Department of Pathology and Laboratory Medicine University of British Columbia, Vancouver, BC, Canada.
J Lipid Res. 2013 Nov;54(11):3139-50. doi: 10.1194/jlr.M042473. Epub 2013 Sep 2.
Apolipoprotein E (apoE) is the major lipid carrier in the central nervous system. As apoE plays a major role in the pathogenesis of Alzheimer disease (AD) and also mediates repair pathways after several forms of acute brain injury, modulating the expression, secretion, or function of apoE may provide potential therapeutic approaches for several neurological disorders. Here we show that progesterone and a synthetic progestin, lynestrenol, significantly induce apoE secretion from human CCF-STTG1 astrocytoma cells, whereas estrogens and the progesterone metabolite allopregnanolone have negligible effects. Intriguingly, lynestrenol also increases expression of the cholesterol transporter ABCA1 in CCF-STTG1 astrocytoma cells, primary murine glia, and immortalized murine astrocytes that express human apoE3. The progesterone receptor inhibitor RU486 attenuates the effect of progestins on apoE expression in CCF-STTG1 astrocytoma cells but has no effect on ABCA1 expression in all glial cell models tested, suggesting that the progesterone receptor (PR) may participate in apoE but does not affect ABCA1 regulation. These results suggest that selective reproductive steroid hormones have the potential to influence glial lipid homeostasis through liver X receptor-dependent and progesterone receptor-dependent pathways.
载脂蛋白 E（apoE）是中枢神经系统中的主要脂质载体。apoE 在阿尔茨海默病（AD）的发病机制中起主要作用，并且还介导几种形式的急性脑损伤后的修复途径，因此调节 apoE 的表达、分泌或功能可能为几种神经疾病提供潜在的治疗方法。在这里，我们发现孕激素和合成孕激素左炔诺孕酮可显著诱导人 CCF-STTG1 星形细胞瘤细胞分泌 apoE，而雌激素和孕激素代谢物孕烷醇酮几乎没有作用。有趣的是，左炔诺孕酮还可增加胆固醇转运蛋白 ABCA1 在 CCF-STTG1 星形细胞瘤细胞、原代小鼠神经胶质细胞和表达人 apoE3 的永生化小鼠星形细胞中的表达。孕激素受体抑制剂 RU486 可减弱孕激素对 CCF-STTG1 星形细胞瘤细胞中 apoE 表达的影响，但对所有测试的神经胶质细胞模型中 ABCA1 的表达均无影响，表明孕激素受体（PR）可能参与 apoE 的调节，但不影响 ABCA1 的调节。这些结果表明，选择性生殖类固醇激素有可能通过肝 X 受体依赖性和孕激素受体依赖性途径影响神经胶质细胞的脂质稳态。
