MPPAR-GAMMA-2 - TISSUE-SPECIFIC REGULATOR OF AN ADIPOCYTE ENHANCER
MPPAR-GAMMA-2 - TISSUE-SPECIFIC REGULATOR OF AN ADIPOCYTE ENHANCER
复制标题
DOI：
10.1101/gad.8.10.1224
复制
发表时间：
1994-05-15
影响因子：
10.5
通讯作者：
SPIEGELMAN, BM
中科院分区：
文献类型：
--
作者：
TONTONOZ, P;HU, E;SPIEGELMAN, BM
以前，我们已经从脂肪细胞P2（aP 2）基因的5 '侧翼区域分离和表征了一种增强子，该增强子在培养细胞和转基因小鼠中指导高水平的脂肪细胞特异性基因表达。这种增强子的关键调节因子是一种称为ARF 6的细胞类型限制性核因子。aP 2增强子中ARF 6的靶序列与间隔一个核苷酸的激素反应元件（HRE）的直接重复序列具有同源性;该基序（DR-1）先前已被证明是类维生素A X受体（RXR）和过氧化物酶体增殖物激活受体（PPAR）异二聚体的首选结合位点。我们已经克隆了一个新的过氧化物酶体增殖物激活受体家族成员指定的mPPAR γ 2，我们证明，mPPAR γ 2和RXR α的异二聚体复合物构成一个功能性的ARF 6复合物。在几种培养的脂肪细胞系的分化过程中，mPPAR γ 2的表达很早就被诱导，并且在体内具有显著的脂肪特异性。mPPAR γ 2和RXR α在体外在ARF 6结合位点上形成异二聚体，RXR α的抗血清特异性抑制脂肪细胞核提取物中的ARF 6活性。此外，mPPAR γ 2和RXR α的强制表达激活了培养的成纤维细胞中的脂肪细胞特异性aP 2增强子，并且这种激活通过过氧化物酶体增殖剂、脂肪酸和9-顺式视黄酸增强。这些结果确定mPPAR γ 2作为第一个脂肪细胞特异性转录因子，并建议机制，脂肪酸，过氧化物酶体增殖物，9-顺式视黄酸，和其他脂质可以调节脂肪细胞基因的表达和分化。
Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic mice. The key regulator of this enhancer is a cell type-restricted nuclear factor termed ARF6. Target sequences for ARF6 in the aP2 enhancer exhibit homology to a direct repeat of hormone response elements (HREs) spaced by one nucleotide; this motif (DR-1) has been demonstrated previously to be the preferred binding site for heterodimers of the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). We have cloned a novel member of the peroxisome proliferator-activated receptor family designated mPPAR gamma 2, and we demonstrate that a heterodimeric complex of mPPAR gamma 2 and RXR alpha constitute a functional ARF6 complex. Expression of mPPAR gamma 2 is induced very early during the differentiation of several cultured adipocyte cell lines and is strikingly adipose-specific in vivo. mPPAR gamma 2 and RXR alpha form heterodimers on ARF6-binding sites in vitro, and antiserum to RXR alpha specifically inhibits ARF6 activity in adipocyte nuclear extracts. Moreover, forced expression of mPPAR gamma 2 and RXR alpha activates the adipocyte-specific aP2 enhancer in cultured fibroblasts, and this activation is potentiated by peroxisome proliferators, fatty acids, and 9-cis retinoic acid. These results identify mPPAR gamma 2 as the first adipocyte-specific transcription factor and suggest mechanisms whereby fatty acids, peroxisome proliferators, 9-cis retinoic acid, and other lipids may regulate adipocyte gene expression and differentiation.