title: Regulation of fetal liver growth in a model of diet restriction in the pregnant rat.
abstract: Limited nutrient availability is a cause of intrauterine growth restriction (IUGR), a condition that has important implications for the well being of the offspring. Using the established IUGR model of maternal fasting in the rat, we investigated mechanisms that control gene expression and mRNA translation in late-gestation fetal liver. Maternal fasting for 48 h during the last one-third of gestation was associated with a 10-15% reduction in fetal body weight and a disproportionate one-third reduction in total fetal liver protein. The fetal liver transcriptome showed only subtle changes consistent with reduced cell proliferation and enhanced differentiation in IUGR. Effects on the transcriptome could not be attributed to specific transcription factors. We purified translating polysomes to profile the population of mRNAs undergoing active translation. Microarray analysis of the fetal liver translatome indicated a global reduction of translation. The only targeted effect was enhanced translation of mitochondrial ribosomal proteins in IUGR, consistent with enhanced mitochondrial biogenesis. There was no evidence for attenuated signaling through the mammalian target of rapamycin (mTOR). Western blot analysis showed no changes in fetal liver mTOR signaling. However, eukaryotic initiation factor 2α (eIF2α) phosphorylation was increased in livers from IUGR fetuses, consistent with a role in global translation control. Our data indicate that IUGR-associated changes in hepatic gene expression and mRNA translation likely involve a network of complex regulatory mechanisms, some of which are novel and distinct from those that mediate the response of the liver to nutrient restriction in the adult rat.
authors.affiliation: Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island;
authors.forename: Joan M
authors.initials: JM
authors.lastname: Boylan
authors.affiliation: Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sanders
authors.affiliation: Division of Pediatric Endocrinology, Rhode Island Hospital and Brown University, Providence, Rhode Island; Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island Philip_Gruppuso@brown.edu.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gruppuso
mesh_terms: D000818:Animals; D031204:Caloric Restriction / Q000009:adverse effects; D005215:Fasting; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D046912:Multiprotein Complexes; D012333:RNA, Messenger; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: fetus; liver; mTOR; protein synthesis; translation initiation