Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice
Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice
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DOI：
10.1124/dmd.110.037507
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发表时间：
2011-06-01
影响因子：
3.9
通讯作者：
Slitt, Angela L.
中科院分区：
文献类型：
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作者：
More, Vijay R.;Slitt, Angela L.
肥胖和糖尿病受试者的药物药代动力学可能会发生改变。考虑到肥胖和糖尿病的患病率，糖尿病和肥胖小鼠模型中转运蛋白表达的表征可能是帮助预测药物药代动力学改变或药物不良反应的有用工具。据报道，表现出严重肥胖和糖尿病表型的ob/ob小鼠在肝脏和肾脏中的药物转运蛋白表达表现出多种变化。在本研究中，测定了饮食诱导肥胖 (DIO) C57BL/6J 雄性小鼠的肝脏和肾脏中主要药物转运蛋白的 mRNA 和蛋白表达。这些小鼠从 6 周龄开始就被喂食高脂肪饮食 (HFD)（60% 脂肪），并表现出肥胖、脂肪肝和轻度高血糖。与饲喂低脂饮食 (LFD) 的对照小鼠中检测到的结果相比，HFD 饮食使肝脏中多药耐药相关蛋白 Abcc3 和 4 mRNA 和蛋白质的表达分别增加了 3.4 倍和 1.4 倍。相比之下，与瘦小鼠的肝脏相比，DIO 小鼠肝脏中的 Abcc1 mRNA 和蛋白质减少了 50%。与 LFD 相比，HFD 不会改变肾脏转运蛋白的表达。总之，与 ob/ob 和 db/db 小鼠不同，DIO 小鼠表现出选择性诱导肝脏中的外排转运蛋白表达（即 Abcc3 和 4）。此外，在 C57BL/6J 小鼠模型中，饮食诱导的肥胖会影响肝脏中转运蛋白的表达，但不会影响肾脏中的转运蛋白表达。这些数据表明，在轻度糖尿病和非酒精性脂肪肝疾病和肥胖模型中，肝脏转运蛋白表达仅略有改变。
Drug pharmacokinetics can be altered in obese and diabetic subjects. In consideration of the prevalence of obesity and diabetes, characterization of transporter expression in mouse models of diabetes and obesity may be a useful tool to aid in prediction of altered drug pharmacokinetics or adverse drug reactions. It has been reported that ob/ob mice, which display a severe obesity and diabetes phenotype, exhibit multiple changes in drug transporter expression in liver and kidney. In the present study, the mRNA and protein expression of major drug transporters was determined in livers and kidneys of diet-induced obese (DIO) C57BL/6J male mice. The mice were fed a high-fat diet (HFD) (60% fat) from 6 weeks of age and display obesity, fatty liver, and mild hyperglycemia. The HFD diet increased expression of multidrug resistance-associated proteins Abcc3 and 4 mRNA and protein in liver by 3.4-and 1.4-fold, respectively, compared with that detected in control mice fed a low-fat diet (LFD). In contrast, Abcc1 mRNA and protein decreased by 50% in livers of DIO mice compared with those in livers to lean mice. The HFD did not alter transporter expression in kidney compared with the LFD. In summary, unlike ob/ob and db/db mice, DIO mice exhibited a selective induction of efflux transporter expression in liver (i.e., Abcc3 and 4). In addition, diet-induced obesity affects transporter expression in liver but not kidney in the C57BL/6J mouse model. These data indicate that hepatic transporter expression is only slightly altered in a model of mild diabetes and nonalcoholic fatty liver disease and obesity.