar for both transcripts. The stimulatory effects of GH and amino acid supply were shown to depend at least in part on transcriptional control, since transcription blockade resulted in the abolition of both the GH and amino acid dependent responses. The effect of amino acid supply could not be attributed to any single amino acid (so far studied). However, partial effects of methionine and the branched chain amino acid limitation on GH dependent IGF-I mRNA expression were observed. Also methionine limitation caused the abolition of GH dependent IGF-I peptide secretion. The observed effects of amino acid supply on IGF-I gene expression were not dependent on the mTOR, PI3 kinase or MAP kinase pathways. However, GH dependent IGF-I peptide secretion was apparently PI3 kinase and MAP kinase sensitive. In conclusion, IGF-I gene expression is highly sensitive to GH and amino acid supply. The mechanism by which amino acid supply regulates IGF-I gene expression is mTOR independent. GH appears to regulate IGF-I production at the gene expression level, and also possibly at a translational/post-translational level through a PI3 kinase and MAP kinase dependent mechanism which may be methionine sensitive.