HIGH-CALORIE TOTAL PARENTERAL-NUTRITION REDUCES HEPATIC INSULIN-LIKE GROWTH-FACTOR-I MESSENGER-RNA AND ALTERS SERUM LEVELS OF INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-1, PROTEIN-3, PROTEIN-5, AND PROTEIN-6 IN THE RAT

High-calorie total parenteral nutrition (TPN) is associated with hepatic dysfunction and steatosis. Because TPN-induced steatosis might compromise hepatic expression of insulin-like growth factor-I (IGF-I) and thereby limit its potential nutritional benefit, we examined hormonal and IGF-I responses in male Sprague-Dawley rats (270 to 300 g) fed by continuous intravenous infusion with high-calorie, high-dextrose (350 kcal/kg) TPN solutions for 0 (control), 2, 4, and 8 days. Since IGF-binding proteins (IGFBPs) are thought to modulate the biological effects of IGFs in target tissues, we also determined serum levels of IGFBPs. Animals developed hepatic steatosis after 2 to 8 days of TPN, as reflected by a sevenfold to 15-fold increase in hepatic triacylglycerol content (P < .001 v control on each day). Serum corticosterone and insulin levels were significantly higher after 2 and 4 days of TPN, whereas serum growth hormone levels were reduced after 4 and 8 days. Serum IGF-I levels were not significantly different during TPN. However, there was a coordinate reduction in the three major hepatic IGF-I transcripts (7.0, 1.9, and 1.0 kb) after 2, 4, or 8 days of TPN, and IGF-I transcripts corresponding to multiple initiation sites within exons 1 and 2 were coordinately downregulated with TPN. Western ligand blotting indicated that serum levels of 38K to 43K, 30K to 34K, and 24K IGFBPs were increased approximately twofold after 4 and 8 days of TPN as compared with control values. Immunoprecipitation with specific antisera revealed that these changes reflect increased levels of immunoreactive IGFBP-3 (38K to 43K), IGFBP-5 (32K), and IGFBP-6 (24K to 26K). In contrast, serum levels of 32K and 34K forms of IGFBP-1 were reduced and levels of IGFBP-2 and -4 were not changed. In summary, high-calorie TPN results in hepatic steatosis and decreased hepatic abundance of IGF-I mRNA, suggesting that hepatic synthesis of IGF-I may be compromised during high-calorie TPN. Changes in circulating levels of IGFBP-1, -3, -5, and -6 emphasize that high-calorie TPN exerts complex effects on the IGF/IGFBP system, which may have important implications for understanding the biological impact of parenteral nutritional therapy.