肝细胞内新的核氧化固醇—3-硫酸-25-羟化胆固醇的生物合成通路、调节及功能研究
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摘要
细胞内胆固醇平衡的维持需要胆固醇的合成，降解，脂化和分泌的协同调节。目前认为氧化的胆固醇衍生物(氧化固醇)在胆固醇平衡中发挥重要作用。最近我们发现一种新的氧化固醇，3-硫酸-25-羟化胆固醇(5-cholesten-3β，25-diol3-sulphate，25HC3S)。在原代培养的大鼠肝细胞中过表达一种线粒体胆固醇转运蛋白，类固醇激素合成急性调节蛋白(StARD1)后，该氧化类固醇在细胞核及线粒体内大量蓄积。作为一种核内氧化固醇，其也存在于正常人肝细胞核内。随后，用三乙胺-三氧化硫络合物成功地化学合成了25HC3S。在此基础上，我们进行了肝细胞内25HC3S的生物合成通路，调节及功能研究。
第一部分：探讨了25HC3S的生物合成通路。依据5-cholesten-3β，25-diol3-sulphate(25-OH cholesterol 3β-sulfate)的分子结构，提出了一个假设的代谢通路，该通路有两个步骤，第一步：线粒体胆固醇27-羟化酶(CYP27A1)催化肝细胞线粒体合成25-羟化胆固醇。第二步：羟基类固醇硫酸基转移酶催化25-羟化胆固醇为25HC3S。在第一节中，我们发现蛋白酶K处理线粒体后，能显著增加27-羟化胆固醇的合成，在第二节中我们观察到生理性的蛋白酶也可发挥类似于蛋白酶K的作用，而且尝试着寻找是何种蛋白酶。在第三节中，我们探讨了合成25HC3S的整个生物通路。
第一节：线粒体胆固醇27-羟化酶(CYP27A1)在维持细胞内胆固醇平衡中发挥重要作用。胆固醇进入线粒体内膜被认为是胆汁酸合成酸性通路的限速步骤。我们的实验显示蛋白酶K(proteinase K)处理线粒体可以显著提高CYP27A1的特异性活性。以内源性线粒体胆固醇为底物，蛋白酶K增加CYP27A1特异性活性5倍。当加入外源性溶解于β-环糊精(β-cyclodextrin)的胆固醇后，CYP27A1活性增加7倍以上。酶动力学实验显示蛋白酶K增加CYP27A1酶活性呈时间，蛋白酶K剂量及底物浓度依赖性。蛋白酶K处理将CYP27A1催化胆固醇羟化反应的Km值从400μM降到150μM。运用这个新的方法，我们观察到与新鲜制备的大鼠肝脏线粒体相比，在大鼠原代肝细胞的分离和培养过程中，线粒体CYP27A1的活性逐渐降低。
第二节：我们已经观察到蛋白酶K显著增加体外线粒体CYP27A1的特异性活性。而蛋白酶在机体组织细胞中无处不在，在线粒体周围的环境中也广泛存在。在机体的生理或病理条件下，某些蛋白酶释放也可以影响线粒体的状态，是否可以改变CYP27A1的酶活性?分离的肝脏细胞浆可以使CYP27A1酶活性增加2倍，煮沸灭活抑制该效应。继而，我们观察到分离的溶酶体释放出的蛋白酶可以刺激27-羟胆固醇的合成。而EDTA和蛋白酶抑制剂AEBSF可以降低27-羟胆固醇生成，而二价钙离子则可以刺激其生成。因此，某种钙离子依赖的金属蛋白酶和某种丝氨酸蛋白酶都有可能是刺激CYP27A1活性的蛋白酶，但我们还不能明确是何种蛋白酶，而蛋白酶又是如何发挥作用的?这些都有待于进一步研究发现。这些现象也显示蛋白酶水解反应可能与控制线粒体胆固醇跨膜转运以及胆汁酸酸性合成途径有关。
第三节：提出了肝细胞中25HC3S的合成通路。大鼠肝脏，野生型和CYP27A1基因敲除小鼠肝脏分离的线粒体与胆固醇孵育进行27-羟化酶反应的实验结果显示，25-羟化胆固醇可以在肝细胞线粒体中由CYP27A1催化产生。孵育纯化的肝脏线粒体和细胞浆可以生物合成25HC3S。RT-PCR和Western-blot显示肝细胞表达羟基胆固醇硫酸基转移酶SULT281b。25HC3S，而非25HC可以反馈性降低SULT281b表达。综上，我们认为CYP27A1催化胆固醇生成25-羟化胆固醇，进而3β羟基被硫酸化，从而合成25HC3S。
第二部分：研究了催化25HC3S合成的羟基类固醇硫酸基转移酶的调节。近年来，一种新的羟基类固醇硫酸基转移酶SULT2B1b被克隆和研究。SULT281被报道表达于激素反应性器官，如胎盘、前列腺、皮肤和乳腺等。我们观察到在大鼠原代肝细胞的培养过程中，即使培养液中没有加入任何激素、血清，SULT281b表达随着培养时间的延长而显著增加。而同时其他羟基类固醇硫酸基转移酶SULT2A亚家族的SULT2A2和ST-40则显著降低。地塞米松对于SULT2A的表达具有重要性，而并不能影响SULT281b的表达。胰岛素可以显著增加SULT281b的mRNA和蛋白的表达，T4可以提高其mRNA水平，但幅度远小于胰岛素。可见，SULT281b是一种高度可调节性羟基类固醇硫酸基转移酶。
第三部分：观察了25HC3S对大鼠原代肝细胞脂质代谢的影响。加入不同剂量的25HC3S到原代培养的大鼠肝细胞中，孵育6小时后，显著抑制CYP7A1，而且该作用显著甚于25HC。25HC3S通过更有效地抑制SRBEP-1和SREBP-2mRNA表达，进而更强烈地抑制HMG辅酶A还原酶mRNA水平。25HC3S降低SREBP-1前体和活化形式的蛋白水平，而25HC升高SREBP-1前体蛋白水平，但不影响其活化蛋白表达。这些结果显示，25HC3S作为一种亲水性的氧化固醇，在大鼠原代肝细胞内脂质代谢中发挥不同于25HC的重要作用。
总之，我们认为25HC3S是一种有功能的核氧化固醇，而且可以在体内生物合成，线粒体胆固醇27-羟化酶(CYP27A1)催化肝细胞线粒体合成25-羟化胆固醇，而后羟基胆固醇硫酸基转移酶SULT2B1b催化25-羟化胆固醇为25HC3S。而且，这两步生物反应都是高度可调节的。
Cellular cholesterol homeostasis is maintained through the coordinated regulation of cholesterol synthesis, degradation, and secretion. Nuclear receptors for oxygenated cholesterol derivatives(oxysterols) are known to play key roles in the regulation of cholesterol homeostasis. We recently identified a novel sulfatedoxysterol, 5-cholesten-3β, 25-diol 3-sulphate(25HC3S), whose concentration increased dramatically in the mitochondria and the nuclei of primary rat hepatocytes in response to over-expression of cholesterol mitochondria delivery protein, StarD1. This oxysterol was also found in human liver nuclei. Then we synthesized the 25HC3S chemically. In the present study, the metabolic pathway, regulation and functions of the nuclear oxysterol were investigated.
In the first part, we studied the biosynthesis pathway of 25HC3S. According to the molecular structure of 25HC3S, we proposed a novel metabolic pathway of nuclear sulfate oxysterol in hepatocytes. The first step is that 25-OH Cholesterol is synthesized by CYP27A1 in mitochondria of hepatocytes. The second step is that 25-OH cholesterol is sulfonated to 25-OH cholesterol sulfate by hydroxysteroid sulfotransferase SULT2B1b in hepatocytes.
Mitochondrial cholesterol 27-hydroxylase(CYP27A1) plays an important role in the maintenance of intracellular cholesterol homeostasis. Cholesterol delivery to the mitochondrial inner membrane is believed to be a rate-limiting step for the "acidic" pathway of bile acid synthesis. The present work reports that proteinase K treatment of mitochondria markedly increases CYP27A1 specific activity. With endogenous mitochondrial cholesterol, treatment with proteinase K increased CYP27A1 specific activity by 5-fold. Moreover, the addition of the exogenous cholesterol inβ-cyclodextrin plus proteinase K treatment increased the specific activity by 7-fold. Kinetic studies showed that the increased activity was time, proteinase K and substrate concentration dependent. Proteinase K treatment decreased the apparent Km of CYP27A1 for cholesterol from 400μM to 150μM. Using this new assay, we found that during rat hepatocyte preparation and cell culture, mitochondria gradually lose CYP27A1 activity as compared with mitochondria fleshly isolated from rat liver tissue.
We already observed proteinase k stimulated CYP27A1 specific activity dramatically. Proteianses are located in the cells comprehensively, which is around mitochondria too. Incubation of isolated mitochondria with the cytosolic fraction stimulated CYP27A1 specific activity 2-fold. Heat-inactivation of the cytosolic fraction prevented this increase. Isolated crude lysosomal fraction stimulated the production of 27-hydroxycholesterol. However, EDTA and preteinase inhibitor AEBSF suppressed CYP27A1 activity, while CaCl_2 perform the opposite effect. These findings suggest that protelysis is involved in the control of transmembrane mitochndrial cholesterol movement and, therefore, in the "acidic" pathway of bile acid biosynthesis.
The present study demonstrates a pathway for synthesis of 25HC3S in hepatocytes. Assays using mitochondria isolated from rats and Cyp27Al~- knockout mice indicated that 25-hydroxycholesterol(25HC) is synthesized by CYP27A1 in mitochondria. Incubation of mitochondrial and cytosol fractions resulted in synthesis of 25HC3S. RT-PCR analysis showed the presence of the hydroxysteroid sulfotransferase 2B1b(SULT2B1b) in the hepatocytes. Its expression was down regulated by 25HC3S but not by 25HC. The current findings suggest that the mitochondria synthesize 25HC, which is subsequently 3β-sulfated to form 25HC3S. A novel biosynthetic pathway of the nuclear oxysterol is proposed in this manuscript.
In the second part, we focused on the regulation of the hydroxysteroid sulfotransferases in hepatocytes. Recently, a novel hydroxysteroid sulfotransferase SULT2B1b was cloned and studied. In contrast to the limited tissue distribution of SULT2A1, SULT2B1b was detected in a variety of hormone-responsive tissues including placenta, breast, skin and prostate. During the culture of primary rat hepatocytes, SULT2B1b mRNA and protein levels increased dramatically without any hormone added, meanwile, SULT2A2 and ST-40 mRNA expressions were suppressed significantly. Dexamethasone is important for SULT2A expression, but no effect on SULT2B1b expression. Insulin upregulated SULT2B1b mRNA and protein levels dose-dependently, but did not effect on SULT2A. T4 stimulated SULT2B1b mRNA expression, but not as strong as Insulin. In conclusion, SULT2B1b is a highly regulated hydroxysteroid sulfotransferase, which is different form the well-known SULT2A1.
In the third part, we studied the effect of 25HC3S on intracellular lipids metabolism in primary rat hepatocytes. 25HC was studied parallelly as comparison. Addition of varying concentrations of 25HC3S to primary rat hepatocytes markedly inhibited CYP7A1 mRNA expression, which is much stronger than 25HC. 25HC3S shows more potent on inhibiting SREBP-1, and SREBP-2 mRNA expression, subsequently HMG CoA reductase than 25HC. 25HC3S decreases both protein levels of SREBP-1 precursor and mature forms. However, 25-HC increases SREBP-1 precursor and does not affect mature form. These results indicate that 25HC3S, a hydrophilic oxysterol, plays an important role, but in different manner from 25HC in intracellular lipids metabolism in primary rat hepatocytes.
In summary, 25HC3S is a functional nuclear oxysterol in hepatocytes. 25-OH Cholesterol is synthesized by CYP27A1 in mitochondria of hepatocytes, and then sulfonated to 25-OH cholesterol sulfate by hydroxysteroid sulfotransferase SULT2B1b in hepatocytes. And the whole pathway is highly regulated.
第一部分：探讨了25HC3S的生物合成通路。依据5-cholesten-3β，25-diol3-sulphate(25-OH cholesterol 3β-sulfate)的分子结构，提出了一个假设的代谢通路，该通路有两个步骤，第一步：线粒体胆固醇27-羟化酶(CYP27A1)催化肝细胞线粒体合成25-羟化胆固醇。第二步：羟基类固醇硫酸基转移酶催化25-羟化胆固醇为25HC3S。在第一节中，我们发现蛋白酶K处理线粒体后，能显著增加27-羟化胆固醇的合成，在第二节中我们观察到生理性的蛋白酶也可发挥类似于蛋白酶K的作用，而且尝试着寻找是何种蛋白酶。在第三节中，我们探讨了合成25HC3S的整个生物通路。
第一节：线粒体胆固醇27-羟化酶(CYP27A1)在维持细胞内胆固醇平衡中发挥重要作用。胆固醇进入线粒体内膜被认为是胆汁酸合成酸性通路的限速步骤。我们的实验显示蛋白酶K(proteinase K)处理线粒体可以显著提高CYP27A1的特异性活性。以内源性线粒体胆固醇为底物，蛋白酶K增加CYP27A1特异性活性5倍。当加入外源性溶解于β-环糊精(β-cyclodextrin)的胆固醇后，CYP27A1活性增加7倍以上。酶动力学实验显示蛋白酶K增加CYP27A1酶活性呈时间，蛋白酶K剂量及底物浓度依赖性。蛋白酶K处理将CYP27A1催化胆固醇羟化反应的Km值从400μM降到150μM。运用这个新的方法，我们观察到与新鲜制备的大鼠肝脏线粒体相比，在大鼠原代肝细胞的分离和培养过程中，线粒体CYP27A1的活性逐渐降低。
第二节：我们已经观察到蛋白酶K显著增加体外线粒体CYP27A1的特异性活性。而蛋白酶在机体组织细胞中无处不在，在线粒体周围的环境中也广泛存在。在机体的生理或病理条件下，某些蛋白酶释放也可以影响线粒体的状态，是否可以改变CYP27A1的酶活性?分离的肝脏细胞浆可以使CYP27A1酶活性增加2倍，煮沸灭活抑制该效应。继而，我们观察到分离的溶酶体释放出的蛋白酶可以刺激27-羟胆固醇的合成。而EDTA和蛋白酶抑制剂AEBSF可以降低27-羟胆固醇生成，而二价钙离子则可以刺激其生成。因此，某种钙离子依赖的金属蛋白酶和某种丝氨酸蛋白酶都有可能是刺激CYP27A1活性的蛋白酶，但我们还不能明确是何种蛋白酶，而蛋白酶又是如何发挥作用的?这些都有待于进一步研究发现。这些现象也显示蛋白酶水解反应可能与控制线粒体胆固醇跨膜转运以及胆汁酸酸性合成途径有关。
第三节：提出了肝细胞中25HC3S的合成通路。大鼠肝脏，野生型和CYP27A1基因敲除小鼠肝脏分离的线粒体与胆固醇孵育进行27-羟化酶反应的实验结果显示，25-羟化胆固醇可以在肝细胞线粒体中由CYP27A1催化产生。孵育纯化的肝脏线粒体和细胞浆可以生物合成25HC3S。RT-PCR和Western-blot显示肝细胞表达羟基胆固醇硫酸基转移酶SULT281b。25HC3S，而非25HC可以反馈性降低SULT281b表达。综上，我们认为CYP27A1催化胆固醇生成25-羟化胆固醇，进而3β羟基被硫酸化，从而合成25HC3S。
第二部分：研究了催化25HC3S合成的羟基类固醇硫酸基转移酶的调节。近年来，一种新的羟基类固醇硫酸基转移酶SULT2B1b被克隆和研究。SULT281被报道表达于激素反应性器官，如胎盘、前列腺、皮肤和乳腺等。我们观察到在大鼠原代肝细胞的培养过程中，即使培养液中没有加入任何激素、血清，SULT281b表达随着培养时间的延长而显著增加。而同时其他羟基类固醇硫酸基转移酶SULT2A亚家族的SULT2A2和ST-40则显著降低。地塞米松对于SULT2A的表达具有重要性，而并不能影响SULT281b的表达。胰岛素可以显著增加SULT281b的mRNA和蛋白的表达，T4可以提高其mRNA水平，但幅度远小于胰岛素。可见，SULT281b是一种高度可调节性羟基类固醇硫酸基转移酶。
第三部分：观察了25HC3S对大鼠原代肝细胞脂质代谢的影响。加入不同剂量的25HC3S到原代培养的大鼠肝细胞中，孵育6小时后，显著抑制CYP7A1，而且该作用显著甚于25HC。25HC3S通过更有效地抑制SRBEP-1和SREBP-2mRNA表达，进而更强烈地抑制HMG辅酶A还原酶mRNA水平。25HC3S降低SREBP-1前体和活化形式的蛋白水平，而25HC升高SREBP-1前体蛋白水平，但不影响其活化蛋白表达。这些结果显示，25HC3S作为一种亲水性的氧化固醇，在大鼠原代肝细胞内脂质代谢中发挥不同于25HC的重要作用。
总之，我们认为25HC3S是一种有功能的核氧化固醇，而且可以在体内生物合成，线粒体胆固醇27-羟化酶(CYP27A1)催化肝细胞线粒体合成25-羟化胆固醇，而后羟基胆固醇硫酸基转移酶SULT2B1b催化25-羟化胆固醇为25HC3S。而且，这两步生物反应都是高度可调节的。
Cellular cholesterol homeostasis is maintained through the coordinated regulation of cholesterol synthesis, degradation, and secretion. Nuclear receptors for oxygenated cholesterol derivatives(oxysterols) are known to play key roles in the regulation of cholesterol homeostasis. We recently identified a novel sulfatedoxysterol, 5-cholesten-3β, 25-diol 3-sulphate(25HC3S), whose concentration increased dramatically in the mitochondria and the nuclei of primary rat hepatocytes in response to over-expression of cholesterol mitochondria delivery protein, StarD1. This oxysterol was also found in human liver nuclei. Then we synthesized the 25HC3S chemically. In the present study, the metabolic pathway, regulation and functions of the nuclear oxysterol were investigated.
In the first part, we studied the biosynthesis pathway of 25HC3S. According to the molecular structure of 25HC3S, we proposed a novel metabolic pathway of nuclear sulfate oxysterol in hepatocytes. The first step is that 25-OH Cholesterol is synthesized by CYP27A1 in mitochondria of hepatocytes. The second step is that 25-OH cholesterol is sulfonated to 25-OH cholesterol sulfate by hydroxysteroid sulfotransferase SULT2B1b in hepatocytes.
Mitochondrial cholesterol 27-hydroxylase(CYP27A1) plays an important role in the maintenance of intracellular cholesterol homeostasis. Cholesterol delivery to the mitochondrial inner membrane is believed to be a rate-limiting step for the "acidic" pathway of bile acid synthesis. The present work reports that proteinase K treatment of mitochondria markedly increases CYP27A1 specific activity. With endogenous mitochondrial cholesterol, treatment with proteinase K increased CYP27A1 specific activity by 5-fold. Moreover, the addition of the exogenous cholesterol inβ-cyclodextrin plus proteinase K treatment increased the specific activity by 7-fold. Kinetic studies showed that the increased activity was time, proteinase K and substrate concentration dependent. Proteinase K treatment decreased the apparent Km of CYP27A1 for cholesterol from 400μM to 150μM. Using this new assay, we found that during rat hepatocyte preparation and cell culture, mitochondria gradually lose CYP27A1 activity as compared with mitochondria fleshly isolated from rat liver tissue.
We already observed proteinase k stimulated CYP27A1 specific activity dramatically. Proteianses are located in the cells comprehensively, which is around mitochondria too. Incubation of isolated mitochondria with the cytosolic fraction stimulated CYP27A1 specific activity 2-fold. Heat-inactivation of the cytosolic fraction prevented this increase. Isolated crude lysosomal fraction stimulated the production of 27-hydroxycholesterol. However, EDTA and preteinase inhibitor AEBSF suppressed CYP27A1 activity, while CaCl_2 perform the opposite effect. These findings suggest that protelysis is involved in the control of transmembrane mitochndrial cholesterol movement and, therefore, in the "acidic" pathway of bile acid biosynthesis.
The present study demonstrates a pathway for synthesis of 25HC3S in hepatocytes. Assays using mitochondria isolated from rats and Cyp27Al~- knockout mice indicated that 25-hydroxycholesterol(25HC) is synthesized by CYP27A1 in mitochondria. Incubation of mitochondrial and cytosol fractions resulted in synthesis of 25HC3S. RT-PCR analysis showed the presence of the hydroxysteroid sulfotransferase 2B1b(SULT2B1b) in the hepatocytes. Its expression was down regulated by 25HC3S but not by 25HC. The current findings suggest that the mitochondria synthesize 25HC, which is subsequently 3β-sulfated to form 25HC3S. A novel biosynthetic pathway of the nuclear oxysterol is proposed in this manuscript.
In the second part, we focused on the regulation of the hydroxysteroid sulfotransferases in hepatocytes. Recently, a novel hydroxysteroid sulfotransferase SULT2B1b was cloned and studied. In contrast to the limited tissue distribution of SULT2A1, SULT2B1b was detected in a variety of hormone-responsive tissues including placenta, breast, skin and prostate. During the culture of primary rat hepatocytes, SULT2B1b mRNA and protein levels increased dramatically without any hormone added, meanwile, SULT2A2 and ST-40 mRNA expressions were suppressed significantly. Dexamethasone is important for SULT2A expression, but no effect on SULT2B1b expression. Insulin upregulated SULT2B1b mRNA and protein levels dose-dependently, but did not effect on SULT2A. T4 stimulated SULT2B1b mRNA expression, but not as strong as Insulin. In conclusion, SULT2B1b is a highly regulated hydroxysteroid sulfotransferase, which is different form the well-known SULT2A1.
In the third part, we studied the effect of 25HC3S on intracellular lipids metabolism in primary rat hepatocytes. 25HC was studied parallelly as comparison. Addition of varying concentrations of 25HC3S to primary rat hepatocytes markedly inhibited CYP7A1 mRNA expression, which is much stronger than 25HC. 25HC3S shows more potent on inhibiting SREBP-1, and SREBP-2 mRNA expression, subsequently HMG CoA reductase than 25HC. 25HC3S decreases both protein levels of SREBP-1 precursor and mature forms. However, 25-HC increases SREBP-1 precursor and does not affect mature form. These results indicate that 25HC3S, a hydrophilic oxysterol, plays an important role, but in different manner from 25HC in intracellular lipids metabolism in primary rat hepatocytes.
In summary, 25HC3S is a functional nuclear oxysterol in hepatocytes. 25-OH Cholesterol is synthesized by CYP27A1 in mitochondria of hepatocytes, and then sulfonated to 25-OH cholesterol sulfate by hydroxysteroid sulfotransferase SULT2B1b in hepatocytes. And the whole pathway is highly regulated.
引文
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9. Her,C., Wood, T.C, Eichler,E.E., Mohrenweiser,H.W., Ramagli,L.S., Siciliano,M.J., and Weinshilboum,R.M. 1998. Human hydroxysteroid sulfotransferase SULT2B1: two enzymes encoded by a single chromosome 19 gene. Genomics 53:284-295.
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