Diabetes (New York, N.Y.), 2019-06, Vol.68 (6), p.1221-1229
2019
Details
- Autor(en) / Beteiligte
- Titel
- Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities
- Ist Teil von
- Diabetes (New York, N.Y.), 2019-06, Vol.68 (6), p.1221-1229
- Ort / Verlag
- United States: American Diabetes Association
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 , the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte 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 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0012-1797eISSN: 1939-327XDOI: 10.2337/db18-1198Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6610025
- Format
- –
- Schlagworte
- Ablation, Animals, Diabetes mellitus, Diabetes mellitus (non-insulin dependent), Diet, High-Fat, Dyslipidemia, Fatty Acids, Nonesterified - metabolism, Febuxostat - pharmacology, Glucose - metabolism, Glucose Tolerance Test, Hepatocytes - drug effects, Hepatocytes - metabolism, Homeostasis, Hyperuricemia, Hyperuricemia - genetics, Hyperuricemia - metabolism, Insulin, Insulin resistance, Lipid Metabolism, Metabolic disorders, Metabolism, Mice, Obesity, Obesity - metabolism, Obesity Studies, Triglycerides - metabolism, Uric acid, Uric Acid - metabolism, Xanthine Dehydrogenase - antagonists & inhibitors, Xanthine Dehydrogenase - genetics, Xanthine oxidoreductase