Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression
Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression
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DOI：
10.1124/dmd.115.066779
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发表时间：
2016-04-01
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：
Donepudi, Ajay C.;Cheng, Qiuqiong;Slitt, Angela L.
代谢综合征是一种与肥胖、胰岛素抵抗、糖尿病和多种代谢激素改变相关的多因素疾病。肥胖率在全球范围内一直在上升，这增加了我们了解这一人群对药物和其他化学物质的反应的必要性。本研究的目的是确定瘦和肥胖小鼠的个体发育的临床生物标志物，如血清激素和血糖水平，以及与核受体和转运蛋白相关的途径的生理标志物。在肥胖症发作之前、期间和之后收集来自雄性和雌性野生型（WT）（C57 BL/6）和ob/ob小鼠同窝仔的肝脏。分析血清激素和mRNA水平。生理变化和基因表达在成熟和肥胖的进展进行了相关性分析，使用典型相关。在WT和ob/ob小鼠中观察到显著的个体发生变化，并且这些个体发生变化在ob/ob小鼠中随着肥胖的发展而不同。在雄性和雌性中，Abcc 3、4、Abcg 2、Cyp 2b 10和4a 14等基因表达的个体发育模式从第3周开始不同，与WT小鼠相比，ob/ob小鼠在第4周和第8周变得显著。在肥胖男性中，血清胰高血糖素，葡萄糖水平与大多数肝ATP结合盒（Abc）转运蛋白的表达相关，而在肥胖女性中，血清胰高血糖素样肽1水平与大多数肝摄取转运蛋白和P450酶相关。总体而言，生理变化和基因表达之间的相关性表明，代谢相关激素可能在调节药物代谢和转运相关基因中发挥作用。
Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor- and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport.