HNF-4-dependent induction of apolipoprotein A-IV gene transcription by an apical supply of lipid micelles in intestinal cells
HNF-4-dependent induction of apolipoprotein A-IV gene transcription by an apical supply of lipid micelles in intestinal cells
复制标题
DOI：
10.1074/jbc.m408002200
复制
发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Lacorte, JM
中科院分区：
文献类型：
--
作者：
Carrière, V;Vidal, R;Lacorte, JM
载脂蛋白 (apo) A-IV 是小肠分泌的富含甘油三酯的脂蛋白的组成部分，已被证明在控制脂质稳态中发挥重要作用。许多研究描述了脂质诱导apoA-IV基因表达，但该过程中涉及的分子机制仍不清楚。在这项研究中，我们证明了脂质丸剂诱导转基因小鼠中apoA-IV基因的转录，并且由apoC-III增强子和apoA-IV启动子（eC3-A4）组成的apoA-IV基因的调控区负责这种诱导。在肠细胞 Caco-2/TC7 细胞中，基极的脂质永久供应可在转录水平和通过 mRNA 稳定诱导 apoA-IV 基因的表达。模拟十二指肠胶束组成的复杂脂质胶束的顶端供应进一步诱导 ApoA-11V 基因转录和蛋白质分泌，并且这种效果不能通过顶端递送不同胶束成分组合来重现。只有脂质胶束对 apoA-IV 基因的诱导涉及肝核因子 (HNF)-4 的参与，如使用该转录因子的显性失活形式所证明的。因此，脂质胶束增加了 HNF-4 在 eC3-A4 区域上的 DNA 结合活性。这些结果强调了膳食脂质的生理传递对 apoA-IV 基因表达的重要性以及 HNF-4 在这种调节中的意义。
Apolipoprotein (apo) A-IV, a component of triglyceride-rich lipoproteins secreted by the small intestine, has been shown to play an important role in the control of lipid homeostasis. Numerous studies have described the induction of apoA-IV gene expression by lipids, but the molecular mechanisms involved in this process remain unknown. In this study, we have demonstrated that a lipid bolus induced transcription of the apoA-IV gene in transgenic mice and that the regulatory region of the apoA-IV gene, composed of the apoC-III enhancer and the apoA-IV promoter (eC3-A4), was responsible for this induction. In enterocyte Caco-2/TC7 cells, a permanent supply of lipids at the basal pole induced expression of the apoA-IV gene both at the transcriptional level and through mRNA stabilization. ApoA-11V gene transcription and protein secretion were further induced by an apical supply of complex lipid micelles mimicking the composition of duodenal micelles, and this effect was not reproduced by apical delivery of different combinations of micelle components. Only induction of the apoA-IV gene by lipid micelles involved the participation of hepatic nuclear factor (HNF)-4, as demonstrated using a dominant negative form of this transcription factor. Accordingly, lipid micelles increased the DNA binding activity of HNF-4 on the eC3-A4 region. These results emphasize the importance of physiological delivery of dietary lipids on apoA-IV gene expression and the implication of HNF-4 in this regulation.