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472 INTRAUTERINE GROWTH RESTRICTION ALTERS HEPATIC INSULIN GROWTH FACTOR 1 PROMOTER UTILIZATION AND EXPRESSION.
  1. Q. Fu,
  2. R. A. McKnight,
  3. X. Yu,
  4. C. W. Callaway,
  5. R. H. Lane
  1. Division of Neonatology, University of Utah, Salt Lake City, UT

Abstract

Background IUGR predisposes towards lower IGF-1 levels, which is significant because decreased IGF-1 levels contribute to insulin resistance during adulthood. In humans and rats, IGF-1 expression involves the use of different promoters and splice variants. This is a characteristic associated with epigenetic regulation of gene, which is altered in the IUGR liver. IGF-1 expression involves the use of two different promoters, while alternative splicing within exon 4 accounts for the IGF-1 variants A (IGF-1A) and B (IGF-1B).

Objective We therefore hypothesized that IUGR in the rat would influence hepatic expression of IGF-1 and promoter utilization.

Methods IUGR was induced via bilateral uterine artery ligation. Liver was harvested from IUGR and sham controls (Con) on day 0 and day 21. IGF-1 gene expression was measured. Initiation at promoter one (P1) and promoter two (P2) transcription start sites were quantified.

Results Results are expression as percent of Con ± SEM. IUGR decreased IGF-1 protein levels in day 0 IUGR female rats to 52 ± 15%** of Con and decreased IGF-1 protein levels in day 21 IUGR male and female rats to 69 ± 5%** and 29 ± 5%*** of Con values respectively. Similarly, IGF-1A mRNA levels were decreased to 38 ± 2.9%*** and 40 ± 10.3%** of Con in male and female day 0 pups respectively, though no difference was noted at day 21. IGF-1B mRNA levels were decreased to 26 ± 2.3%*** and 39 ± 3.9%*** in male and female day 0 pups respectively. At day 21, IGF-1B mRNA levels were also decreased to 68 ± 6%* and 86 ± 2.9%* of male and female Con levels respectively. At day 0, transcription initiation from P1 in IUGR males and females was 25 ± 2.6%*** and 41 ± 6%*** of Con, with no difference at day 21. Transcription initiation from P2 in day 0 IUGR animals was 39 ± 7%** and 46 ± 2.6%*** in male and females respectively, while at day 21, IUGR still reduced P2 transcription initiation to 75 ± 2.5%*** and 79 ± 4.1%** of male and female control values (*p < .05; **p < .01; ***p < .001).

Conclusions IUGR decreased hepatic IGF-1 gene expression in neonatal and adolescent rats. IGF-1 promoter activity in IUGR from P1 and P2 was decreased at day 0 and P1 remained low at day 21. These findings are novel by demonstrating the effects of IUGR upon IUGF-1 splice variation and promoter utilization. We speculated that IUGR-induced epigenetic reprogramming may play a role in IGF-1 gene expression change using the P2 promoter.

March of Dimes and HD41075.

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