Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities.

Autor:	Harmon DB; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Mandler WK; Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV., Sipula IJ; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Dedousis N; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Lewis SE; Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV., Eckels JT; Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV., Du J; Department of Ophthalmology and Biochemistry, Health Sciences Center, West Virginia University, Morgantown, WV., Wang Y; Department of Ophthalmology and Biochemistry, Health Sciences Center, West Virginia University, Morgantown, WV., Huckestein BR; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Pagano PJ; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA., Cifuentes-Pagano E; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA., Homanics GE; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA.; Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA., Van't Erve TJ; Immunity, Inflammation, and Disease Laboratory/Free Radical Metabolism Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC., Stefanovic-Racic M; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Jurczak MJ; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., O'Doherty RM; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA eric.kelley@hsc.wvu.edu rmo1@pitt.edu.; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA., Kelley EE; Department of Physiology and Pharmacology, Health Sciences Center, West Virginia University, Morgantown, WV eric.kelley@hsc.wvu.edu rmo1@pitt.edu.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2019 Jun; Vol. 68 (6), pp. 1221-1229. Date of Electronic Publication: 2019 Apr 01.
DOI:	10.2337/db18-1198
Abstrakt:	Systemic hyperuricemia (HyUA) in obesity/type 2 diabetes facilitated by elevated activity of xanthine oxidoreductase (XOR), which is the sole source of uric acid (UA) in mammals, has been proposed to contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. Here, the effects of hepatocyte-specific ablation of Xdh , the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte Xdh substantially lowered liver and plasma UA concentration. When exposed to an obesogenic diet, HXO and control floxed (FLX) mice became equally obese, but systemic HyUA was absent in HXO mice. Despite this, obese HXO mice became as insulin resistant and dyslipidemic as obese FLX mice. Similarly, febuxostat dramatically lowered plasma and tissue UA and XOR activity in obese wild-type mice without altering obesity-associated insulin resistance/dyslipidemia. These data demonstrate that hepatocyte XOR activity is a critical determinant of systemic UA homeostasis, that deletion of hepatocyte Xdh is sufficient to prevent systemic HyUA of obesity, and that neither prevention nor correction of HyUA improves insulin resistance/dyslipidemia in obesity. Thus, systemic HyUA, although clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be causative. (© 2019 by the American Diabetes Association.)
Databáze:	MEDLINE
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