脂联素基因的表达和分泌调控
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摘要
脂肪组织作为一种能量储存器官在脂肪的贮存、动员及其调控中具有不可替代的作用,近年来的研究表明脂肪组织在内分泌和旁分泌方面也具有十分重要的作用,可分泌大量的激素和细胞因子以调控机体内各组织和细胞的代谢功能。
脂联素是近来发现的一种重要的脂肪细胞因子,在调节脂质和葡萄糖代谢方面扮演着重要角色。它可刺激脂肪酸氧化、抑制肝糖原异生和增强胰岛素敏感性,在慢性炎症病理调节、抗动脉粥样硬化及通过神经系统调节进食和体重等功能调控方面也不断具有新的发现。
脂联素由脂肪细胞分泌后在循环系统中存在三聚体、六聚体和高分子量多聚体三种形式。脂联素的每种亚型在不同的靶组织中都有不同的生物学功能,其中高分子量多聚体是脂联素调控胰岛素敏感性的重要形式,而主要的作用形式为六聚体或三聚体。脂联素的生物合成是一个十分复杂的过程,包括大量的翻译后修饰作用,脂联素分子的胶原结构域中保守的赖氨酸残基的羟基化和糖基化对于其胞内多聚体组装和维持其高聚体结构十分必要。
已有研究报道,脂联素在转录水平上受到多种转录因子的调控,可通过其启动子区的顺式作用元件或第一个内含子区而调控脂联素的表达,合成后的脂联素借助44 kDa内质网蛋白(ERp44)和内质网氧化还原酶1-Lα(EROl-Lα)以调节型分泌方式分泌到胞外。但脂联素基因表达通过启动子的反式调控和分泌调控的分子机制尚须精细的系统研究。
本研究利用稳定转染脂联素基因的HEK293细胞系和分离纯化得到的猪骨髓间充值干细胞(MSCs),运用实时定量PCR、Western Blot、染色质免疫共沉淀、细胞转染和基因启动子荧光素酶报告检测系统等研究技术,对脂联素的表达、分泌及其调控机制进行分析,得到以下结果：
1.采用同源序列法克隆了猪ERp44和EROl-Lα基因。实时定量PCR检测了ERp44和EROl-Lα基因在12个组织样中的表达水平,ERp44和EROl-Lα基因主要在脂肪组织中表达。以基因电子定位的方法,将猪ERp44和EROl-Lα基因分别定位于染色体1q29和1q21。
2.生物信息学分析预测ERp44基因启动子存在PPARγ结合位点,基因共转染证实ERp44基因表达受PPARγ的调控。利用染色质免疫共沉淀和荧光素酶报告基因系统,证明PPARγ通过结合到ERp44基因启动子-981至-1004区域的PPRE位点而抑制ERp44基因的表达。
3.罗格列酮(PPARγ激动剂)处理或过量表达PPARγ均可降低ERp44基因的转录,进而引起脂联素分泌的显著提高。
4.从一月龄梅山猪骨髓中分离获得一株骨髓间充质干细胞,通过细胞形态、生长特征和标志基因(PouV, Sox2和Nanog等)分析,表明该细胞具有间充质干细胞的形态特征和细胞全能性(如分化为成熟的脂肪细胞)。
5.生物信息学分析预测脂联素启动子上具有KLF结合位点,在猪骨髓间充质干细胞成脂分化后脂联素基因表达受KLF15的调控。用染色质免疫共沉淀和荧光素酶报告基因系统进分析证明,KLF15可与脂联素基因启动子-93至-77区域特异结合以激活脂联素基因的表达。
Adipose tissue as an energy storage organ has an irreplaceable role in triglyceride storage, mobilization and its regulation, recent studies show that the adipose tissue also plays an important role in the endocrine and paracrine, can secrete a large number of hormones and cytokines to regulate the metabolism of the tissue and cell functions.
Adiponectin is a recently discovered key adipokine, it play an important role in the regulation of lipid and glucose metabolism. Adiponectin stimulates fatty acid oxidation, suppresses gluconeogenesis in liver, increases insulin sensitivity, exerts a protective role against chronic inflammation, possess anti-atherosclerosis and regulates feeding and body weight through the nervous system.
Adiponectin is secreted from adipocytes into the circulation as three oligomeric isoforms,. including trimeric, hexameric and the high-molecular-mass oligomeric complex. Each oligomeric isoform of adiponectin exerts distinct biological properties in its various target tissues. The high-molecular-mass oligomer is the major active form mediating the insulin-sensitizing effects of adiponectin, whereas the central actions of this adipokine are attributed primarily to the hexameric and trimeric oligomers. The biosynthesis of the adiponectin oligomers is a complex process involving extensive post-translational modifications. Hydroxylation and glycosylation of several conserved lysine residues in the collagenous domain of adiponectin are necessary for the intracellular assembly and stabilization of its high-order oligomeric structures.
Previous studies reported that adiponectin is transcriptionally regulated by various transcription factors through cis-regulatory elements in its promoter region or first intron. Secretion of the adiponectin oligomers is tightly controlled by a pair of molecular chaperones in the endoplasmic reticulum (ER), including ERp44 (ER protein of 44 kDa) and EROl-Lα(ER oxidoreductase 1-Lα). But the systematic study on the expressional and secretional regulation of adiponectin is yet to be elaborated.
In this study, by choosing adiponectin stable transfected HEK293 cells and isolated pig bone marrow recharge stem cells (MSCs), using real-time quantitative PCR, Western blot, chromatin immunoprecipitation, cell transfection and promoter fluorescence luciferase reporter detection techniques, the expression, secretion and regulation mechanism of adiponectin was analysis, the following results:
1. Using homologous comparative analysis, we cloned the pig ERp44 and EROl-Lαgene. Real-time quantitative PCR detected the tissue expression patten of ERp44 and EROl-Lαgene in 12 tissue samples, ERp44 and EROl-Lαgene expressed mainly in adipose tissue. By in silico mapping analysis, pig ERp44 and EROl-La was located in chromosome 1q29 and 1q21, respectively.
2. Bioinformatic analysis predicted the existence of PPARy binding sites in the ERp44 gene promoter; co-transfection found that ERp44 gene expression regulation by PPARy. Using chromatin immunoprecipitation and luciferase reporter system, we confirmed that PPARy can bind to the PPRE site in 981 to-1004 region of ERp44 gene promoter, and then repress the expression of ERp44 gene.
3. Rosiglitazone (PPARy agonist) treatment or over-expression of PPARy could reduce the ERp44 gene transcription, thereby causing the secretion of adiponectin were significantly increased.
4. Bone marrow MSCs was isolated from a month-old Meishan pig, by cell morphology, growth characteristics and marker genes (PouV, Sox2, and Nanog, etc.) analysis showed that the MSCs have mesenchymal stem cell morphology and cell pluripotency (for example, to differentiate into mature adipocyte).
5. Bioinformatic analysis predicted the KLF binding sites in adiponectin gene promoter, and the adiponectin gene expression was regulated by KLF 15 during the porcine bone marrow MSCs differentiated into adipocyte,. Using chromatin immunoprecipitation and luciferase reporter gene system to analysis, the results shows that KLF 15 can specifically bind to the adiponectin gene promoter-93 to-77 region, and then activate the expression of adiponectin gene.
脂联素是近来发现的一种重要的脂肪细胞因子,在调节脂质和葡萄糖代谢方面扮演着重要角色。它可刺激脂肪酸氧化、抑制肝糖原异生和增强胰岛素敏感性,在慢性炎症病理调节、抗动脉粥样硬化及通过神经系统调节进食和体重等功能调控方面也不断具有新的发现。
脂联素由脂肪细胞分泌后在循环系统中存在三聚体、六聚体和高分子量多聚体三种形式。脂联素的每种亚型在不同的靶组织中都有不同的生物学功能,其中高分子量多聚体是脂联素调控胰岛素敏感性的重要形式,而主要的作用形式为六聚体或三聚体。脂联素的生物合成是一个十分复杂的过程,包括大量的翻译后修饰作用,脂联素分子的胶原结构域中保守的赖氨酸残基的羟基化和糖基化对于其胞内多聚体组装和维持其高聚体结构十分必要。
已有研究报道,脂联素在转录水平上受到多种转录因子的调控,可通过其启动子区的顺式作用元件或第一个内含子区而调控脂联素的表达,合成后的脂联素借助44 kDa内质网蛋白(ERp44)和内质网氧化还原酶1-Lα(EROl-Lα)以调节型分泌方式分泌到胞外。但脂联素基因表达通过启动子的反式调控和分泌调控的分子机制尚须精细的系统研究。
本研究利用稳定转染脂联素基因的HEK293细胞系和分离纯化得到的猪骨髓间充值干细胞(MSCs),运用实时定量PCR、Western Blot、染色质免疫共沉淀、细胞转染和基因启动子荧光素酶报告检测系统等研究技术,对脂联素的表达、分泌及其调控机制进行分析,得到以下结果：
1.采用同源序列法克隆了猪ERp44和EROl-Lα基因。实时定量PCR检测了ERp44和EROl-Lα基因在12个组织样中的表达水平,ERp44和EROl-Lα基因主要在脂肪组织中表达。以基因电子定位的方法,将猪ERp44和EROl-Lα基因分别定位于染色体1q29和1q21。
2.生物信息学分析预测ERp44基因启动子存在PPARγ结合位点,基因共转染证实ERp44基因表达受PPARγ的调控。利用染色质免疫共沉淀和荧光素酶报告基因系统,证明PPARγ通过结合到ERp44基因启动子-981至-1004区域的PPRE位点而抑制ERp44基因的表达。
3.罗格列酮(PPARγ激动剂)处理或过量表达PPARγ均可降低ERp44基因的转录,进而引起脂联素分泌的显著提高。
4.从一月龄梅山猪骨髓中分离获得一株骨髓间充质干细胞,通过细胞形态、生长特征和标志基因(PouV, Sox2和Nanog等)分析,表明该细胞具有间充质干细胞的形态特征和细胞全能性(如分化为成熟的脂肪细胞)。
5.生物信息学分析预测脂联素启动子上具有KLF结合位点,在猪骨髓间充质干细胞成脂分化后脂联素基因表达受KLF15的调控。用染色质免疫共沉淀和荧光素酶报告基因系统进分析证明,KLF15可与脂联素基因启动子-93至-77区域特异结合以激活脂联素基因的表达。
Adipose tissue as an energy storage organ has an irreplaceable role in triglyceride storage, mobilization and its regulation, recent studies show that the adipose tissue also plays an important role in the endocrine and paracrine, can secrete a large number of hormones and cytokines to regulate the metabolism of the tissue and cell functions.
Adiponectin is a recently discovered key adipokine, it play an important role in the regulation of lipid and glucose metabolism. Adiponectin stimulates fatty acid oxidation, suppresses gluconeogenesis in liver, increases insulin sensitivity, exerts a protective role against chronic inflammation, possess anti-atherosclerosis and regulates feeding and body weight through the nervous system.
Adiponectin is secreted from adipocytes into the circulation as three oligomeric isoforms,. including trimeric, hexameric and the high-molecular-mass oligomeric complex. Each oligomeric isoform of adiponectin exerts distinct biological properties in its various target tissues. The high-molecular-mass oligomer is the major active form mediating the insulin-sensitizing effects of adiponectin, whereas the central actions of this adipokine are attributed primarily to the hexameric and trimeric oligomers. The biosynthesis of the adiponectin oligomers is a complex process involving extensive post-translational modifications. Hydroxylation and glycosylation of several conserved lysine residues in the collagenous domain of adiponectin are necessary for the intracellular assembly and stabilization of its high-order oligomeric structures.
Previous studies reported that adiponectin is transcriptionally regulated by various transcription factors through cis-regulatory elements in its promoter region or first intron. Secretion of the adiponectin oligomers is tightly controlled by a pair of molecular chaperones in the endoplasmic reticulum (ER), including ERp44 (ER protein of 44 kDa) and EROl-Lα(ER oxidoreductase 1-Lα). But the systematic study on the expressional and secretional regulation of adiponectin is yet to be elaborated.
In this study, by choosing adiponectin stable transfected HEK293 cells and isolated pig bone marrow recharge stem cells (MSCs), using real-time quantitative PCR, Western blot, chromatin immunoprecipitation, cell transfection and promoter fluorescence luciferase reporter detection techniques, the expression, secretion and regulation mechanism of adiponectin was analysis, the following results:
1. Using homologous comparative analysis, we cloned the pig ERp44 and EROl-Lαgene. Real-time quantitative PCR detected the tissue expression patten of ERp44 and EROl-Lαgene in 12 tissue samples, ERp44 and EROl-Lαgene expressed mainly in adipose tissue. By in silico mapping analysis, pig ERp44 and EROl-La was located in chromosome 1q29 and 1q21, respectively.
2. Bioinformatic analysis predicted the existence of PPARy binding sites in the ERp44 gene promoter; co-transfection found that ERp44 gene expression regulation by PPARy. Using chromatin immunoprecipitation and luciferase reporter system, we confirmed that PPARy can bind to the PPRE site in 981 to-1004 region of ERp44 gene promoter, and then repress the expression of ERp44 gene.
3. Rosiglitazone (PPARy agonist) treatment or over-expression of PPARy could reduce the ERp44 gene transcription, thereby causing the secretion of adiponectin were significantly increased.
4. Bone marrow MSCs was isolated from a month-old Meishan pig, by cell morphology, growth characteristics and marker genes (PouV, Sox2, and Nanog, etc.) analysis showed that the MSCs have mesenchymal stem cell morphology and cell pluripotency (for example, to differentiate into mature adipocyte).
5. Bioinformatic analysis predicted the KLF binding sites in adiponectin gene promoter, and the adiponectin gene expression was regulated by KLF 15 during the porcine bone marrow MSCs differentiated into adipocyte,. Using chromatin immunoprecipitation and luciferase reporter gene system to analysis, the results shows that KLF 15 can specifically bind to the adiponectin gene promoter-93 to-77 region, and then activate the expression of adiponectin gene.
引文
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