Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease.
Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease.
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DOI：
10.1016/j.bbrc.2016.09.036
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发表时间：
2016-10-21
影响因子：
3.1
通讯作者：
Burris TP
中科院分区：
文献类型：
--
作者：
Griffett K;Burris TP
肝脏X受体（LXR）作为氧固醇的受体发挥功能，并在葡萄糖和脂质代谢的调节中发挥关键作用。我们最近描述了一种合成的LXR反向激动剂，其在非酒精性脂肪性肝病（NAFLD）小鼠模型中显示出治疗肝脂肪变性的功效。该化合物SR9238旨在显示肝脏特异性，以避免对外周组织中胆固醇逆向转运的潜在有害影响。在这里，我们研究了LXR拮抗剂/反向激动剂GSK 2033的作用，其显示全身暴露。尽管GSK 2033在基于细胞的模型中作为LXR反向激动剂表现出预期的效果，但它在小鼠NAFLD模型中显示出意想不到的活性。脂肪酸合成酶和固醇调节结合蛋白1c等脂肪生成酶基因的表达被诱导而不是抑制，对肝脂肪变性没有影响，进一步表征GSK 2033的特异性表明，它显示出显着程度的混杂性，靶向一些其他核受体，可以清楚地改变肝基因表达。
The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inverse agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression.
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LXR反向激动剂SR9238在非酒精性脂肪性肝炎模型中抑制纤维化。
影响因子：
8.1
作者：
Griffett K;Welch RD;Flaveny CA;Kolar GR;Neuschwander-Tetri BA;Burris TP
通讯作者：
Burris TP
影响因子：
4.8
作者：
Cao, GQ;Liang, Y;Etgen, GJ
通讯作者：
Etgen, GJ
影响因子：
6.5
作者：
Chisholm, JW;Hong, J;Lawn, RM
通讯作者：
Lawn, RM
影响因子：
4.8
作者：
Kumar, Naresh;Solt, Laura A.;Burris, Thomas P.
通讯作者：
Burris, Thomas P.
DOI：
10.1073/pnas.0404297101
发表时间：
2004-08-03
影响因子：
11.1
作者：
Chen, GX;Liang, GS;Brown, MS
通讯作者：
Brown, MS