The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria
The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria
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DOI：
10.1126/sciadv.aaw6127
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发表时间：
2019-09-01
期刊：
影响因子：
13.6
通讯作者：
Ma, Xiaochao
中科院分区：
文献类型：
--
作者：
Wang, Pengcheng;Sachar, Madhav;Ma, Xiaochao
红细胞生成性原卟啉症（EPP）是一种遗传性疾病，由亚铁螯合酶功能丧失突变引起，亚铁螯合酶是血红素生物合成途径中的一种酶，可将原卟啉IX（PPIX）转化为血红素。PPIX在EPP患者中的积累导致光毒性和肝毒性，并且无法治愈。在这里，我们证明了PPIX外排转运蛋白ABCG 2（也称为BCRP）决定了EP相关的光毒性和肝毒性。我们发现，ABCG2缺乏减少PPIX分布到皮肤，从而防止EP相关的光毒性。我们还发现，ABCG 2缺乏通过调节PPIX分布、代谢和排泄来保护EPP相关的肝毒性。总之，我们的工作揭示了ABCG 2在EPP的病理生理学中的重要作用，这表明了EPP治疗发展中新策略的潜力。
Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.