The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria

Pengcheng Wang, Madhav Sachar, Jie Lu, Amina I. Shehu, Junjie Zhu, Jing Chen, Ke Liu, Karl E. Anderson, Wen Xie, Frank J. Gonzalez, Curtis D. Klaassen, Xiaochao Ma

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbereaaw6127
JournalScience Advances
Volume5
Issue number9
DOIs
StatePublished - Sep 18 2019

ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)
  • General

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    Wang, P., Sachar, M., Lu, J., Shehu, A. I., Zhu, J., Chen, J., Liu, K., Anderson, K. E., Xie, W., Gonzalez, F. J., Klaassen, C. D., & Ma, X. (2019). The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria. Science Advances, 5(9), [eaaw6127]. https://doi.org/10.1126/sciadv.aaw6127