Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities
Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities
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DOI：
10.2337/db18-1198
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发表时间：
2019-06-01
期刊：
影响因子：
7.7
通讯作者：
Kelley, Eric E.
中科院分区：
文献类型：
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作者：
Harmon, Daniel B.;Mandler, W. Kyle;Kelley, Eric E.
肥胖/ 2型糖尿病患者的系统性高尿酸血症（HyUA）是由黄嘌呤氧化还原酶（XOR）活性升高引起的，黄嘌呤氧化还原酶是哺乳动物尿酸（UA）的唯一来源，已被认为是肥胖患者胰岛素抵抗/血脂异常的发病机制之一。本研究评估了肝细胞特异性消融Xdh、编码XOR基因（HXO）以及XOR（非布司他）的全身药理学抑制对肥胖诱导的胰岛素抵抗/血脂异常的影响。肝细胞Xdh的缺失显著降低肝脏和血浆UA浓度。当暴露于致肥性饮食时，HXO和对照组（FLX）小鼠变得同样肥胖，但HXO小鼠没有系统性HyUA。尽管如此，肥胖的HXO小鼠变得和肥胖的FLX小鼠一样胰岛素抵抗和血脂异常。同样，非布司他显著降低肥胖野生型小鼠血浆和组织UA和XOR活性，而不改变肥胖相关的胰岛素抵抗/血脂异常。这些数据表明，肝细胞XOR活性是全身性UA稳态的关键决定因素，肝细胞Xdh的缺失足以防止肥胖的全身性HyUA，预防和纠正HyUA都不能改善肥胖的胰岛素抵抗/血脂异常。因此，尽管系统性HyUA明显是肥胖代谢异常的生物标志物，但似乎不是病因。
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.