Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.
Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.
复制标题
含硼的化合物对SREBP转录活性的抑制可改善饮食诱导的肥胖症中的脂质稳态。
作者：
Zhao X;Xiaoli;Zong H;Abdulla A;Yang ES;Wang Q;Ji JY;Pessin JE;Das BC;Yang F
脂质稳态失调与肥胖、2型糖尿病和心血管疾病密切相关。甾醇调节元件结合蛋白（SREBP）是脂质生物合成的主要调节因子。先前的研究表明，保守的转录辅因子介体复合物是SREBP转录活性所必需的，并且介体复合物向SREBP反式激活结构域（TADs）的募集是通过MED 15-KIX结构域。最近，我们合成了几种含硼小分子。在这些新化合物中，BF 175在体外可特异性阻断MED 15-KIX与SREBP 1a-SREBP的结合，从而抑制SREBP的转录活性并降低培养肝细胞中SREBP靶基因的表达。此外，BF 175可以改善饮食诱导的肥胖症小鼠模型中的脂质稳态。与对照组相比，BF 175处理降低了小鼠肝脏中SREBP靶基因的表达，并降低了肝脏和血液中的脂质水平。这些结果表明，通过小分子阻断SREBP-TADs和介体复合物之间的相互作用可能代表了治疗脂质稳态异常疾病的新方法。
Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes, and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity, and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared with the control, BF175 treatment decreased the expression of SREBP target genes in mouse livers and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.
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影响因子：
2.7
作者：
Das, Bhaskar C.;Zhao, Xiaoping;Tang, Xiang-Ying;Yang, Fajun
通讯作者：
Yang, Fajun
影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
影响因子：
7.7
作者：
Laudes, M;Barroso, I;O'Rahilly, S
通讯作者：
O'Rahilly, S
影响因子：
5.9
作者：
Reaven, Gerald M.
通讯作者：
Reaven, Gerald M.
DOI：
10.1073/pnas.0401516101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Iizuka, K;Bruick, RK;Uyeda, K
通讯作者：
Uyeda, K