N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRalpha.
N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRalpha.
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DOI：
10.1016/j.bbalip.2009.08.008
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发表时间：
2009-12
影响因子：
4.8
通讯作者：
Elam, Marshall B.
中科院分区：
文献类型：
--
作者：
Howell, George, III;Deng, Xiong;Yellaturu, Chandrahassa;Park, Edwards A.;Wilcox, Henry G.;Raghow, Rajendra;Elam, Marshall B.
关键词：
胰岛素通过诱导固醇调节元件结合蛋白-1c（SREBP-1c）协同上调脂肪生成基因转录。相反，多不饱和脂肪酸（PUFA）通过抑制SREBP-1c降低脂肪生成基因的转录。因此，我们在原代大鼠肝细胞培养物中检测了n-3 PUFA减轻胰岛素诱导SREBP-1c及其下游脂肪生成靶点的能力。胰岛素诱导SREBP-1c mRNA表达5-6倍以及大鼠SREBP-1c启动子活性。这些作用可被n-3脂肪酸二十碳五烯酸（20：5 n-3; EPA）和二十二碳六烯酸（22：6 n-3，DHA）阻止，但不能被单不饱和脂肪酸油酸（18：1 n-6，奥拉）阻止。N-3脂肪酸还有效地阻止了胰岛素对下游脂肪生成酶靶点脂肪酸合成酶（FAS）和乙酰羧基辅酶乙酰转移酶-1（ACC-1）的诱导，并减少了从头脂肪生成。SREBP-1c启动子包含由串联LXRα反应元件（LXRE）组成的胰岛素反应单元以及NF-Y、Sp1和SREBP-1c本身的位点。LXRE被鉴定为介导n-3 PUFA抑制SREBP-1c转录的主要位点。DHA有效地阻止了野生型SREBP-1c启动子和合成的LXRE驱动启动子的LXRα依赖性激活，并显著减弱了Gal 4-LXRα嵌合蛋白的LXRα依赖性激活，因此证明n-3 PUFA通过降低LXRα的反式激活有效地减轻了胰岛素对SREBP-1c的诱导。
Insulin coordinately up-regulates lipogenic gene transcription via induction of sterol regulatory element binding protein-1c (SREBP-1c). Conversely, polyunsaturated fatty acids (PUFA) decrease lipogenic gene transcription via suppression of SREBP-1c. We therefore examined the ability of n-3 PUFA to mitigate induction of SREBP-1c and its downstream lipogenic targets by insulin in primary rat hepatocyte cultures. Insulin induced expression of SREBP-1c mRNA 5–6 fold as well as rat SREBP-1c promoter activity. These effects were prevented by the n-3 fatty acids eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3, DHA), but not by the monounsaturated fatty acid oleic acid (18:1 n-6, OLA). N-3 fatty acids also effectively prevented insulin induction of the downstream lipogenic enzyme targets fatty acid synthase (FAS) and acetyl carboxyl coenzyme acetyltransferase-1 (ACC-1), and reduced de novo lipogenesis. The SREBP-1c promoter contains an insulin response unit consisting of tandem LXRα response elements (LXREs) as well as sites for NF-Y, Sp1, and SREBP-1c itself. The LXREs were identified as a primary site mediating suppression of SREBP-1c transcription by n-3 PUFA. DHA effectively prevented LXRα-dependent activation of both the wild type SREBP-1c promoter and the synthetic LXRE-driven promoter, and significantly blunted LXRα-dependent activation of a Gal4-LXRα chimeric protein thus demonstrating that n-3 PUFA effectively mitigate induction of SREBP-1c by insulin via reduced trans-activation of LXRα.
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影响因子：
6.9
作者：
Ginsberg, Henry N.;Zhang, Yuan-Li;Hernandez-Ono, Antonio
通讯作者：
Hernandez-Ono, Antonio
影响因子：
4.8
作者：
Hannah, VC;Ou, JF;Brown, MS
通讯作者：
Brown, MS
影响因子：
2.8
作者：
Davidson, Michael H.
通讯作者：
Davidson, Michael H.
影响因子：
4.8
作者：
Deng, Xiong;Yellaturu, Chandrahasa;Elam, Marshall B.
通讯作者：
Elam, Marshall B.
DOI：
10.1016/j.advenzreg.2003.11.020
发表时间：
2004-01-01
期刊：
ADVANCES IN ENZYME REGULATION, VOL 44
影响因子：
--
作者：
Kwon, HS;Harris, RA
通讯作者：
Harris, RA