Faculty, Staff and Student Publications
Language
English
Publication Date
7-1-2025
Journal
Drug Metabolism and Disposition
DOI
10.1016/j.dmd.2025.100105
PMID
40540978
PMCID
PMC12405900
PubMedCentral® Posted Date
5-27-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in ferrochelatase (FECH), leading to the accumulation of its substrate, protoporphyrin IX (PPIX). PPIX is primarily produced in the bone marrow and transported to the liver for excretion. Because PPIX is hydrophobic, its elevated levels can cause bile duct blockage, cholestatic liver injury, and even liver failure. However, the specific transporter responsible for PPIX uptake into hepatocytes remains unclear. The OATP1B1/1B3 transporters, which are expressed in hepatocytes, facilitate the uptake of coproporphyrin III, a structural analog of PPIX. Additionally, OATP1B1/1B3 mediates the uptake of bilirubin, a biomarker of liver injury, from plasma into the liver for excretion. Therefore, we aimed to determine the role of OATP1B1/1B3 in regulating PPIX and bilirubin homeostasis under EPP conditions. A mouse strain carrying a Fech mutation was used as an EPP model. Building on this, we generated a new EPP mouse model with Oatp1a/1b deficiency. Using these EPP mouse models, along with OATP1B1/1B3-overexpressing cells, our study revealed that PPIX is not a substrate of OATP1B1/1B3. Notably, our work found that genetic deficiency or pharmacologic suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mice without worsening liver injury. Mechanistically, Oatp1a/1b deficiency impairs bilirubin uptake from plasma, while Fech deficiency leads to PPIX-mediated bile duct blockage and reduced bilirubin excretion, synergistically exacerbating hyperbilirubinemia. In summary, our work demonstrated that deficiency or suppression of Oatp1a/1b exacerbates hyperbilirubinemia in EPP mouse models, suggesting that assessment of OATP1B1/1B3 function is crucial in EPP patients with EPP with hyperbilirubinemia. SIGNIFICANCE STATEMENT: This work revealed that serum bilirubin levels are not paralleled with liver damage in the erythropoietic protoporphyria mouse models with Oatp1a/1b deficiency. Our findings suggest that assessment of OATP1B1/1B3 function is crucial in patients with erythropoietic protoporphyria with hyperbilirubinemia.
Keywords
Animals, Liver-Specific Organic Anion Transporter 1, Mice, Protoporphyria, Erythropoietic, Bilirubin, Hyperbilirubinemia, Solute Carrier Organic Anion Transporter Family Member 1B3, Protoporphyrins, Hepatocytes, Humans, Mice, Knockout, Coproporphyrins, Male, Liver, Mice, Inbred C57BL, Disease Models, Animal, OATPs, Protoporphyrin IX, Bilirubin, Liver diseases
Published Open-Access
yes
Recommended Citation
Gu, Ruizhi; Qin, Fu-Ying; Wang, Luxuan; et al., "OATP1B1/1B3 Deficiency Exacerbates Hyperbilirubinemia in Erythropoietic Protoporphyria" (2025). Faculty, Staff and Student Publications. 6218.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6218
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons