Department of Biosciences and Nutrition and Center for Biosciences at NOVUM, Karolinska Institutet, Lipid Laboratory, Huddinge, Sweden.
Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E210-22. doi: 10.1152/ajpendo.00541.2010. Epub 2011 Apr 26.
The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ(-/-) mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ(-/-) mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ(-/-) mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ(-/-) mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from Vo(2) and Vco(2) was significantly higher in LXRαβ(-/-) than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ(-/-) mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ(-/-) mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ(-/-) mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ(-/-) mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
肝 X 受体 (LXRs) 在胆固醇和胆汁酸代谢中发挥关键作用，但也是葡萄糖代谢的重要调节剂。最近，LXR 被认为是一种影响 LXR 依赖性基因表达的葡萄糖传感器。我们用正常饮食 (ND) 或高碳水化合物饮食 (HCD) 对野生型 (WT) 和 LXRαβ(-/-) 小鼠进行了挑战。磁共振成像显示 WT 和 LXRαβ(-/-) 小鼠之间的脂肪分布不同。令人惊讶的是，与 ND 相比，WT 小鼠的生殖腺 (GL) 脂肪细胞体积在 HCD 下减少，而 LXRαβ(-/-) 小鼠则略有增加。有趣的是，与 ND 相比，HCD 下 LXRαβ(-/-) 小鼠的分离 GL 脂肪细胞的胰岛素刺激脂肪生成减少，而 WT 小鼠则没有变化。从 Vo(2) 和 Vco(2) 计算的净从头脂肪生成 (DNL) 在 HCD 下 LXRαβ(-/-) 小鼠中明显高于 WT 小鼠。HCD 喂养肝脏的组织学显示 WT 小鼠存在肝脂肪变性，但 LXRαβ(-/-) 小鼠则没有。各组之间的葡萄糖耐量没有差异，但 HCD 使 WT 小鼠而非 LXRαβ(-/-) 小鼠的胰岛素敏感性降低。最后，对脂肪组织的基因表达分析显示，与 WT 动物相比，LXRαβ(-/-) 小鼠中参与 DNL 的基因表达上调，而在 LXRαβ(-/-) 小鼠中，肝内 DNL 基因的表达受到抑制。因此，我们得出结论，缺乏 LXR 会刺激脂肪组织中的 DNL，但会抑制肝脏中的 DNL，这表明 LXR 在这两种组织中的 DNL 调节中具有相反的作用。这些结果表明 LXR 活性具有组织特异性调节作用，这是药物开发的关键发现。
