Isocaloric maternal low-protein diet alters IGF-I, IGFBPs, and hepatocyte proliferation in the fetal rat.
We investigated the effect of an isocaloric maternal low-protein diet during pregnancy in rats on the proliferative capacity of cultured fetal hepatocytes. The potential roles of these changes on the IGF-IGF-binding protein (IGFBP) axis, and the role of insulin and glucocorticoids in liver growth retardation, were also evaluated. Pregnant Wistar rats were fed a control (C) diet (20% protein) or a low-protein (LP) diet (8%) throughout gestation. In primary culture, the DNA synthesis of hepatocytes derived from LP fetuses was decreased by approximately 30% compared with control hepatocytes (P < 0.05). In parallel, in vivo moderate protein restriction in the dam reduced the fetal liver weight and IGF-I level in fetal plasma (P < 0.01) and augmented the abundance of 29- to 32-kDa IGFBPs in fetal plasma (P < 0.01) and fetal liver (P < 0.01). By contrast, the abundance of IGF-II mRNA in liver of LP fetuses was unaffected by the LP diet. In vitro, the LP-derived hepatocytes produced less IGF-I (P < 0.01) and more 29- to 32-kDa IGFBPs (P < 0.01) than hepatocytes derived from control fetuses. These alterations still appeared after 3-4 days of culture, indicating some persistence in programming. Dexamethasone treatment of control-derived hepatocytes decreased cell proliferation (54 +/- 2.3%, P < 0.01) and stimulated 29- to 32-kDa IGFBPs, whereas insulin promoted fetal hepatocyte growth (127 +/- 5.5%, P < 0.01) and inhibited 29- to 32-kDa IGFBPs. These results show that liver growth and cell proliferation in association with IGF-I and IGFBP levels are affected in utero by fetal undernutrition. It also suggests that glucocorticoids and insulin may modulate these effects.
El-Khattabi
Ilham
I
Laboratoire de Biologie Cellulaire, Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
Grégoire
Francine
F
Remacle
Claude
C
Reusens
Brigitte
B
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D018753:Diet, Protein-Restricted; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005333:Fetus; D005938:Glucocorticoids / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000494:pharmacology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000032:analysis / Q000494:pharmacology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis* / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis* / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000196:embryology*; D008431:Maternal-Fetal Exchange; D009929:Organ Size; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
D005938:Glucocorticoids; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone