RESUMO
Enterocytes assemble dietary lipids into chylomicron particles that are taken up by intestinal lacteal vessels and peripheral tissues. Although chylomicrons are known to assemble in part within membrane secretory pathways, the modifications required for efficient vascular uptake are unknown. Here we report that the transcription factor pleomorphic adenoma gene-like 2 (PlagL2) is essential for this aspect of dietary lipid metabolism. PlagL2(-/-) mice die from postnatal wasting owing to failure of fat absorption. Lipids modified in the absence of PlagL2 exit from enterocytes but fail to enter interstitial lacteal vessels. Dysregulation of enterocyte genes closely linked to intracellular membrane transport identified candidate regulators of critical steps in chylomicron assembly. PlagL2 thus regulates important aspects of dietary lipid absorption, and the PlagL2(-/-) animal model has implications for the amelioration of obesity and the metabolic syndrome.
Assuntos
Quilomícrons/metabolismo , Proteínas de Ligação a DNA/fisiologia , Proteínas de Ligação a RNA/fisiologia , Fatores de Transcrição/fisiologia , Animais , Transporte Biológico , Northern Blotting , Quilomícrons/farmacocinética , Proteínas de Ligação a DNA/genética , Gorduras na Dieta/metabolismo , Gorduras na Dieta/farmacocinética , Enterócitos/metabolismo , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genéticaRESUMO
IMP2 (insulin-like growth factor-II mRNA binding protein 2) is an oncofetal protein that is aberrantly expressed in several types of cancer. We recently identified the Imp2 gene as a target gene of the architectural transcription factor HMGA2 (high mobility group A2) and its tumor-specific truncated form HMGA2Tr. In this study, we investigated the mechanism via which HMGA2 regulates Imp2 gene expression. We show that HMGA2 and HMGA2Tr directly regulate transcription of the Imp2 gene by binding to an AT-rich regulatory region located in the first intron. In reporter experiments, we show that this AT-rich regulatory region mimics the response of the endogenous Imp2 gene to HMGA2 and HMGA2Tr. Furthermore, we show that a consensus nuclear factor-kappaB (NF-kappaB) binding site located immediately adjacent to the AT-rich regulatory region binds NF-kappaB and that NF-kappaB and HMGA2 cooperate to regulate Imp2 gene expression. Finally, we provide evidence that there is a strong and statistically significant correlation between HMGA2 and IMP2 gene expression in human liposarcomas.
