Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes
Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes
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DOI：
10.1124/dmd.116.071415
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发表时间：
2016-11-01
影响因子：
3.9
通讯作者：
Cherrington, N. J.
中科院分区：
文献类型：
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作者：
Dzierlenga, A. L.;Clarke, J. D.;Cherrington, N. J.
非酒精性脂肪性肝炎 (NASH) 药物反应的个体差异可以通过药物代谢酶和转运蛋白调节的改变来介导。其中之一是多药耐药相关蛋白 (MRP2)/Mrp2 远离小管膜的错误定位，导致 MRP2/Mrp2 底物的转运减少。这种错误定位的确切机制尚不清楚，尽管膜修复过程的激活增加可能是一种可能性。目前的研究测量了与主动膜修复或膜蛋白插入相关的各种介质的激活状态，以确定哪些过程可能在啮齿类动物蛋氨酸和胆碱缺乏饮食诱发的 NASH 中起重要作用。目前已知与转运蛋白错位相关的介质受到氧化应激源和利胆刺激物的刺激，这在 NASH 的发病机制中发挥着作用。通过比较对照和 NASH 之间的表达、磷酸化和膜易位，测量蛋白激酶 PKA、PKC α、PKC δ 和 PKC epsilon 以及底物 radixin、肉豆蔻酰化富含丙氨酸的 C 激酶底物和 Rab11 的激活。 NASH 大鼠中许多介质的激活发生了改变。与Mrp2的膜修复一致，NASH大鼠表现出根素磷酸化降低和PKC δ和PKC epsilon膜定位增加，这被认为是根素去磷酸化的介质。 PKC δ、PKA 和 PKC α 激活的改变可能会损害 Rab11 介导的 Mrp2 主动插入。总体而言，这些数据表明膜检索和插入过程的改变可能导致 NASH 中膜蛋白定位的改变。
Interindividual variability in drug response in nonalcoholic steatohepatitis (NASH) can be mediated by altered regulation of drug metabolizing enzymes and transporters. Among these is the mislocalization of multidrug resistance-associated protein (MRP2)/Mrp2 away from the canalicular membrane, which results in decreased transport of MRP2/Mrp2 substrates. The exact mechanism of this mislocalization is unknown, although increased activation of membrane retrieval processes may be one possibility. The current study measures the activation status of various mediators implicated in the active membrane retrieval or insertion of membrane proteins to identify which processes may be important in rodent methionine and choline deficient diet-induced NASH. The mediators currently known to be associated with transporter mislocalization are stimulated by oxidative stressors and choleretic stimuli, which play a role in the pathogenesis of NASH. The activation of protein kinases PKA, PKC alpha, PKC delta, and PKC epsilon and substrates radixin, myristoylated alanine-rich C-kinase substrate, and Rab11 were measured by comparing the expression, phosphorylation, and membrane translocation between control and NASH. Many of the mediators exhibited altered activation in NASH rats. Consistent with membrane retrieval of Mrp2, NASH rats exhibited a decreased phosphorylation of radixin and increased membrane localization of PKC delta and PKC epsilon, thought to be mediators of radixin dephosphorylation. Altered activation of PKC delta, PKA, and PKC alpha may impair the Rab11-mediated active insertion of Mrp2. Overall, these data suggest alterations in membrane retrieval and insertion processes that may contribute to altered localization of membrane proteins in NASH.