The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse
The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse
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DOI：
10.1194/jlr.m300135-jlr200
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发表时间：
2003-11-01
影响因子：
6.5
通讯作者：
Lawn, RM
中科院分区：
文献类型：
--
作者：
Chisholm, JW;Hong, J;Lawn, RM
目前正在评估肝脏 X 受体 (LXR) 配体作为治疗低 HDL 的潜在治疗药物。 LXR 配体 T0901317 可提高动物模型中 ATP 结合盒转运蛋白 A1 (ABCA1) 和 HDL 水平，并通过上调甾醇调节元件结合蛋白 1c (SREBP1c) 诱导适度的脂肪生成。由于胰岛素还可以通过 SREBP1c 和脂肪酸合酶 (FAS) 调节脂肪生成，因此我们研究了 LXR 配体对高胰岛素血症小鼠的影响。与非糖尿病小鼠相比，对雄性 db/db 小鼠施用 T0901317 12 天导致更严重的高三酰甘油血症和肝脏三酰甘油蓄积。在糖尿病 db/db 和非糖尿病 C57BLKS 小鼠中，T0901317 治疗后 LXR 靶基因 ABCA1、SREBP1c、FAS 和硬脂酰辅酶 A 去饱和酶 1 均上调。脂肪生成基因表达的变化与小鼠品系无关，表明在LXR配体处理的db/db小鼠中观察到的严重脂肪生成并不是由于胰岛素对脂肪生成基因表达的附加作用。磷酸烯醇丙酮酸羧激酶表达受到抑制，表明从糖异生到脂肪生成的转变可以部分解释我们在 db/db 小鼠中的观察结果。jlr 我们的数据表明，对脂肪酸和碳水化合物代谢都有影响的 LXR 配体应在肥胖、胰岛素和瘦素抵抗中仔细评估。-Chisholm，J. W.，J. Hong，S.A. 米尔斯和 R.M. 劳恩。 LXR 配体 T0901317 在 db/db 糖尿病小鼠中诱导严重的脂肪生成。
Liver X receptor (LXR) ligands are currently being evaluated as potential therapeutic agents for the treatment of low HDL. The LXR ligand T0901317 elevates ATP binding cassette transporter A1 (ABCA1) and HDL levels in animal models and induces moderate lipogenesis through upregulation of sterol regulatory element binding protein 1c (SREBP1c). Because insulin may also regulate lipogenesis through SREBP1c and fatty acid synthase (FAS), we investigated the effect of an LXR ligand in hyperinsulinemic mice. Administration of T0901317 to male db/db mice for 12 days resulted in a more severe hypertriacylglycerolemia and hepatic triacylglycerol accumulation than observed in nondiabetic mice. The LXR target genes ABCA1, SREBP1c, FAS, and stearoyl-CoA desaturase 1 were upregulated by T0901317 treatment in both diabetic db/db and nondiabetic C57BLKS mice. Changes in lipogenic gene expression were independent of mouse strain, indicating that the severe lipogenesis observed in LXR ligand-treated db/db mice was not due to additive effects of insulin on lipogenic gene expression. Phosphoenolpyruvate carboxykinase expression was suppressed, suggesting that a shift from gluconeogenesis toward lipogenesis could partially explain our observations in db/db mice.jlr Our data suggest that LXR ligands that have effects on both fatty acid and carbohydrate metabolism should be carefully evaluated in obesity, insulin, and leptin resistance.-Chisholm, J. W., J. Hong, S. A. Mills, and R. M. Lawn. The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse.