Evidence that an iron chelator regulates collagen synthesis by decreasing the stability of procollagen mRNA

✍ Scribed by Hitoshi Ikeda; George Y. Wu; Catherine H. Wu

• Book ID: 102848621
• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 672 KB
• Volume: 15
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840150218

✦ Synopsis

Iron chelation has been shown previously to decrease collagen synthesis at a posttranslational level by inhibiting prolyl4-hydroxylase, one of the key enzymes in collagen metabolism. On the other hand, recent in vivo studies of iron overload in rats suggest that iron could specifically activate collagen gene expression in liver tissues. These findings led us to investigate whether iron chelation might also affect collagen gene expression and posttranslational modification. Our data indicate that %a'-dipyridyl, an iron chelator, at a concentration of 1 mmolb, decreased steady-state levels of type I procollagen messenger RNA by 42% (p < 0.001) without affecting &actin messenger RNA levels. Nuclear runoff studies demonstrated that transcription of the type I procollagen gene was unchanged by a,d-dipyridyl. However, the turnover rate of type I procollagen messenger RNA was increased by 30%. This pretranslational inhibition of collagen synthesis was not due to decreased lipid peroxidation, because thiobarbituric acid-reactive substances were un- changed by a+'-dipyridyl. However, cycloheximide totally abolished the effect, indicating that de nouo protein synthesis was required. (HEPATOLOGY 1992;15: 282-287.)

Iron is an essential cofactor in the activity of prolyl 4-hydroxylase (1-4), one of the key enzymes in collagen synthesis. During synthesis of procollagen molecules, hydroxylation of proline residues occurs, catalyzed by prolyl 4-hydroxylase. Hydroxylation of proline is essential for the stable formation of the triple helix of procollagen, the lack of which results in slower procollagen secretion than normal (1, 5). In addition, under-