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  1. Article ; Online: Hemin and iron increase synthesis and trigger export of xanthine oxidoreductase from hepatocytes to the circulation.

    DeVallance, Evan R / Schmidt, Heidi M / Seman, Madison / Lewis, Sara E / Wood, Katherine C / Vickers, Schuyler D / Hahn, Scott A / Velayutham, Murugesan / Hileman, Emily A / Vitturi, Dario A / Leonardi, Roberta / Straub, Adam C / Kelley, Eric E

    Redox biology

    2023  Volume 67, Page(s) 102866

    Abstract: We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the ... ...

    Abstract We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the cellular signaling and export mechanisms underpinning this process were not identified. Here, we present novel data showing hepatocytes upregulate XOR expression/protein abundance and actively release it to the extracellular compartment following exposure to hemopexin-bound hemin, hemin or free iron. For example, murine (AML-12 cells) hepatocytes treated with hemin (10 μM) exported XOR to the medium in the absence of cell death or loss of membrane integrity (2.0 ± 1.0 vs 16 ± 9 μU/mL p < 0.0001). The path of exocytosis was found to be noncanonical as pretreatment of the hepatocytes with Vaculin-1, a lysosomal trafficking inhibitor, and not Brefeldin A inhibited XOR release and promoted intracellular XOR accumulation (84 ± 17 vs 24 ± 8 hemin vs 5 ± 3 control μU/mg). Interestingly, free iron (Fe
    MeSH term(s) Animals ; Mice ; Xanthine Dehydrogenase/genetics ; Xanthine Dehydrogenase/metabolism ; Hemin/pharmacology ; Iron ; NF-kappa B ; Heme ; Hepatocytes/metabolism
    Chemical Substances Xanthine Dehydrogenase (EC 1.17.1.4) ; Hemin (743LRP9S7N) ; Iron (E1UOL152H7) ; NF-kappa B ; Heme (42VZT0U6YR)
    Language English
    Publishing date 2023-09-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701011-9
    ISSN 2213-2317 ; 2213-2317
    ISSN (online) 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2023.102866
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Release of hepatic xanthine oxidase (XO) to the circulation is protective in intravascular hemolytic crisis.

    Schmidt, Heidi M / DeVallance, Evan R / Lewis, Sara E / Wood, Katherine C / Annarapu, Gowtham K / Carreño, Mara / Hahn, Scott A / Seman, Madison / Maxwell, Brooke A / Hileman, Emily A / Xu, Julia Z / Velayutham, Murugesan / Geldenhuys, Werner J / Vitturi, Dario A / Shiva, Sruti / Kelley, Eric E / Straub, Adam C

    Redox biology

    2023  Volume 62, Page(s) 102636

    Abstract: Xanthine oxidase (XO) catalyzes the catabolism of hypoxanthine to xanthine and xanthine to uric acid, generating oxidants as a byproduct. Importantly, XO activity is elevated in numerous hemolytic conditions including sickle cell disease (SCD); however, ... ...

    Abstract Xanthine oxidase (XO) catalyzes the catabolism of hypoxanthine to xanthine and xanthine to uric acid, generating oxidants as a byproduct. Importantly, XO activity is elevated in numerous hemolytic conditions including sickle cell disease (SCD); however, the role of XO in this context has not been elucidated. Whereas long-standing dogma suggests elevated levels of XO in the vascular compartment contribute to vascular pathology via increased oxidant production, herein, we demonstrate, for the first time, that XO has an unexpected protective role during hemolysis. Using an established hemolysis model, we found that intravascular hemin challenge (40 μmol/kg) resulted in a significant increase in hemolysis and an immense (20-fold) elevation in plasma XO activity in Townes sickle cell phenotype (SS) sickle mice compared to controls. Repeating the hemin challenge model in hepatocyte-specific XO knockout mice transplanted with SS bone marrow confirmed the liver as the source of enhanced circulating XO as these mice demonstrated 100% lethality compared to 40% survival in controls. In addition, studies in murine hepatocytes (AML12) revealed hemin mediates upregulation and release of XO to the medium in a toll like receptor 4 (TLR4)-dependent manner. Furthermore, we demonstrate that XO degrades oxyhemoglobin and releases free hemin and iron in a hydrogen peroxide-dependent manner. Additional biochemical studies revealed purified XO binds free hemin to diminish the potential for deleterious hemin-related redox reactions as well as prevents platelet aggregation. In the aggregate, data herein reveals that intravascular hemin challenge induces XO release by hepatocytes through hemin-TLR4 signaling, resulting in an immense elevation of circulating XO. This increased XO activity in the vascular compartment mediates protection from intravascular hemin crisis by binding and potentially degrading hemin at the apical surface of the endothelium where XO is known to be bound and sequestered by endothelial glycosaminoglycans (GAGs).
    MeSH term(s) Animals ; Mice ; Hemin ; Hemolysis ; Liver/metabolism ; Mice, Knockout ; Oxidants ; Toll-Like Receptor 4 ; Xanthine ; Xanthine Oxidase/metabolism ; Xanthines
    Chemical Substances Hemin (743LRP9S7N) ; Oxidants ; Toll-Like Receptor 4 ; Xanthine (1AVZ07U9S7) ; Xanthine Oxidase (EC 1.17.3.2) ; Xanthines
    Language English
    Publishing date 2023-02-13
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2701011-9
    ISSN 2213-2317 ; 2213-2317
    ISSN (online) 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2023.102636
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Obese female mice do not exhibit overt hyperuricemia despite hepatic steatosis and impaired glucose tolerance.

    Lewis, Sara E / Li, Lihua / Fazzari, Marco / Salvatore, Sonia R / Li, Jiang / Hileman, Emily A / Maxwell, Brooke A / Schopfer, Francisco J / Arteel, Gavin E / Khoo, Nicholas K H / Kelley, Eric E

    Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe

    2022  Volume 6

    Abstract: Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a ... ...

    Abstract Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (~2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.
    Language English
    Publishing date 2022-10-07
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2667-1379
    ISSN (online) 2667-1379
    DOI 10.1016/j.arres.2022.100051
    Database MEDical Literature Analysis and Retrieval System OnLINE

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