Estrogen Reduces Lipid Content in the Liver Exclusively from Membrane Receptor Signaling
Estrogen Reduces Lipid Content in the Liver Exclusively from Membrane Receptor Signaling
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DOI：
10.1126/scisignal.2004013
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发表时间：
2013-05-21
影响因子：
7.3
通讯作者：
Levin, Ellis R.
中科院分区：
文献类型：
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作者：
Pedram, Ali;Razandi, Mahnaz;Levin, Ellis R.
雌激素通过雌激素受体α（ER α）诱导信号转导，ER α定位于质膜和细胞核。使用野生型小鼠、ER α敲除（ERKO）小鼠或仅在质膜（MOER）处仅表达ER α的配体结合结构域的转基因小鼠，我们比较了在用ER α激动剂丙基吡唑三醇（PPT）注射小鼠后肝组织提取物的转录谱。许多脂质合成相关基因的表达在MOER或野生型小鼠的肝脏中明显降低，但在ERKO小鼠中没有受到抑制，这表明只有膜定位的ER α是抑制它们所必需的。胆固醇、甘油三酯和脂肪酸含量仅在暴露于PPT的野生型和MOER小鼠的肝脏中降低，但在ERKO小鼠的肝脏中没有降低，从而在生理水平上验证了膜驱动的信号传导途径。PPT触发的ER α在膜上的激活诱导腺苷一磷酸激活的蛋白激酶磷酸化固醇调节元件结合因子1（Srebf1），阻止其与位点1蛋白酶的结合并因此阻止其被位点1蛋白酶蛋白水解裂解。因此，Srebf1被隔离在细胞质中，阻止胆固醇合成相关基因的表达。因此，我们表明，抑制基因表达介导的膜定位的ER α引起的代谢表型，不需要核ER α。
Estrogen induces signal transduction through estrogen receptor alpha (ER alpha), which localizes to both the plasma membrane and nucleus. Using wild-type mice, ER alpha knockout (ERKO) mice, or transgenic mice expressing only the ligand-binding domain of ER alpha exclusively at the plasma membrane (MOER), we compared the transcriptional profiles of liver tissue extracts after mice were injected with the ERa agonist propyl-pyrazole-triol (PPT). The expression of many lipid synthesis-related genes was comparably decreased in livers from MOER or wild-type mice but was not suppressed in ERKO mice, indicating that only membrane-localized ER alpha was necessary for their suppression. Cholesterol, triglyceride, and fatty acid content was decreased only in livers from wild-type and MOER mice exposed to PPT, but not in the livers from the ERKO mice, validating the membrane-driven signaling pathway on a physiological level. PPT-triggered activation of ER alpha at the membrane induced adenosine monophosphate-activated protein kinase to phosphorylate sterol regulatory element-binding factor 1 (Srebf1), preventing its association with and therefore its proteolytic cleavage by site-1 protease. Consequently, Srebf1 was sequestered in the cytoplasm, preventing the expression of cholesterol synthesis-associated genes. Thus, we showed that inhibition of gene expression mediated by membrane-localized ER alpha caused a metabolic phenotype that did not require nuclear ER alpha.