Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells.
Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells.
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DOI：
10.3390/nu14020288
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发表时间：
2022-01-11
期刊：
影响因子：
5.9
通讯作者：
Murao K
中科院分区：
文献类型：
--
作者：
Ibata T;Lyu J;Imachi H;Fukunaga K;Sato S;Kobayashi T;Saheki T;Yoshimura T;Murao K
三磷酸腺苷结合盒转运体A1(ABCA1)是脂质外流的关键调节因子，ABCA1的缺失导致肝脏脂肪堆积，是脂肪肝的主要原因之一。2-甲氧基雌二醇(2-ME2)已被证明可以预防脂肪肝。在本研究中，我们观察了2-ME2对大鼠肝脏脂质含量和ABCA1表达的影响。我们发现，2-ME2呈剂量依赖性地增加ABCA1的表达，从而显著降低HepG2细胞的脂质含量。2-ME2增强ABCA1启动子活性，但抑制PI3K途径后，这种作用减弱。Akt或p110过表达诱导ABCA1启动子活性，而显性负Akt抑制2-ME2对ABCA1启动子活性的影响。此外，2-ME2刺激Akt和FoxO1的快速磷酸化，减少FoxO1的核积累。染色质免疫沉淀证实FoxO1与ABCA1启动子区域结合。2-ME2减少了结合，促进了ABCA1基因的转录。此外，突变ABCA1启动子区域的FoxO1结合位点或用FoxO1特异性siRNA处理可阻断2-ME2对ABCA1表达的影响。以上结果表明，2-ME2可能通过PI3K/Akt/FoxO1途径上调ABCA1的表达，从而降低肝细胞中的脂质含量。
ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.
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影响因子：
4.1
作者：
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通讯作者：
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