Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes - In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes - In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines
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脂肪酸水平的增加有助于诱导糖尿病引起的肝 CYP3A4 活性 - 来自 HepG2 细胞和 Fa2N-4 细胞系的体外证据
DOI：
10.1254/jphs.13212fp
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Hu, Nan;Hu, Mengyue;Liu, Xiaodong
越来越多的证据表明，糖尿病可上调CYP 3A 4的功能和表达，但其机制尚不清楚。本研究采用链脲佐菌素诱导的糖尿病大鼠血清与HepG 2细胞共孵育，通过底物代谢法检测细胞色素P450 3A 4（CYP 3A 4）活性。结果表明，糖尿病血清可显著诱导HepG 2细胞中CYP 3A 4的活性。为了确定特定的因素，对糖尿病患者血清中异常改变的成分，包括葡萄糖、胰岛素、胆固醇和游离脂肪酸进行了筛选。结果发现，只有脂肪酸浓度依赖性地上调CYP 3A 4活性，脂肪酸的诱导作用在Fa 2N-4细胞中得到进一步证实。Western blotting和QT-PCR结果显示，CYP 3A 4蛋白和mRNA水平的上调与CYP 3A 4活性的诱导有关。此外，还研究了药理学抑制剂对脂肪酸诱导的CYP 3A 4活性的影响。结果表明，油酸对CYP 3A 4活性的诱导可能部分通过AMPK-、PKC-和NF-κ B依赖性途径，而棕榈酸对CYP 3A 4活性的诱导可能与PKC依赖性途径有关。因此，脂肪酸水平的增加可能是导致糖尿病状态下CYP 3A 4功能和表达升高的原因之一。
Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-kappa B-dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.