Phagocytosis-dependent ketogenesis in retinal pigment epithelium
Phagocytosis-dependent ketogenesis in retinal pigment epithelium
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DOI：
10.1074/jbc.m116.770784
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发表时间：
2017-05-12
影响因子：
4.8
通讯作者：
Boesze-Battaglia, Kathleen
中科院分区：
文献类型：
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作者：
Reyes-Reveles, Juan;Dhingra, Anuradha;Boesze-Battaglia, Kathleen
每天，视网膜色素上皮（RPE）以吞噬的光感受器外节（OS）的形式摄取大量脂质和蛋白质。与肝脏一样，RPE表达脂肪酸氧化和生酮所需的酶。这表明，这些途径在处置来自摄入的OS的脂质中起作用，以及提供将代谢中间体再循环回到外层视网膜的机制。在这项研究中，我们研究了OS吞噬作用是否与生酮有关。我们发现在Transwell插入物上培养的人胎儿RPE和ARPE 19细胞摄入OS后，顶端培养基中β-羟基丁酸（β-HB）水平增加。摄入氧化OS或乳胶珠后，未观察到生酮增加。我们的研究使用小鼠RPE外植体模型进一步确定了野生型小鼠和吞噬体成熟缺陷小鼠中OS吞噬作用和生酮作用之间的联系。在外植体研究中，释放的β-HB水平与光照后OS吞噬爆发在时间上相关。在吞噬体成熟延迟的Mreg（-/-）小鼠中，β-HB的释放存在时间偏移。在Abca 4（-/-）RPE中观察到最大β-HB产生的甚至更明显的变化，其中ATP结合盒A4转运蛋白的丢失导致吞噬体加工缺陷和脂质碎片的积累。这些研究表明，FAO和生酮是支持RPE代谢和防止脂质积累的关键，脂质积累会导致氧化应激和线粒体功能障碍。
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE, like the liver, expresses enzymes required for fatty acid oxidation and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS, as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of beta-hydroxybutyrate (beta-HB) in the apical medium following ingestion of OS by human fetal RPE and ARPE19 cells cultured on Transwell inserts. No increase in ketogenesis was observed following ingestion of oxidized OS or latex beads. Our studies further defined the connection between OS phagocytosis and ketogenesis in wild-type mice and mice with defects in phagosome maturation using a mouse RPE explant model. In explant studies, the levels of beta-HB released were temporally correlated with OS phagocytic burst after light onset. In the Mreg(-/-) mouse where phagosome maturation is delayed, there was a temporal shift in the release of beta-HB. An even more pronounced shift in maximal beta-HB production was observed in the Abca4(-/-) RPE, in which loss of the ATP-binding cassette A4 transporter results in defective phagosome processing and accumulation of lipid debris. These studies suggest that FAO and ketogenesis are key to supporting the metabolism of the RPE and preventing the accumulation of lipids that lead to oxidative stress and mitochondrial dysfunction.