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Hepatic ABC Transporter Expression in A Hemochromatosis‐Linked Murine Model of Porphyria Cutanea Tarda
Author(s) -
Arch Dorinda D,
Phillips John D,
Kushner James P,
Franklin Michael R
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.921.21
Subject(s) - porphyria cutanea tarda , hereditary hemochromatosis , porphyria , uroporphyrinogen iii decarboxylase , hemochromatosis , medicine , endocrinology , dmt1 , biology , transporter , heme , genetics , biochemistry , enzyme , gene
Iron overload can lead to hepatic fibrogenesis and high liver iron is frequently associated with porphyria cutanea tarda (PCT), a disease characterized by hepatic accumulation of highly carboxylated porphyrins. To assess whether porphyrin accumulation could arise from impaired anion transport, ABC transporter expression in a porphyria‐susceptible mouse model was investigated by qPCR. Mice with the Urod+/– (uroporphyrinogen decarboxylase), Hfe−/− (hemochromatosis) genotype spontaneously develop PCT, with severely decreased UROD activity and hepatic iron overload. Control animals with only the Urod+/– genotype do not accumulate porphyrins and had no change in expression of twelve ABC transporters examined. Accompanying the high iron accumulation in the Hfe−/− animals, expression of Abca3, Abcb1a, and Abcc4 were increased and expression of Abcc2, Abcc6 and Abcg2 were decreased. In mice with the Urod+/–, Hfe−/− genotype, porphyrin accumulation was accompanied by elevated expression of Abca3 and Abcc4 while Abcc2 and Abcc6 expression was depressed. The elevation in expression of Abcb1a and depression of Abcc2 were no longer present. Novel in these animals was an elevation of Abcc1 expression. The porphyrin accumulation exacerbated the repression of Abcc2 and Abcc6 expression and attenuated the increase in Abca3 seen in Hfe−/− control mice. Supported USPHS Grants DK20503 and DK07115