Saving the Liver: PCBP1 and PCBP2 Iron Chaperones are Essential for Hepatocyte Survival

Authors

• E Messager
• O Protchenko
• AJ Tietgens
• S Jadhav
• S Grounds
• M Shakoury-Elizeh
• C Philpott

Abstract

Iron is a vital but very reactive nutrient as it promotes the Fenton reaction. Poly(c)-binding proteins PCBP1 and PCBP2 are iron chaperones that bind iron and single-stranded nucleic acids, protect from iron-generated ROS, metalate iron enzymes, and promote ferritin iron storage. The liver is the main iron storage organ in the body and orchestrates systemic iron homeostasis. We explored the roles of PCBP1/2 in liver function and iron homeostasis. To deplete PCBPs in the liver, mice with floxed alleles of PCBP1fl/fl, PCBP2fl/fl, or both PCBP1,2fl/fl (P1P2Δhep) were transduced with AAV expressing Cre-recombinase under a hepatocyte-specific promoter. The knockout of PCBP1 or PCBP2 resulted in minimal liver damage, while the double knockout of PCBP1/2 induced acute hepatitis. P1P2Δhep mice demonstrated liver damage with increased plasma ALT and AST, low glucose, and increased mRNA levels of oxidative stress and inflammation markers. We also observed heightened TUNEL staining indicating cell death and increased proliferation staining of the Ki67 marker via IHC. Dietary iron restriction prevented pathological changes in P1P2Δhep livers; however, supplementation with a Vitamin E antioxidant was less efficient. Thus, the loss of iron chaperones had directly resulted in iron toxicity under normal iron conditions. In sum, PCBP1 and PCBP2 iron chaperones manage liver iron and are both crucial for maintaining iron homeostasis and liver function.

Scientific Focus Area: Cell Biology

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