Mechanism for peroxisome proliferator-activated receptor-α activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes
Mechanism for peroxisome proliferator-activated receptor-α activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes
复制标题
DOI：
10.1074/jbc.m110132200
复制
发表时间：
2002-03-15
影响因子：
4.8
通讯作者：
Ezaki, O
中科院分区：
文献类型：
--
作者：
Nakatani, T;Tsuboyama-Kasaoka, N;Ezaki, O
过氧化物酶体增殖物激活受体-α (PPARα) 激活剂、鱼油喂养或贝特类药物可使小鼠肝脏中线粒体解偶联蛋白 (UCP2) mRNA 表达上调 5-9 倍，而肿瘤坏死因子-α (TNFα) 也上调肝脏中 UCP2。在本研究中，研究了 PPARa 激活剂诱导的 UCP2 mRNA 上调（与 TNFα 和活性氧 (ROS) 相关）的机制。 PPARa 激活剂在小鼠/大鼠肝组织中诱导 UCP2 上调，这是由于它们在肝细胞中的增加，而不是在非实质细胞中的增加。向培养的肝细胞中添加 PPARα 激活剂 WY14,643 或非诺贝特可使 UCP2 mRNA 上调 5-10 倍。 PPARa 激活剂诱导的 UCP2 mRNA 上调并非由于 mRNA 稳定性增加以及需要放线菌酮敏感的短期周转蛋白。然而，PPARα/类视黄醇X受体-α和PGC-1的表达并不是WY14,643诱导的UCP2上调的速率限制。在原代肝细胞中，外源性氧化剂叔丁基过氧化氢 (TBHP) 会增加 ROS 的产生，上调 UCP2 mRNA，而 WY14,643 处理则不会产生这种情况。在贝特显着上调UCP2的条件下可检测到ROS。在体内研究中，PPARα 激活剂适度上调小鼠肝脏中 TNFα mRNA 的表达。抗氧化剂吡咯烷二硫代氨基甲酸铵盐注射完全阻止了TNFα mRNA 的增加，但没有阻止大部分UCP2 mRNA 的增加。这些数据表明，PPARα激活剂通过增加转录，通过未知蛋白上调肝细胞中UCP2的表达，并且ROS和TNFa的产生都不是PPARα激活剂诱导UCP2上调的主要原因。
Peroxisome proliferator-activated receptor-alpha (PPARalpha) activators, fish oil feeding, or fibrate administration up-regulated mitochondrial uncoupling protein (UCP2) mRNA expression in mouse liver by 5-9-fold, whereas tumor necrosis factor-alpha (TNFalpha) also up-regulated UCP2 in liver. In this study, the mechanisms for PPARa activators-induced up-regulation of UCP2 mRNA, related to TNFalpha and reactive oxygen species (ROS), were investigated. PPARa activators-induced UCP2 up-regulation in mouse/rat liver tissues was due to their increases in hepatocytes but not in non-parenchymal cells. Addition of PPARalpha activators, WY14,643 or fenofibrate, to cultured hepatocytes up-regulated UCP2 mRNA by 5-10-fold. PPARa activators-induced up-regulation of UCP2 mRNA was not due to increased mRNA stability and required cycloheximide-sensitive short term turnover protein(s). However, expression of PPARalpha/retinoid X receptor-alpha and PGC-1 was not rate-limiting for WY14,643-induced UCP2 up-regulation. In primary hepatocytes, an exogenous oxidant, tert-butyl-hydroperoxide (TBHP), which increased ROS production, up-regulated UCP2 mRNA, whereas WY14,643 treatment did not produce. detectable ROS under the condition that fibrate markedly up-regulated UCP2. In in vivo studies, PPARalpha activators moderately up-regulated TNFalpha mRNA expression in mouse liver. An anti-oxidant pyrrolidine dithiocarbamate ammonium salt injection completely prevented their TNFalpha mRNA increases but did not prevent most of their UCP2 mRNA increases. These data indicate that PPARalpha activators upregulate UCP2 expression in hepatocytes through unknown proteins by increased transcription, and neither ROS nor TNFa production are the major causes for PPARalpha activators-induced UCP2 up-regulation.