Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity.

BACKGROUND AND AIMS: Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the 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 (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr-/- mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered 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 fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with ß-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 1 and 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 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 ß-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 IO-associated chronic liver diseases.

Glucocorticoids Increase Renal Excretion of Urate in Mice by Downregulating Urate Transporter 1.

Both nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids have been widely used for the treatment of gout, a disease promoted by an excess body burden of uric acid (UA); however, their effects on the homeostasis of UA remain poorly understood. The present study showed that 1-week treatments with three NSAIDs (ibuprofen, diclofenac, and indomethacin) had little effect on UA homeostasis in mice, whereas 1-week low doses (1 and 5 mg/kg) of dexamethasone (DEX) significantly decreased serum UA by about 15%. Additionally, low doses of DEX also resulted in increases in hepatic UA concentration and urinary UA excretion, which were associated with an induction of xanthine oxidoreductase (XOR) in the liver and a downregulation of urate transporter 1 (URAT1) in the kidney, respectively. Neither 75 mg/kg DEX nor 100 mg/kg pregnenolone-16α-carbonitrile altered UA concentrations in serum and livers of mice, suggesting that the effect of DEX on UA homeostasis was not due to the pregnane X receptor pathway. Further in vitro studies demonstrated that glucocorticoid receptor (GR) was involved in DEX-mediated downregulation of URAT1. Knockdown of both p65 and c-Jun completely blocked the effect of DEX on URAT1, suggesting that GR regulates URAT1 via its interaction with both nuclear factor κB and activator protein 1 signaling pathways. To conclude, the present study identifies, for the first time, a critical role of glucocorticoids in regulating UA homeostasis and elucidates the mechanism for GR-mediated regulation of URAT1 in mice. SIGNIFICANCE STATEMENT: This study demonstrates, for the first time, a critical role of glucocorticoid receptor in regulating urate transporter 1 in mouse kidney.

Comparative toxicity analysis of corannulene and benzo[a]pyrene in mice.

Increasing production of corannulene (COR), a non-planar polycyclic aromatic hydrocarbon (PAH) with promising applications in many fields, has raised a concern about its potential toxic effects. However, no study has been undertaken to evaluate its metabolism and toxicity in mammals. In this study, the acute toxicities of COR in mice were compared with benzo[apyrene (BaP), a typical planar PAH with almost the same molecular weight. After 3-day exposures, the concentrations of COR in both plasma and tissues of mice were higher than that of BaP. However, blood chemistry and tissue weight monitoring showed no observable toxicities in COR-exposed mice. Compared to BaP, exposure to COR resulted in less activation of the aryl hydrocarbon receptor (AhR) and thus less induction of hepatic cytochrome P450 1A(CYP1A) enzymes, which play a critical role in metabolism of both COR and BaP. Additionally, COR also elicited less oxidative stress and microbiota alteration in the intestine than did BaP. RNA-seq analysis revealed that liver transcriptomes are responsive to COR and BaP, with less alterations observed in COR-exposed mice. Unlike BaP, exposure to COR had no effects on hepatic lipid and xenobiotic metabolism pathways. Nonetheless, COR appeared to alter the mRNA expressions of genes involved in carcinogenicity, oxidative stress, and immune-suppression. To conclude, this study for the first time unveils a comparative understanding of the acute toxic effects of COR to BaP in mice, and provides crucial insights into the future safety assessment of COR.