Estrogen-related receptor α (ERRα) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine
Estrogen-related receptor α (ERRα) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine
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DOI：
10.1074/jbc.m410337200
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发表时间：
2004-12-10
影响因子：
4.8
通讯作者：
Giguère, V
中科院分区：
文献类型：
--
作者：
Carrier, JC;Deblois, GV;Giguère, V
雌激素相关受体α（ERRalpha）是参与能量代谢控制的核受体超家族的孤儿成员。特别是，ERR α在辅活化剂PGC-1 α存在下诱导高能量消耗。然而，ERR α基因敲除小鼠的脂肪量减少，并且对饮食诱导的肥胖有抵抗力。ERRalpha在小肠上皮细胞中表达，由于肠道是能量链的第一步，我们研究了ERRalpha是否在饮食能量处理中发挥作用。肠道中的基因表达谱鉴定了参与氧化磷酸化的基因子集，其在没有ERR α的情况下下调。为了支持ERR α在该途径中的生理作用，来自ERR α敲除小鼠的分离的肠细胞显示出较低的β-氧化能力。微阵列结果还显示了参与膳食脂质消化和吸收的基因表达的改变，如胰腺脂肪酶相关蛋白2（PLRP 2），脂肪酸结合蛋白1和2（L-FABP和I-FABP），载脂蛋白A-IV（apoA-IV）。与此一致，我们发现ERRalpha（-/-）幼崽表现出明显的脂质吸收不良。我们进一步表明，apoA-IV启动子是ERR α的直接靶点，它的存在是维持基础水平所必需的，但不是小鼠中apoA-IV基因的喂养诱导调节。ERR α与PGC-1 α协同作用，通过与人和小鼠apoC-III增强子相互作用激活apoA-IV启动子。我们的研究结果表明，载脂蛋白A-IV是一个直接ERRalpha靶基因，并建议ERRalpha在肠道脂肪转运，能量平衡的关键步骤的功能。
The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha. However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRalpha. In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 ( L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRalpha(-/-) pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRalpha and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRalpha, in cooperation with PGC-1alpha, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRalpha target gene and suggest a function for ERRalpha in intestinal fat transport, a crucial step in energy balance.