肝细胞高胆固醇负荷活化未折叠蛋白应答介导细胞凋亡损伤的研究
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摘要
资料显示肝细胞胆固醇聚积可导致细胞损伤，为了探讨胆固醇负荷时肝细胞损伤作用及可能机制，我们体外检测了在胆固醇负荷条件下肝细胞的凋亡发生，未折叠蛋白应答活化，以及它们间的相关性。采用200μg/ml LDL或者200μg/ml LDL联合20μg/ml胆固醇酯化酶ACAT抑制剂58035孵育人正常肝L02细胞24h；采用胆固醇氧化酶胆固醇酯酶法联合高效液相色谱(HPLC)法检测胞内总胆固醇(TC)，游离胆固醇(FC)和胆固醇酯(CE)的含量；RT-PCR分析UPR主要标志分子(BiP，XBP1，ATF6，ATF4，CHOP)基因mRNA表达水平；Western Blot检测BiP，ATF6表达及活化caspase-3蛋白片段的表达变化；Annexin V-FITC-PI荧光标记染色观察细胞凋亡；在LDL孵育的不同细胞组别中进一步添加3mM UPR抑制剂PBA，观察细胞凋亡及活性caspase-3的表达变化。结果发现，与对照组相比：用LDL孵育的细胞内胆固醇含量增加明显，对照组细胞FC含量为5．90±0．36μg/mg，LDL组中FC为11．17±0．35μg/mg，LDL+58035组为13．20±0．66μg/mg；LDL组中伴侣分子BiP mRNA和蛋白表达水平明显诱导上调，sXBP1和CHOP mRNA表达水平诱导增加，而LDL+58035组中它们的诱导表达增加更明显，同时还诱导上调ATF4，ATF6的表达；对照组中细胞凋亡率为1．1±0．6％，而LDL组中活化的caspase-3增加到4．8±0．21倍，细胞凋亡率上升到12．9±1．4％，LDL+58035组中活化的caspase-3增加到8．4±0．46倍，细胞凋亡率达到21．3±2．4％。进一步在LDL孵育的组别中添加UPR抑制剂PBA后分别检测细胞凋亡发生与活化caspase-3蛋白表达的变化，与对应的未加PBA的组别相比：LDL+PBA组和LDL+58035+PBA组中细胞凋亡率分别降至8．8±1．1％和14．9±1．6％，活化caspase-3蛋白表达减至对照组的2．5±0．13倍和5．7±0．35倍。以上结果表明胆固醇负荷能使L02肝细胞发生内质网应激，激活UPR，并引起细胞凋亡损伤，而活化的UPR介导了该凋亡损伤。
Reported data demonstrated that cholesterol loading in liver could cause the hepatic injury. To explore the possible mechanisms of cell damage resulted from cholesterol overloading in hepatocyte, the cell apoptosis, the unfolded protein response (UPR) and the correlation between them were tested in cholesterol-overloading human normal hepatic cell line L02. L02 cells were incubated with 200μg/ml of low density Hpoprotein (LDL) for 24h with or without 20μg/ml of 58035, an inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). In LDL+58035 group, the intracellular cholesterol level was dramatically increased, which was measured by an enzymetic combinated high performance liquid chromatography (HPLC) assay. The expression of immunoglobulin-binding protein (BiP), X-box binding protein (XBP1), activating transcription factor 6(ATF6), activating transcription factor 4(ATF4), CCAAT/enhancer-binding protein homologous protein-10 (CHOP), which were all the markers of endoplasmic reticulum (ERS)/UPR, were up-regulated by reverse transcription-polymerase chains reaction (RT-PCR) or Western Blot analysis. The rate of apoptotic cell death increased to 21.3±2.4%. Meanwhile, the active caspase-3 protein expression increased to 8.4 folds of that in the controls. Furthermore, 4-Phenylbutyric acid (PBA), an inhibitor of UPR, could partly reduce the cell apoptosis and activation of caspase-3. This study suggests that cholesterol overloading in hepatic L02 cells induced the ERS and activated UPR which partly leads to apoptotic damage of cells.
Reported data demonstrated that cholesterol loading in liver could cause the hepatic injury. To explore the possible mechanisms of cell damage resulted from cholesterol overloading in hepatocyte, the cell apoptosis, the unfolded protein response (UPR) and the correlation between them were tested in cholesterol-overloading human normal hepatic cell line L02. L02 cells were incubated with 200μg/ml of low density Hpoprotein (LDL) for 24h with or without 20μg/ml of 58035, an inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). In LDL+58035 group, the intracellular cholesterol level was dramatically increased, which was measured by an enzymetic combinated high performance liquid chromatography (HPLC) assay. The expression of immunoglobulin-binding protein (BiP), X-box binding protein (XBP1), activating transcription factor 6(ATF6), activating transcription factor 4(ATF4), CCAAT/enhancer-binding protein homologous protein-10 (CHOP), which were all the markers of endoplasmic reticulum (ERS)/UPR, were up-regulated by reverse transcription-polymerase chains reaction (RT-PCR) or Western Blot analysis. The rate of apoptotic cell death increased to 21.3±2.4%. Meanwhile, the active caspase-3 protein expression increased to 8.4 folds of that in the controls. Furthermore, 4-Phenylbutyric acid (PBA), an inhibitor of UPR, could partly reduce the cell apoptosis and activation of caspase-3. This study suggests that cholesterol overloading in hepatic L02 cells induced the ERS and activated UPR which partly leads to apoptotic damage of cells.
引文
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