ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver
ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver
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DOI：
10.1172/jci34314
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发表时间：
2008-03-01
影响因子：
15.9
通讯作者：
Postic, Catherine
中科院分区：
文献类型：
--
作者：
Denechaud, Pierre-Damien;Bossard, Pascale;Postic, Catherine
转录因子碳水化合物反应元件结合蛋白 (ChREBP) 已成为肝脏脂质合成的中心调节因子，因为它是葡萄糖诱导的糖酵解酶肝丙酮酸激酶 (L-PK) 表达所必需的，并与 SREBP 协同作用以诱导脂肪生成基因，例如乙酰辅酶 A 羧化酶 (ACC) 和脂肪酸合酶（FAS）。肝脏X受体(LXRs)也是脂肪生成途径的重要调节因子，最近发现ChREBP是LXRs的直接靶标，并且葡萄糖本身可以结合并激活LXRs，促使我们研究LXRs在肝脏中诱导葡萄糖调节基因中的作用。在野生型小鼠中使用 LXR 激动剂，我们发现在肝内葡萄糖通量不增加的情况下，LXR 刺激不会促进 ChREBP 磷酸化或核定位。此外，与野生型小鼠相比，葡萄糖或高碳水化合物饮食对 LXR α/β 敲除小鼠的 ChREBP、L-PK 和 ACC 的诱导作用相似，表明葡萄糖对这些基因的激活是通过不依赖于 LXR 的机制发生的。我们使用荧光共振能量转移分析来证明葡萄糖未能促进 LXR α/β 与特定辅因子的相互作用。最后，LXR α/β 敲除肝细胞中 ChREBP 的 siRNA 沉默消除了葡萄糖诱导的 L-PK 和 ACC 表达，进一步证明了 ChREBP 在葡萄糖信号传导中的核心作用。综上所述，我们的结果表明 ChREBP 功能活性需要葡萄糖，而 LXR 对于肝脏中葡萄糖调节基因的诱导不是必需的。
The transcription factor carbohydrate-responsive element-binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver-pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetylCoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us to study the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXR alpha/beta knockout compared with wild-type mice, suggesting that the activation of these genes by glucose occurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXR alpha/beta with specific cofactors. Finally, siRNA silencing of ChREBP in LXR alpha/beta knockout hepatocytes abrogated glucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP in glucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver.