1型多聚ADP核糖合成酶调控代谢性核受体转录激活的机制研究
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摘要
目的:高胆固醇饮食（HCD）是引起高胆固醇血症的重要原因之一。本部分主要目的是研究在小鼠肝脏中PARP1参与调节高胆固醇血症的作用及机制。
方法和结果:使用蛋白印迹实验等方法检测老鼠肝脏中PARP活性，血生化检测及病理学检查监测血及肝脏中胆固醇，低密度脂蛋白等脂质成分变化和肝脏脂质沉积水平。使用实时定量PCR法检测老鼠肝脏中胆固醇代谢相关基因RNA表达水平，凝胶迁移电泳检测老鼠肝脏中肝X受体α（LXRα）DNA结合能力。结果显示，HCD引起野生型老鼠肝脏PARP激活，使用PARP抑制剂改善HCD引起的血脂异常和肝脏脂质沉积。进一步的研究发现PARP抑制剂能够增强肝脏组织中LXRα的DNA结合能力，并显著增加老鼠肝脏中胆固醇代谢相关基因表达水平；然而PARP1基因敲除并不能改善血脂紊乱，反而抑制肝脏中LXRα胆固醇代谢相关靶基因表达。此外，PARP1基因敲除消除了PARP抑制剂降低血及肝脏胆固醇沉积，促进胆固醇相关基因表达等保护作用。
结论：PARP1在HCD引起的胆固醇代谢紊乱的机制中起重要作用。
目的：肝X受体α（LXRα）参与人体脂质代谢，细胞增殖、分化，免疫，炎症等生理活动。本部分主要目的是研究PARP1对LXRα转录调控的作用及机制。
方法和结果：蛋白印迹实验、免疫沉淀实验、PARP活性检测等方法证实LXR人工配体能够降低体内外蛋白核糖化程度。凝胶迁移电泳、染色质免疫沉淀、报告基因、蛋白印迹、实时定量PCR等方法证实活化的PARP1可催化LXRα的核糖化，使其DNA结合能力下降，从而降低其转录活性。然而未核糖化的PARP1能够促进LXRα结合与靶基因启动子上的LXR结合位点，并增强其转录活性。
结论：PARP1在LXRα转录调控中起重要作用。LXR的配体激活形式是通过抑制核糖化水平实现的，LXRα调控的强度及时程与由PARP1所致的核糖化水平相关。
目的：法尼酯X受体（FXR）是重要的肝脏保护因子。本部分主要目的是研究PARP1对FXR转录调控的作用及机制。
方法和结果：蛋白印迹、免疫沉淀技术等方法证实活化的PARP1可催化FXR配体结合域的核糖化。凝胶迁移电泳、染色质免疫沉淀、报告基因、实时定量PCR等方法使FXR的DNA结合能力下降，从而降低其转录活性。蛋白印迹实验、免疫沉淀实验、PARP活性检测、免疫沉淀技术、蛋白印迹实验等方法证实FXR人工配体能够降低核糖化程度，从而促进FXR的转录激活。
结论：PARP1在FXR转录调控中起重要作用。FXR的配体激活形式是通过抑制核糖化水平实现的，FXR调控的强度及时程与由PARP1所致的核糖化水平相关。
Chronic high cholesterol diet (HCD) is one major cause of hypercholesterolemia. To explorewhether or not hepatic poly(ADP-ribose) polymerase (PARP)1is involved in the HCD-inducedabnormalities in cholesterol metabolism, we employed the rodent model of HCD-inducedhypercholesterolemia, and biochemically studied the role of PARP1in cholesterol metabolism.HCD-feeding promoted hepatic PARP1activation. Treatment with PARP inhibitor preventedHCD-induced hypercholesterolemia and hepatic lipid accumulation. Further studies revealed thatinhibition of PARP activity stimulated the hepatic expression of liver X receptor (LXR) α targetgenes involved in cholesterol metabolism, and enhanced the LXRα-LXR response element complexformation in nuclear extracts from liver tissues. Knockout of PARP1failed to prevent HCD-inducedabnormalities in cholesterol metabolism, and inhibited LXRα target gene expression in liver.Moreover, the effects of PARP inhibitor on the HCD induced hypercholesterolemia, hepatic lipidaccumulation and expression of LXRα target genes were also diminished in PARP1knock out(PKO) mice. These results illustmicee that activation of PARP1plays a crucial role inHCD-induced abnormalities in cholesterol metabolism.
Liver X receptor α (LXRα) functions importantly in lipid metabolism, cell proliferation anddifferentiation, reproduction, growth and development, immune and inflammation. In the absenceof ligand, LXRα binds to target promoter and inhibits transcription by recruiting nuclearco-repressors. Ligand binding causes an exchange of co-repressor with co-activator, thusstimulating transcription. Here, we report that poly(ADP-ribosyl)ation plays an essential role in thecontrol of LXRα mediated transcription. PARP1mediated poly(ADP-ribosyl)ation of LXRα anditself prevents LXRα binding to the target promoter, thus inhibiting transcription.Un-poly(ADP-ribosyl)ated PARP1assists LXRα binding to target promoter through directassociation with LXRα, thereby promoting transcription. We further demonstrate that LXR ligandsare potent PARP1inhibitors. Inhibition of poly(ADP-ribosyl)ation mediates the ligand-inducedLXRα activation. Thus, the strength and duration of LXRα dependent transcription is controlled bypoly(ADP-ribosyl)ation levels.
Farnesoid X receptor α (FXR) is highly expressed in liver and regulates the expression ofvarious genes involved in liver repair. In this study, we demonstrated that activatedpoly(ADP-ribose) polymerase1(PARP1) promoted cell death by inhibiting the expressionof FXR dependent hepatoprotective genes. PARP1could bind to andpoly(ADP-ribosyl)ated FXR. Poly(ADP-ribosyl)ation dissociated FXR from FXR responseelement (FXRE) present in the promoter of target genes, and blocked FXR mediated genetranscription. Moreover, FXR agonist treatment attenuated poly(ADP-ribosyl)ation of FXRand promoted FXR dependant gene expression in cultured hepatic cells. Thus, our resultsidentified poly(ADP-ribosyl)ation of FXR by PARP1as a key step in oxidativestress-induced cell death. The molecular cooperation between PARP1and FXR intranscription activation provided a new insight into the mechanism underlying theinhibition of PARP1prevents liver injury.
方法和结果:使用蛋白印迹实验等方法检测老鼠肝脏中PARP活性，血生化检测及病理学检查监测血及肝脏中胆固醇，低密度脂蛋白等脂质成分变化和肝脏脂质沉积水平。使用实时定量PCR法检测老鼠肝脏中胆固醇代谢相关基因RNA表达水平，凝胶迁移电泳检测老鼠肝脏中肝X受体α（LXRα）DNA结合能力。结果显示，HCD引起野生型老鼠肝脏PARP激活，使用PARP抑制剂改善HCD引起的血脂异常和肝脏脂质沉积。进一步的研究发现PARP抑制剂能够增强肝脏组织中LXRα的DNA结合能力，并显著增加老鼠肝脏中胆固醇代谢相关基因表达水平；然而PARP1基因敲除并不能改善血脂紊乱，反而抑制肝脏中LXRα胆固醇代谢相关靶基因表达。此外，PARP1基因敲除消除了PARP抑制剂降低血及肝脏胆固醇沉积，促进胆固醇相关基因表达等保护作用。
结论：PARP1在HCD引起的胆固醇代谢紊乱的机制中起重要作用。
目的：肝X受体α（LXRα）参与人体脂质代谢，细胞增殖、分化，免疫，炎症等生理活动。本部分主要目的是研究PARP1对LXRα转录调控的作用及机制。
方法和结果：蛋白印迹实验、免疫沉淀实验、PARP活性检测等方法证实LXR人工配体能够降低体内外蛋白核糖化程度。凝胶迁移电泳、染色质免疫沉淀、报告基因、蛋白印迹、实时定量PCR等方法证实活化的PARP1可催化LXRα的核糖化，使其DNA结合能力下降，从而降低其转录活性。然而未核糖化的PARP1能够促进LXRα结合与靶基因启动子上的LXR结合位点，并增强其转录活性。
结论：PARP1在LXRα转录调控中起重要作用。LXR的配体激活形式是通过抑制核糖化水平实现的，LXRα调控的强度及时程与由PARP1所致的核糖化水平相关。
目的：法尼酯X受体（FXR）是重要的肝脏保护因子。本部分主要目的是研究PARP1对FXR转录调控的作用及机制。
方法和结果：蛋白印迹、免疫沉淀技术等方法证实活化的PARP1可催化FXR配体结合域的核糖化。凝胶迁移电泳、染色质免疫沉淀、报告基因、实时定量PCR等方法使FXR的DNA结合能力下降，从而降低其转录活性。蛋白印迹实验、免疫沉淀实验、PARP活性检测、免疫沉淀技术、蛋白印迹实验等方法证实FXR人工配体能够降低核糖化程度，从而促进FXR的转录激活。
结论：PARP1在FXR转录调控中起重要作用。FXR的配体激活形式是通过抑制核糖化水平实现的，FXR调控的强度及时程与由PARP1所致的核糖化水平相关。
Chronic high cholesterol diet (HCD) is one major cause of hypercholesterolemia. To explorewhether or not hepatic poly(ADP-ribose) polymerase (PARP)1is involved in the HCD-inducedabnormalities in cholesterol metabolism, we employed the rodent model of HCD-inducedhypercholesterolemia, and biochemically studied the role of PARP1in cholesterol metabolism.HCD-feeding promoted hepatic PARP1activation. Treatment with PARP inhibitor preventedHCD-induced hypercholesterolemia and hepatic lipid accumulation. Further studies revealed thatinhibition of PARP activity stimulated the hepatic expression of liver X receptor (LXR) α targetgenes involved in cholesterol metabolism, and enhanced the LXRα-LXR response element complexformation in nuclear extracts from liver tissues. Knockout of PARP1failed to prevent HCD-inducedabnormalities in cholesterol metabolism, and inhibited LXRα target gene expression in liver.Moreover, the effects of PARP inhibitor on the HCD induced hypercholesterolemia, hepatic lipidaccumulation and expression of LXRα target genes were also diminished in PARP1knock out(PKO) mice. These results illustmicee that activation of PARP1plays a crucial role inHCD-induced abnormalities in cholesterol metabolism.
Liver X receptor α (LXRα) functions importantly in lipid metabolism, cell proliferation anddifferentiation, reproduction, growth and development, immune and inflammation. In the absenceof ligand, LXRα binds to target promoter and inhibits transcription by recruiting nuclearco-repressors. Ligand binding causes an exchange of co-repressor with co-activator, thusstimulating transcription. Here, we report that poly(ADP-ribosyl)ation plays an essential role in thecontrol of LXRα mediated transcription. PARP1mediated poly(ADP-ribosyl)ation of LXRα anditself prevents LXRα binding to the target promoter, thus inhibiting transcription.Un-poly(ADP-ribosyl)ated PARP1assists LXRα binding to target promoter through directassociation with LXRα, thereby promoting transcription. We further demonstrate that LXR ligandsare potent PARP1inhibitors. Inhibition of poly(ADP-ribosyl)ation mediates the ligand-inducedLXRα activation. Thus, the strength and duration of LXRα dependent transcription is controlled bypoly(ADP-ribosyl)ation levels.
Farnesoid X receptor α (FXR) is highly expressed in liver and regulates the expression ofvarious genes involved in liver repair. In this study, we demonstrated that activatedpoly(ADP-ribose) polymerase1(PARP1) promoted cell death by inhibiting the expressionof FXR dependent hepatoprotective genes. PARP1could bind to andpoly(ADP-ribosyl)ated FXR. Poly(ADP-ribosyl)ation dissociated FXR from FXR responseelement (FXRE) present in the promoter of target genes, and blocked FXR mediated genetranscription. Moreover, FXR agonist treatment attenuated poly(ADP-ribosyl)ation of FXRand promoted FXR dependant gene expression in cultured hepatic cells. Thus, our resultsidentified poly(ADP-ribosyl)ation of FXR by PARP1as a key step in oxidativestress-induced cell death. The molecular cooperation between PARP1and FXR intranscription activation provided a new insight into the mechanism underlying theinhibition of PARP1prevents liver injury.
引文
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