腺苷受体A_1在肝脏疾病发病机制中的作用研究
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摘要
腺苷是生物体的自然代谢物,在众多的生理及病理过程扮演着重要的角色。胞外腺苷浓度受到许多生理病理条件的动态调控。腺苷一旦被释放到胞外,便可通过激活细胞膜表面的腺苷受体来调节细胞功能。腺苷受体与G蛋白偶联,通过改变第二信使系统活性来调节胞内蛋白激酶信号通路和调控下游靶基因表达。由于腺苷受体可介导胞内外信号传导,其作为疾病的潜在治疗靶点受到越来越多的关注。有越来越多的证据表明,腺苷受体有希望成为一系列疾病的治疗靶点,如大脑和心脏缺血性疾病,睡眠障碍,免疫和炎症性疾病,以及癌症。但是腺苷受体在肝脏疾病中的作用和临床价值还未受到充分揭示。本研究采用腺苷受体基因敲除动物作为模型,探索了腺苷—腺苷受体信号通路在肝脏重大代谢疾病中的作用,揭示了腺苷信号调节和传导机制。同时,评估了腺苷受体作为新型基因和药物靶点在治疗和预防肝脏疾病中的潜在价值。
本研究发现腺苷受体A1基因参与调节肝纤维化的发展进程。证明腺苷受体A1基因在肝毒素四氯化碳(CC14)和胆管结扎(BDL)导致的肝纤维化过程中扮演了相反的角色。研究表明,在慢性CC14肝纤维化模型中,腺苷受体Al基因缺失延缓了肝纤维化进程,胶原的沉积和肝星状细胞的激活在腺苷受体A1基因敲除(A1AR-/-)小鼠中都削弱了。然而,在BDL肝纤维化模型中,腺苷受体A1基因缺失却加速了肝纤维化进程,胶原的合成和汇管区纤维母细胞的激活在A1AR-/-小鼠中都加重了。我们进一步研究了腺苷受体Al基因参与调节CCl4和BDL肝纤维化的不同分子机制。发现腺苷受体A1基因缺失减轻了单次CCl4注射产生的急性肝损伤。血清转氨酶活性和肝细胞坏死程度在A1AR-/-小鼠中都降低了,这很可能是通过下调肝脏CYP2E1和UCP2基因表达水平达到的。另外,在CCl4长期处理过程中,“致肝纤维化因子”的表达水平,包括：TGFβ2, TNFα, IL-1,和IL-6都在A1AR-/-小鼠中下调。而在BDL模型中,A1AR-/-小鼠血清胆汁酸浓度显著升高,由此加重了胆汁淤积性肝细胞梗死,并增加了胆管上皮细胞增生,最终导致了肝纤维化的恶化。我们的实验结果表明腺苷受体A1基因通过复杂的机制参与肝纤维化的进程,建议在运用腺苷及其受体作为抗肝纤维化策略时应加以仔细的评估。
发现腺苷受体A1参与肝内胆汁淤积性肝损伤的发病过程,并且是潜在的治疗肝内胆汁淤积疾病的基因和药物靶点。在α-荼基异硫氰酸酯(ANIT)致肝内胆汁淤积小鼠模型中,肝内腺苷浓度显著升高并且腺苷受体A1呈高表达,这预示着腺苷-腺苷受体A1信号很可能参与了ANIT肝损伤的发病过程。接下来研究表明,小鼠腺苷受体A1基因缺失对ANIT诱导的肝损伤有保护作用,可降低血清转氨酶活性和肝细胞坏死程度。与野生型(WT)小鼠相比,A1AR-/-小鼠肝脏和血清中胆汁酸的淤积显著减轻,然而胆汁和尿液中胆汁酸的排泌却显著增强。在A1AR-/-小鼠肝脏中,胆汁酸转运体Bsep和Mdr2,以及胆汁酸羟化酶Cyp3α11的基因表达水平都显著上调。在肾脏中,腺苷受体A1基因缺失可防止ANIT造成肾小球过滤速率降低。另外,腺苷受体A1拮抗剂同样可以削弱ANIT对小鼠的肝毒性作用。我们的实验结果证实,小鼠腺苷受体A1基因缺失对肝内胆汁淤积性肝损伤有保护作用,这是通过增强具有毒性的胆汁成分从胆汁分泌途径和肾脏排泄途径排出来实现的,而且表明了腺苷受体A1作为治疗肝内胆汁淤积疾病治疗靶点的潜在价值。
发现内源性腺苷受体Al激活可保护急性酒精肝损伤。与野生型小鼠相比,A1AR-/-小鼠对急性酒精导致的肝损害更加敏感,血清转氨酶活性升高,肝脏病理学改变更加严重。酒精会诱导血清和肝脏中脂质的累积,这种脂质累积在A1AR-/-小鼠中更加显著。通过对肝脏中脂质代谢相关基因表达分析发现,在A1AR-/-小鼠中肝脏脂质合成基因(包括：FAS, SCD1, ACC1, DGAT2, PPARy)表达水平都显著上调,由此加重了急性酒精性脂肪肝。另外,腺苷受体A1基因缺失加剧了酒精导致的肝脏脂质过氧化和抗氧化物的耗竭,由此加重了氧化压力。研究还发现,腺苷受体A1的药理阻断同样会加重急性酒精造成的肝损伤和早期脂肪变性。总的来讲,实验结果表明内源性腺苷受体A1激活可以削弱急性酒精诱导产生的氧化压力,并通过下调脂肪合成相关基因的表达降低肝脏脂质堆积,从而对抗急性酒精肝损伤。
发现腺苷受体A1基因缺失会加重非酒精性脂肪肝和胰岛素抵抗的发生。通过建立"western diet"高脂小鼠模型,我们发现与WT小鼠相比,A1AR-/-小鼠在高脂饮食诱导后表现出一系列的代谢异常,如：体重和总脂肪含量增加,白色脂肪组织肥大,血清脂类物质增加,肝脏脂肪变性和胰岛素抵抗加重等。深入研究发现,高脂饮食诱导后,A1AR-/-小鼠肝脏中脂质合成相关基因(包括FAS, SCD1, ACC1, DGAT2,和PPARy)的表达水平都显著上调,由此加强了肝内脂肪合成过程。研究还发现,小鼠腺苷受体A1基因缺失加重了白色脂肪组织炎症反应和巨噬细胞浸润,并上调了F4/80, MCP-1,和TNFa基因表达水平。脂肪组织的炎症反应和巨噬细胞浸润是胰岛素抵抗发生的重要机制。另外,腺苷受体A1基因缺失加强了脂肪细胞分化的主要转录调控因子C/EBPα和PPARγ的表达,这导致了A1AR-/-小鼠脂肪细胞分化增加,促进了肥胖的产生。总的来讲,我们的实验结果表明,小鼠腺苷受体A1基因可通过抑制肝脏脂质合成,降低脂肪细胞分化,以及削弱脂肪组织的炎症反应,来改善高脂饮食引起的导致代谢紊乱。
Adenosine is a natural metabolite in organisms, which plays an important role in many physiological and pathological processes. Extracellular adenosine concentrations are dynamically regulated by a variety of pathophysiological conditions. Adenosine once released can activate cell-surface adenosine receptors which in turn regulate cellular function. Adenosine receptors are coupled to G proteins, though altering the activity of a second messenger system, can modulate protein kinase signaling pathways and regulate downstream target gene expression. Because adenosine receptors mediate extracellular and intracellular signal transduction, they attract more and more attentions as potential targets for disease. There is growing evidence that adenosine receptors could be promising therapeutic targets in a wide range of diseases, including cerebral and cardiac ischemic diseases, sleep disorders, immune and inflammatory disorders, and cancer. However, adenosine receptor's role and value in liver disease have not yet been fully revealed. In this study, by using adenosine receptor knockout animals, we examined the contribution of adenosine-adenosine receptor signaling pathway to liver metabolic disease, and demonstrated its regulation mechanism at the molecular level. We also evaluate the potential role of adenosine receptors as gene or drug targets in the prevention and treatment of liver disease.
In this study, we found that adenosine A1receptor (A1AR) involves in the development of liver fibrosis. A1AR plays a contradictory role in carbon tetrachloride-(CCl4) and bile duct ligation-(BDL) induced liver fibrosis. Our results demonstrated that, lack of A1AR attenuates hepatic fibrosis resulting from chronic CCl4exposure, with markedly decreased collagen deposition and reduced hepatic stellate cell activation in A1AR-/-mice. Whereas, hepatic fibrosis caused by BDL ligation was aggravated in A1AR-/-mice, with significantly increased collagen synthesis and induced fibroblasts activation in portal tracts. We further investigated the different molecular mechanisms through which A1AR gene regulates CCl4-and BDL-induced hepatic fibrosis. A1AR deficiency reduces acute reactivity to liver injury induced by a single CCl4injection. In A1AR-/-mice, serum transaminase levels were lower and the extent of hepatocyte damage was reduced, which was probably achieved by down-regulating hepatic CYP2E1and UCP2gene expression. Besides, the levels of "profibrotic mediators", including TGFβ2, TNFα, IL-1, and IL-6were decreased in A/AR-/-mice during chronic CCl4treatment. Whereas in the BDL model, enhanced biliary infarcts and cholangiocyte proliferation due to elevation of bile acid levels should be the primary causes leading to increased fibrosis in A1AR-/-mice. These results indicate that A/AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.
We found that A1AR involves in the pathogenesis of intrahepatic cholestatic liver injury, and is a potential gene and drug target for the treatment of intrahepatic cholestatsis. In the mouse model of a-naphthylisothiocyanate-(ANIT) induced intrahepatic cholestasis, hepatic adenosine levels and A1AR expression were markedly increased, which suggested that adenosine-A1AR signal may participate in the development of ANIT-induced liver injury. Our study revealed that mice lacking A1AR are protected from ANIT induced liver injury as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A1AR-/-mice compared with wild-type (WT) mice, however, biliary and urinary outputs of bile acids were significantly enhanced in A1AR-/-mice. In the liver, mRNA expression of genes related to bile acid transport Bsep and Mdr2and hydroxylation Cyp3all was increased in A1AR-/-mice. In the kidney, A1AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. In addition, treatment of mice with A1AR antagonist also protected against ANIT hepatotoxicity. Our results indicated that lack of A1AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A1AR as therapeutic target for the treatment of intrahepatic cholestasis.
We also found that endogenous A1AR activation protects against acute ethanol-induced liver injury. Mice lacking A1AR were more susceptible to acute ethanol-induced liver damage than WT mice, which was evidenced by elevated serum transaminase levels and increased extent of histopathological changes. Ethanol induced triglycerides accumulation in the serum and liver, and this accumulation was augmented in A1AR-/-mice. Analysis of gene expression in the liver revealed up-regulated mRNA levels of lipogenic genes (including:FAS, SCD1, ACC1, DGAT2, and PPARy) in A1AR-/-mice after ethanol treatment. In addition, lack of A1AR aggravated lipid peroxidation and worsened antioxidants depletion which was caused by ethanol exposure. A subsequent study revealed that pharmacological block of A1AR also exacerbated liver injury and steatosis induced by acute ethanol administration. In conclusion, these results indicated that endogenous A1AR protects mice against acute ethanol-induced liver injury by reducing oxidative stress and decreasing lipid accumulation though down-regulation of lipogenesis-related genes.
In addition, we found that lack of A1AR exaggerates the development of nonalcoholic fatty liver and insulin resistance. Compared with WT mice,"western diet" induced a series of metabolic abnormalities in A1AR-/-mice, such as increased body weight and fat, adipose tissue hypertrophy, high blood lipids, deteriorated hepatic steatosis and insulin resistance. Further studies showed that increased lipogenesis due to up-regulated mRNA expression of lipogenic genes (including:FAS, SCD1, ACC1, DGAT2, and PPARy) in A1AR-/-mice after high-fat diet feeding. Besides, lack of A1AR exaggerated inflammation and macrophage infiltration into white adipose tissue, and increased mRNA expression of F4/80, MCP-1, and TNFa. Inflammation and macrophage infiltration into adipose tissue appear to participate in the pathogenesis of obesity-induced insulin resistance. Moreover, A1AR deficiency enhanced expression of C/EBPa and PPARy, the major transcriptional regulators of adipocyte differentiation, which should contribute to increased adipogenesis and obesity in A1AR-/-mice. Taken together, our results indicated that endogenous A1AR activation protects mice from high fat diet-induced metabolic disorders, though inhibiting hepatic lipogenesis, decreasing adipocyte differentiation, and alleviating inflammation in adipose tissue.
本研究发现腺苷受体A1基因参与调节肝纤维化的发展进程。证明腺苷受体A1基因在肝毒素四氯化碳(CC14)和胆管结扎(BDL)导致的肝纤维化过程中扮演了相反的角色。研究表明,在慢性CC14肝纤维化模型中,腺苷受体Al基因缺失延缓了肝纤维化进程,胶原的沉积和肝星状细胞的激活在腺苷受体A1基因敲除(A1AR-/-)小鼠中都削弱了。然而,在BDL肝纤维化模型中,腺苷受体A1基因缺失却加速了肝纤维化进程,胶原的合成和汇管区纤维母细胞的激活在A1AR-/-小鼠中都加重了。我们进一步研究了腺苷受体Al基因参与调节CCl4和BDL肝纤维化的不同分子机制。发现腺苷受体A1基因缺失减轻了单次CCl4注射产生的急性肝损伤。血清转氨酶活性和肝细胞坏死程度在A1AR-/-小鼠中都降低了,这很可能是通过下调肝脏CYP2E1和UCP2基因表达水平达到的。另外,在CCl4长期处理过程中,“致肝纤维化因子”的表达水平,包括：TGFβ2, TNFα, IL-1,和IL-6都在A1AR-/-小鼠中下调。而在BDL模型中,A1AR-/-小鼠血清胆汁酸浓度显著升高,由此加重了胆汁淤积性肝细胞梗死,并增加了胆管上皮细胞增生,最终导致了肝纤维化的恶化。我们的实验结果表明腺苷受体A1基因通过复杂的机制参与肝纤维化的进程,建议在运用腺苷及其受体作为抗肝纤维化策略时应加以仔细的评估。
发现腺苷受体A1参与肝内胆汁淤积性肝损伤的发病过程,并且是潜在的治疗肝内胆汁淤积疾病的基因和药物靶点。在α-荼基异硫氰酸酯(ANIT)致肝内胆汁淤积小鼠模型中,肝内腺苷浓度显著升高并且腺苷受体A1呈高表达,这预示着腺苷-腺苷受体A1信号很可能参与了ANIT肝损伤的发病过程。接下来研究表明,小鼠腺苷受体A1基因缺失对ANIT诱导的肝损伤有保护作用,可降低血清转氨酶活性和肝细胞坏死程度。与野生型(WT)小鼠相比,A1AR-/-小鼠肝脏和血清中胆汁酸的淤积显著减轻,然而胆汁和尿液中胆汁酸的排泌却显著增强。在A1AR-/-小鼠肝脏中,胆汁酸转运体Bsep和Mdr2,以及胆汁酸羟化酶Cyp3α11的基因表达水平都显著上调。在肾脏中,腺苷受体A1基因缺失可防止ANIT造成肾小球过滤速率降低。另外,腺苷受体A1拮抗剂同样可以削弱ANIT对小鼠的肝毒性作用。我们的实验结果证实,小鼠腺苷受体A1基因缺失对肝内胆汁淤积性肝损伤有保护作用,这是通过增强具有毒性的胆汁成分从胆汁分泌途径和肾脏排泄途径排出来实现的,而且表明了腺苷受体A1作为治疗肝内胆汁淤积疾病治疗靶点的潜在价值。
发现内源性腺苷受体Al激活可保护急性酒精肝损伤。与野生型小鼠相比,A1AR-/-小鼠对急性酒精导致的肝损害更加敏感,血清转氨酶活性升高,肝脏病理学改变更加严重。酒精会诱导血清和肝脏中脂质的累积,这种脂质累积在A1AR-/-小鼠中更加显著。通过对肝脏中脂质代谢相关基因表达分析发现,在A1AR-/-小鼠中肝脏脂质合成基因(包括：FAS, SCD1, ACC1, DGAT2, PPARy)表达水平都显著上调,由此加重了急性酒精性脂肪肝。另外,腺苷受体A1基因缺失加剧了酒精导致的肝脏脂质过氧化和抗氧化物的耗竭,由此加重了氧化压力。研究还发现,腺苷受体A1的药理阻断同样会加重急性酒精造成的肝损伤和早期脂肪变性。总的来讲,实验结果表明内源性腺苷受体A1激活可以削弱急性酒精诱导产生的氧化压力,并通过下调脂肪合成相关基因的表达降低肝脏脂质堆积,从而对抗急性酒精肝损伤。
发现腺苷受体A1基因缺失会加重非酒精性脂肪肝和胰岛素抵抗的发生。通过建立"western diet"高脂小鼠模型,我们发现与WT小鼠相比,A1AR-/-小鼠在高脂饮食诱导后表现出一系列的代谢异常,如：体重和总脂肪含量增加,白色脂肪组织肥大,血清脂类物质增加,肝脏脂肪变性和胰岛素抵抗加重等。深入研究发现,高脂饮食诱导后,A1AR-/-小鼠肝脏中脂质合成相关基因(包括FAS, SCD1, ACC1, DGAT2,和PPARy)的表达水平都显著上调,由此加强了肝内脂肪合成过程。研究还发现,小鼠腺苷受体A1基因缺失加重了白色脂肪组织炎症反应和巨噬细胞浸润,并上调了F4/80, MCP-1,和TNFa基因表达水平。脂肪组织的炎症反应和巨噬细胞浸润是胰岛素抵抗发生的重要机制。另外,腺苷受体A1基因缺失加强了脂肪细胞分化的主要转录调控因子C/EBPα和PPARγ的表达,这导致了A1AR-/-小鼠脂肪细胞分化增加,促进了肥胖的产生。总的来讲,我们的实验结果表明,小鼠腺苷受体A1基因可通过抑制肝脏脂质合成,降低脂肪细胞分化,以及削弱脂肪组织的炎症反应,来改善高脂饮食引起的导致代谢紊乱。
Adenosine is a natural metabolite in organisms, which plays an important role in many physiological and pathological processes. Extracellular adenosine concentrations are dynamically regulated by a variety of pathophysiological conditions. Adenosine once released can activate cell-surface adenosine receptors which in turn regulate cellular function. Adenosine receptors are coupled to G proteins, though altering the activity of a second messenger system, can modulate protein kinase signaling pathways and regulate downstream target gene expression. Because adenosine receptors mediate extracellular and intracellular signal transduction, they attract more and more attentions as potential targets for disease. There is growing evidence that adenosine receptors could be promising therapeutic targets in a wide range of diseases, including cerebral and cardiac ischemic diseases, sleep disorders, immune and inflammatory disorders, and cancer. However, adenosine receptor's role and value in liver disease have not yet been fully revealed. In this study, by using adenosine receptor knockout animals, we examined the contribution of adenosine-adenosine receptor signaling pathway to liver metabolic disease, and demonstrated its regulation mechanism at the molecular level. We also evaluate the potential role of adenosine receptors as gene or drug targets in the prevention and treatment of liver disease.
In this study, we found that adenosine A1receptor (A1AR) involves in the development of liver fibrosis. A1AR plays a contradictory role in carbon tetrachloride-(CCl4) and bile duct ligation-(BDL) induced liver fibrosis. Our results demonstrated that, lack of A1AR attenuates hepatic fibrosis resulting from chronic CCl4exposure, with markedly decreased collagen deposition and reduced hepatic stellate cell activation in A1AR-/-mice. Whereas, hepatic fibrosis caused by BDL ligation was aggravated in A1AR-/-mice, with significantly increased collagen synthesis and induced fibroblasts activation in portal tracts. We further investigated the different molecular mechanisms through which A1AR gene regulates CCl4-and BDL-induced hepatic fibrosis. A1AR deficiency reduces acute reactivity to liver injury induced by a single CCl4injection. In A1AR-/-mice, serum transaminase levels were lower and the extent of hepatocyte damage was reduced, which was probably achieved by down-regulating hepatic CYP2E1and UCP2gene expression. Besides, the levels of "profibrotic mediators", including TGFβ2, TNFα, IL-1, and IL-6were decreased in A/AR-/-mice during chronic CCl4treatment. Whereas in the BDL model, enhanced biliary infarcts and cholangiocyte proliferation due to elevation of bile acid levels should be the primary causes leading to increased fibrosis in A1AR-/-mice. These results indicate that A/AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.
We found that A1AR involves in the pathogenesis of intrahepatic cholestatic liver injury, and is a potential gene and drug target for the treatment of intrahepatic cholestatsis. In the mouse model of a-naphthylisothiocyanate-(ANIT) induced intrahepatic cholestasis, hepatic adenosine levels and A1AR expression were markedly increased, which suggested that adenosine-A1AR signal may participate in the development of ANIT-induced liver injury. Our study revealed that mice lacking A1AR are protected from ANIT induced liver injury as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A1AR-/-mice compared with wild-type (WT) mice, however, biliary and urinary outputs of bile acids were significantly enhanced in A1AR-/-mice. In the liver, mRNA expression of genes related to bile acid transport Bsep and Mdr2and hydroxylation Cyp3all was increased in A1AR-/-mice. In the kidney, A1AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. In addition, treatment of mice with A1AR antagonist also protected against ANIT hepatotoxicity. Our results indicated that lack of A1AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A1AR as therapeutic target for the treatment of intrahepatic cholestasis.
We also found that endogenous A1AR activation protects against acute ethanol-induced liver injury. Mice lacking A1AR were more susceptible to acute ethanol-induced liver damage than WT mice, which was evidenced by elevated serum transaminase levels and increased extent of histopathological changes. Ethanol induced triglycerides accumulation in the serum and liver, and this accumulation was augmented in A1AR-/-mice. Analysis of gene expression in the liver revealed up-regulated mRNA levels of lipogenic genes (including:FAS, SCD1, ACC1, DGAT2, and PPARy) in A1AR-/-mice after ethanol treatment. In addition, lack of A1AR aggravated lipid peroxidation and worsened antioxidants depletion which was caused by ethanol exposure. A subsequent study revealed that pharmacological block of A1AR also exacerbated liver injury and steatosis induced by acute ethanol administration. In conclusion, these results indicated that endogenous A1AR protects mice against acute ethanol-induced liver injury by reducing oxidative stress and decreasing lipid accumulation though down-regulation of lipogenesis-related genes.
In addition, we found that lack of A1AR exaggerates the development of nonalcoholic fatty liver and insulin resistance. Compared with WT mice,"western diet" induced a series of metabolic abnormalities in A1AR-/-mice, such as increased body weight and fat, adipose tissue hypertrophy, high blood lipids, deteriorated hepatic steatosis and insulin resistance. Further studies showed that increased lipogenesis due to up-regulated mRNA expression of lipogenic genes (including:FAS, SCD1, ACC1, DGAT2, and PPARy) in A1AR-/-mice after high-fat diet feeding. Besides, lack of A1AR exaggerated inflammation and macrophage infiltration into white adipose tissue, and increased mRNA expression of F4/80, MCP-1, and TNFa. Inflammation and macrophage infiltration into adipose tissue appear to participate in the pathogenesis of obesity-induced insulin resistance. Moreover, A1AR deficiency enhanced expression of C/EBPa and PPARy, the major transcriptional regulators of adipocyte differentiation, which should contribute to increased adipogenesis and obesity in A1AR-/-mice. Taken together, our results indicated that endogenous A1AR activation protects mice from high fat diet-induced metabolic disorders, though inhibiting hepatic lipogenesis, decreasing adipocyte differentiation, and alleviating inflammation in adipose tissue.
引文
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