小鼠高脂晚餐对肝脏生物钟和脂质生成基因表达影响以及蛇床子素干预作用研究
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摘要
目的：观察定时高脂晚餐是否会影响小鼠肝脏生物钟和PPARα介导脂质生成相关基因的表达量和节律性的改变；在此基础上进一步观察不同时间给予等量蛇床子素干预作用的差异。
方法：选用ICR雄性小鼠，以晚上定时给予高脂饮食和严格控制明/暗条件（8:30-20:30/20:30-次日8:30）4周复制高脂性脂肪肝小鼠模型，然后分别在不同授时时相（6:00，12:00，18:00和24:00）或经不同时间（早给药组，晚给药和早晚给药组）等量蛇床子素(20mg/kg)治疗4周后处置，用比色法测定肝中总胆固醇(TC)、甘油三酯(TG)和游离脂肪酸(FFA)含量；用光镜检查肝脏的形态学变化；采用RT-PCR法检测小鼠肝脏生物钟基因Clock、Bmal1、Per1-2和Cry1-2，以及过氧化物酶体增殖物激活受体α (PPAR α)和PPARα介导的脂质生成基因包括胆固醇7α羟化酶(CYP7A1)、羟甲基戊二酰辅酶A还原酶(HMGCR)、低密度脂蛋白受体(LDLR)、脂蛋白酯酶(LPL)、二脂酰甘油酰基转移酶(DGAT)和脂肪酸合酶(FAS)mRNA表达的情况。
结果：实验结果显示，晚上定时给予高脂饮食后，可致小鼠肝脏中TC和TG含量升高，特别是在6:00，18:00和24:00，而且与正常对照组相比，TC含量的峰值延迟了6h而TG含量的峰值提前了12h。同时伴有肝脏生物钟基因Clock、Bmal1、Per2和Cry2mRNA表达在节律或振幅上发生明显的变化，钟控基因PPARα以及它介导的靶基因CYP7A1、HMGCR、LDLR、LPL和DGAT mRNA表达在节律或振幅上亦发生明显的改变，尤其是CYP7A1和DGAT的基因表达改变更为明显。
如以不同时间给予等量蛇床子素治疗高脂性脂肪肝4周后，则肝脏中的TC和TG含量可降低，但程度有所不同。蛇床子素晚给药组可显著下调肝脏钟基因Clock和Bmal1mRNA的表达，而早给药组则明显下调Per1mRNA的表达，不同时间给药组均能明显下调Cry2mRNA的表达。小鼠肝中的PPAR α mRNA在不同时间给药组均有不同程度的上调，尤以早晚给药组的最为明显，同时伴有各个给药组CYP7A1和早给药组LPL mRNA表达的上调；相反地，肝中的LDLR mRNA表达在各个给药组均下调，肝中的DGAT mRNA表达在晚给药组和早晚给药组也明显下调。
结论：小鼠定时高脂晚餐会改变肝脏内部分生物钟基因的节律表达，以及影响PPARα介导脂质生成基因表达的节律性，从而导致肝脏脂质的增加及昼夜节律的改变。不同时间给予等量蛇床子素治疗高脂性脂肪肝后，肝脏的脂质含量降低程度会有所不同，这可能与不同时间给药对脂肪肝小鼠肝脏生物钟基因节律表达的影响不同有关，继而导致PPARα及它的靶基因表达不同而产生不同的治疗效果。
Aim: To investigate whether timed high-fat diet in the evening affects the hepaticcircadian clock and PPARα-mediated lipogenic gene expressions and their rhythms infatty liver mice. On this basis, we further observe the differences of the interventioneffects of equal osthole at different time administration.
Methods: ICR male mice were used in the study. A mouse model withhyperlipidemic fatty liver was established by timed high-fat diet in the evening and a12-h light (8:30-20:30) and12-h dark (20:30-8:30) cycle for4weeks. Whereafter, micewere either sacrificed at the different time-points (6:00,12:00,18:00and24:00) orsacrificed after treatment with equal osthole at different time administration (morning-,evening-, and mixed morning and evening-treated groups) for4weeks. The totalcholesterol (TC), triglycerides (TG), and free fatty acids (FFA) contents in liver weremeasured with the colorimetric methods, and hepatic morphological changes wereexamined under a light microscope. The hepatic mRNA expressions of Clock, Bmal1,Per1-2, Cry1-2, peroxisome proliferator-activated receptor α (PPARα), andPPARα-mediated lipogenic genes expressions, including cholesterol7α-hydroxylase(CYP7A1),3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), low densitylipoprotein receptor (LDLR), lipoprotein lipase (LPL), diacylglycerol acyltransferase(DGAT), and fatty acid synthase (FAS) were determined by the RT-PCR methods.
Results: The present experimental results showed that the hepatic TC and TGcontents were higher in the evening timed high-fat diet-fed mice at all time-points ascompared with matched normal control group, especially at6:00,18:00, and24:00. Andthe peak was present in a6-h delay for TC and a12-h advance for TG relative tomatched control mice. At the same time, the hepatic circadian clock genes Clock, Bmal1,Per2, and Cry2mRNA expressions in the high-fat diet-fed mice had significant changesin the rhythms and/or amplitudes. The clock-controlled gene PPARα and PPARα-mediated lipogenic genes such as CYP7A1, HMGCR, LDLR, LPL, and DGATmRNA expressions in liver had also significant changes in the rhythms and/oramplitudes, especially CYP7A1and DGAT mRNA expressions.
After treatment with equal osthole at different time for4weeks, the hepatic TC andTG contents were decreased in varying degrees in the evening timed high-fat diet-fedmice. Meanwhile, the hepatic clock genes Clock and Bmal1mRNA expressions in theosthole evening-treated group were notablely reduced, and the hepatic Per1mRNAexpression in the osthole morning-treated group was obviously down-regulated as well.In the osthole-treated groups, the hepatic Cry2mRNA expression was all significantlydecreased, while the PPARα mRNA expression in liver was increased, especiallyosthole mixed morning and evening-treated group. The hepatic CYP7A1mRNAexpression in the osthole-treated groups and LPL mRNA expression in the ostholemorning-treated group were significantly increased. Reversely, the hepatic LDLRmRNA expression in the osthole-treated groups, and DGAT mRNA expression in theosthole evening-treated and mixed morning and evening-treated groups weresignificantly decreased.
Conclusion: Timed high-fat diet in the evening could change the hepatic circadianrhythmic expressions of some clock genes and PPARα-mediated lipogenic genes, andled to the hepatic lipid accumulation and its diurnal rhythmic alteration. Afteradministration of equal osthole at different time, the reduced degree of the hepatic lipidaccumulation was significantly different, the results might were from the differenteffects of different time administration on the hepatic clock gene expressions inhyperlipidemic fatty liver mice, which subsequently regulated the different expressionsof clock-controlled gene PPARα and its target genes, and resulted in the differenttherapeutic effects.
方法：选用ICR雄性小鼠，以晚上定时给予高脂饮食和严格控制明/暗条件（8:30-20:30/20:30-次日8:30）4周复制高脂性脂肪肝小鼠模型，然后分别在不同授时时相（6:00，12:00，18:00和24:00）或经不同时间（早给药组，晚给药和早晚给药组）等量蛇床子素(20mg/kg)治疗4周后处置，用比色法测定肝中总胆固醇(TC)、甘油三酯(TG)和游离脂肪酸(FFA)含量；用光镜检查肝脏的形态学变化；采用RT-PCR法检测小鼠肝脏生物钟基因Clock、Bmal1、Per1-2和Cry1-2，以及过氧化物酶体增殖物激活受体α (PPAR α)和PPARα介导的脂质生成基因包括胆固醇7α羟化酶(CYP7A1)、羟甲基戊二酰辅酶A还原酶(HMGCR)、低密度脂蛋白受体(LDLR)、脂蛋白酯酶(LPL)、二脂酰甘油酰基转移酶(DGAT)和脂肪酸合酶(FAS)mRNA表达的情况。
结果：实验结果显示，晚上定时给予高脂饮食后，可致小鼠肝脏中TC和TG含量升高，特别是在6:00，18:00和24:00，而且与正常对照组相比，TC含量的峰值延迟了6h而TG含量的峰值提前了12h。同时伴有肝脏生物钟基因Clock、Bmal1、Per2和Cry2mRNA表达在节律或振幅上发生明显的变化，钟控基因PPARα以及它介导的靶基因CYP7A1、HMGCR、LDLR、LPL和DGAT mRNA表达在节律或振幅上亦发生明显的改变，尤其是CYP7A1和DGAT的基因表达改变更为明显。
如以不同时间给予等量蛇床子素治疗高脂性脂肪肝4周后，则肝脏中的TC和TG含量可降低，但程度有所不同。蛇床子素晚给药组可显著下调肝脏钟基因Clock和Bmal1mRNA的表达，而早给药组则明显下调Per1mRNA的表达，不同时间给药组均能明显下调Cry2mRNA的表达。小鼠肝中的PPAR α mRNA在不同时间给药组均有不同程度的上调，尤以早晚给药组的最为明显，同时伴有各个给药组CYP7A1和早给药组LPL mRNA表达的上调；相反地，肝中的LDLR mRNA表达在各个给药组均下调，肝中的DGAT mRNA表达在晚给药组和早晚给药组也明显下调。
结论：小鼠定时高脂晚餐会改变肝脏内部分生物钟基因的节律表达，以及影响PPARα介导脂质生成基因表达的节律性，从而导致肝脏脂质的增加及昼夜节律的改变。不同时间给予等量蛇床子素治疗高脂性脂肪肝后，肝脏的脂质含量降低程度会有所不同，这可能与不同时间给药对脂肪肝小鼠肝脏生物钟基因节律表达的影响不同有关，继而导致PPARα及它的靶基因表达不同而产生不同的治疗效果。
Aim: To investigate whether timed high-fat diet in the evening affects the hepaticcircadian clock and PPARα-mediated lipogenic gene expressions and their rhythms infatty liver mice. On this basis, we further observe the differences of the interventioneffects of equal osthole at different time administration.
Methods: ICR male mice were used in the study. A mouse model withhyperlipidemic fatty liver was established by timed high-fat diet in the evening and a12-h light (8:30-20:30) and12-h dark (20:30-8:30) cycle for4weeks. Whereafter, micewere either sacrificed at the different time-points (6:00,12:00,18:00and24:00) orsacrificed after treatment with equal osthole at different time administration (morning-,evening-, and mixed morning and evening-treated groups) for4weeks. The totalcholesterol (TC), triglycerides (TG), and free fatty acids (FFA) contents in liver weremeasured with the colorimetric methods, and hepatic morphological changes wereexamined under a light microscope. The hepatic mRNA expressions of Clock, Bmal1,Per1-2, Cry1-2, peroxisome proliferator-activated receptor α (PPARα), andPPARα-mediated lipogenic genes expressions, including cholesterol7α-hydroxylase(CYP7A1),3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), low densitylipoprotein receptor (LDLR), lipoprotein lipase (LPL), diacylglycerol acyltransferase(DGAT), and fatty acid synthase (FAS) were determined by the RT-PCR methods.
Results: The present experimental results showed that the hepatic TC and TGcontents were higher in the evening timed high-fat diet-fed mice at all time-points ascompared with matched normal control group, especially at6:00,18:00, and24:00. Andthe peak was present in a6-h delay for TC and a12-h advance for TG relative tomatched control mice. At the same time, the hepatic circadian clock genes Clock, Bmal1,Per2, and Cry2mRNA expressions in the high-fat diet-fed mice had significant changesin the rhythms and/or amplitudes. The clock-controlled gene PPARα and PPARα-mediated lipogenic genes such as CYP7A1, HMGCR, LDLR, LPL, and DGATmRNA expressions in liver had also significant changes in the rhythms and/oramplitudes, especially CYP7A1and DGAT mRNA expressions.
After treatment with equal osthole at different time for4weeks, the hepatic TC andTG contents were decreased in varying degrees in the evening timed high-fat diet-fedmice. Meanwhile, the hepatic clock genes Clock and Bmal1mRNA expressions in theosthole evening-treated group were notablely reduced, and the hepatic Per1mRNAexpression in the osthole morning-treated group was obviously down-regulated as well.In the osthole-treated groups, the hepatic Cry2mRNA expression was all significantlydecreased, while the PPARα mRNA expression in liver was increased, especiallyosthole mixed morning and evening-treated group. The hepatic CYP7A1mRNAexpression in the osthole-treated groups and LPL mRNA expression in the ostholemorning-treated group were significantly increased. Reversely, the hepatic LDLRmRNA expression in the osthole-treated groups, and DGAT mRNA expression in theosthole evening-treated and mixed morning and evening-treated groups weresignificantly decreased.
Conclusion: Timed high-fat diet in the evening could change the hepatic circadianrhythmic expressions of some clock genes and PPARα-mediated lipogenic genes, andled to the hepatic lipid accumulation and its diurnal rhythmic alteration. Afteradministration of equal osthole at different time, the reduced degree of the hepatic lipidaccumulation was significantly different, the results might were from the differenteffects of different time administration on the hepatic clock gene expressions inhyperlipidemic fatty liver mice, which subsequently regulated the different expressionsof clock-controlled gene PPARα and its target genes, and resulted in the differenttherapeutic effects.
引文
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