Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities
Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities
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DOI：
10.1074/jbc.m700270200
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发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Sato, Ryuichiro
中科院分区：
文献类型：
--
作者：
Kanayama, Tomohiko;Arito, Mitsumi;Sato, Ryuichiro
先前的研究表明，甾醇调节元件结合蛋白 (SREBP) 能够与核受体之一肝细胞核受体 (HNF)-4 相互作用，并且这种相互作用调节这些蛋白质的转录活性（Misawa, K.、Horiba, T.、Arimura, N.、Hirano, Y.、Inoue, J.、Emoto, N.、Shimano, H.、Shimizu, M. 和 Sato， R. (2003) J. Biol. 278, 36176 - 36182; Yamamoto, T., Nakakawa, Y., Ide, T., Yahagi, N., Matsuzaka, T., Nakakuki, M., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Sato, R., 和山田，N. (2004) 化学杂志 279, 12027 12035)。在试图鉴定影响 SREBP 转录活性的其他核受体家族成员时，我们发现肝受体同源物 (LRH)-1 会抑制它们。几种类型的荧光素酶测定表明，这两种蛋白（LRH-1 和 SREBP-1a、-1c 或 -2）的共表达会导致每种蛋白转录活性的相互抑制。已证实，小干扰RNA对内源LRH-1的抑制会刺激某些SREBP靶基因的mRNA水平，并且细胞核中响应胆固醇消耗而升高的活性SREBP会抑制LRH-1活性。体外/体内谷胱甘肽S-转移酶下拉实验表明，SREBP-2中的基本螺旋-环-螺旋-亮氨酸拉链结构域与LRH-1中的配体结合结构域结合。此外，我们发现SREBP-2干扰LRH-1共激活剂（过氧化物酶体增殖物激活受体γ共激活剂-1α）的募集，从而导致LRH-1转录抑制活动。这些结果清楚地表明，SREBP 和 LRH-1 之间的相互作用对其负责胆固醇和胆汁酸代谢的靶基因表达产生抑制影响。
In previous studies it was demonstrated that sterol regulatory element-binding proteins ( SREBPs) are able to interact with one of the nuclear receptors, hepatocyte nuclear receptor (HNF)-4, and that this interaction regulates transcriptional activities of these proteins (Misawa, K., Horiba, T., Arimura, N., Hirano, Y., Inoue, J., Emoto, N., Shimano, H., Shimizu, M., and Sato, R. (2003) J. Biol. Chem. 278, 36176 - 36182; Yamamoto, T., Shimano, H., Nakagawa, Y., Ide, T., Yahagi, N., Matsuzaka, T., Nakakuki, M., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Sato, R., and Yamada, N. ( 2004) J. Biol. Chem. 279, 12027 12035). In an attempt to identify other nuclear receptor family members affecting the SREBP transcriptional activities, we found that the liver receptor homolog (LRH)-1 suppresses them. Several types of luciferase assays revealed that coexpression of these two proteins (LRH- 1 and SREBP- 1a, - 1c, or - 2) results in reciprocal inhibition of the transcriptional activity of each protein. It was confirmed that suppression in endogenous LRH- 1 by small interference RNA stimulates the mRNA levels of certain SREBP target genes and that elevation in active SREBPs in the nucleus in response to cholesterol depletion suppresses the LRH- 1 activity. In vitro/ in vivo glutathione S-transferase pulldown experiments demonstrated that the basic helix-loop-helix-leucine zipper domain in SREBP- 2 binds to the ligand-binding domain in LRH- 1. Furthermore, we found that SREBP- 2 interferes with the recruitment of a coactivator of LRH-1, the peroxisome proliferator- activated receptor gamma coactivator-1 alpha, thereby leading to the inhibition of the LRH- 1 transcriptional activity. These results clearly indicate that the interaction between SREBPs and LRH-1 exerts a suppressive influence on their target gene expression responsible for cholesterol and bile acid metabolism.