Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
Biochem Pharmacol. 2018 Aug;154:474-481. doi: 10.1016/j.bcp.2018.06.011. Epub 2018 Jun 12.
Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.
红细胞生成性原卟啉症 (EPP) 是一种遗传性疾病，由编码亚铁螯合酶 (FECH) 的基因突变引起，该酶将原卟啉 IX (PPIX) 转化为血红素。由于 PPIX 在肝脏中的积累，EPP 患者可能会发生肝损伤甚至肝衰竭。本研究对由 Fech 突变 (Fech-mut) 引起的 EPP 小鼠模型的肝脏代谢组进行了分析。正如预期的那样，我们观察到 Fech-mut 小鼠肝脏中 PPIX 的积累。此外，我们的代谢组学分析显示，Fech-mut 小鼠肝脏中胆汁酸和神经酰胺 (Cer) 的积累。高浓度的胆汁酸和 Cer 对肝脏有毒。此外，我们发现与野生型小鼠相比，Fech-mut 小鼠肝脏中的主要磷脂酰胆碱 (PC) 以及胆汁中总 PC 与 PPIX 的比值降低。胆汁中 PC 与 PPIX 的比值降低会加剧 PPIX 在肝脏中的积累，因为 PC 会增加 PPIX 的溶解度和排泄。这些代谢组学发现表明，PPIX 的积累，加上胆汁酸、Cer 和 PC 平衡的破坏，导致了与 EPP 相关的肝损伤。
