LAUSR

BACKGROUND AND AIMS Iron overload is a frequent finding in the general population. As the major iron storage site, liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity. APPROACH AND RESULTS Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran. Mice were orally administered ferrous sulfate or injected intraperitoneally with iron dextran. Wild-type and Fxr-/- mice were fed an iron-rich diet for 1 week or 5 weeks. Mice fed an iron-rich diet were co-administered the FXR agonist GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and FGF19 were quantified in adults with hyperferritinemia and children with β-thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron-regulatory proteins IRP1/2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron-fed mice. The FXR agonist GW4064 almost completely restored the dysregulated bile acid signaling and metabolic syndrome in iron-fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with β-thalassemia. CONCLUSIONS FXR plays a pivotal role in regulating iron homeostasis, and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for iron overload-associated chronic liver diseases.