Selective Proteolytic Processing of Rat Hepatic Sterol Regulatory Element Binding Protein-1 (SREBP-1) and SREBP-2 During Postnatal Development

Sterol regulatory element-binding protein-1c (SREBP-1c) plays a major role in hepatic lipogenic gene expression. In adult animals, insulin and oxysterols induce SREBP-1c gene transcription, whereas polyunsaturated fatty acids suppress the nuclear content of SREBP-1c through pre-translational regulatory mechanisms. A decline in nuclear SREBP-1 is associated with suppression of hepatic lipogenesis. In contrast to adult rats, hepatic lipogenesis in preweaned neonatal rats is low. Ingestion of milk fat by the neonate may contribute to low hepatic lipogenesis. In this report, we tested the hypothesis that low lipogenic gene expression prior to weaning correlates with low mRNA(SREBP-1c), as well as low precursor and nuclear forms of SREBP-1. In contrast to expectations, levels of mRNA(SREBP-1c) and the 125-kDa SREBP-1 precursor in livers of preweaned rats was comparable with adult levels. Despite high levels of SREBP-1 precursor, mature (65 kDa) SREBP-1 was not detected in rat liver nuclei prior to 18 days postpartum. Weaning rats at 21 days postpartum was accompanied by a rise in nuclear SREBP-1 levels as well as increased lipogenic gene expression. In contrast, SREBP-2 was present in rat liver nuclei, and its target gene, HMG-CoA reductase, was expressed above adult levels prior to weaning. These studies indicate that, prior to weaning, SREBP-2 but not SREBP-1 is proteolytically processed to the mature form. As such, SREBP-2-regulated genes are active. Failure of SREBP-1 to be processed to the mature form <18 days postpartum correlates with low hepatic lipogenic gene expression. This mechanism differs from the hormonal and fatty acid-mediated pre-translational control of SREBP-1c in adult liver.