肝脏中的APOA4在动脉粥样硬化和肝脏损伤中的作用研究

发布时间：2018-06-26 19:33

本文选题：APOA4 + 肝脏　；参考：《东北师范大学》2017年硕士论文

【摘要】：APOA4是一种血浆脂蛋白,参与许多代谢途径,如脂质代谢和葡萄糖代谢。APOA4最初由肝脏和小肠合成,随后分泌到血液中。APOA4可以增强胰岛素分泌并抑制肝脏中的葡萄糖产生,也可以增加肝脏中TG分泌。此外APOA4还具有抗氧化和抗炎的性质。APOA4与一些疾病的关系也逐渐被发现,如血浆中APOA4与可以抗动脉粥样硬化形成。作为APOA4的合成器官之一,肝脏在VLDL合成分泌、脂质代谢和葡萄糖代谢中有着重要作用。而肝脏也容易受到药物和CCl4等化学毒物的损伤。但目前有关肝脏中APOA4是否调控动脉粥样硬化与肝损伤在很大程度上还是未知的。因此,在本研究中,我们通过使用多种方法来确定肝脏中APOA4是否调控动脉粥样硬化,以及其与肝损伤的联系。最终获得如下成果:第一:为研究肝脏中APOA4是否调控动脉粥样硬化,我们通过杂交与基因型鉴定获得了ob/ob APOE-/-双基因敲除小鼠。并通过HFD饲喂法,获得了HFD诱导ob/ob APOE-/-双基因敲除动脉粥样硬化小鼠模型,与常用单基因敲除小鼠相比,其形成动脉粥样硬化所需时间明显缩短,并伴有血脂和体重异常。第二:通过检测HFD诱导ob/ob APOE-/-双基因敲除动脉粥样硬化小鼠模型,我们发现小鼠肝脏中APOA4水平异常升高。这一结果提示二者可能存在联系,因此我们对模型小鼠肝脏中APOA4进行特异性敲低,检测小鼠血脂水平与体重,观察动脉粥样硬化形成情况。结果表明,肝脏中APOA4可调节血浆TG水平,但对动脉粥样硬化形成无显著影响。第三:为了初步探讨肝脏中APOA4与肝损伤是否存在联系,我们建立了CCl4诱导的急性肝损伤小鼠模型,并发现CCl4诱导的急性肝损伤可引起小鼠肝脏中APOA4水平异常升高。结果提示肝脏中APOA4异常升高可能参与了CCl4诱导的肝脏损伤过程。综上所述,本研究建立了HFD诱导ob/ob APOE-/-双基因敲除动脉粥样硬化小鼠模型。特异性敲低肝脏中APOA4可降低血浆TG水平,但对动脉粥样硬化形成无显著影响。同时肝损伤可引起肝损伤小鼠肝脏中APOA4水平异常升高,这提示APOA4可能调节了肝损伤。
[Abstract]:APOA4 is a plasma lipoprotein involved in many metabolic pathways, such as lipid metabolism and glucose metabolism. APOA4 is initially synthesized by the liver and small intestine and then secreted into the blood. APOA4 enhances insulin secretion and inhibits glucose production in the liver. It can also increase the secretion of TG in the liver. In addition, APOA4 has antioxidant and anti-inflammatory properties. APOA4 has been gradually found to be associated with some diseases, such as APOA4 in plasma and anti-atherosclerosis. As one of the synthetic organs of APOA4, liver plays an important role in VLDL synthesis and secretion, lipid metabolism and glucose metabolism. The liver is also vulnerable to drugs and CCL 4 and other chemical poisons. However, whether APOA4 regulates atherosclerosis and liver injury is still unknown. Therefore, in this study, we used a variety of methods to determine whether APOA4 in the liver regulates atherosclerosis and its association with liver injury. The results are as follows: first, in order to study whether APOA4 regulates atherosclerosis in liver, we obtained ob/ob APOE-r-double gene knockout mice by hybridization and genotyping. The model of ob/ob APOE-r-double gene knockout mice induced by HFD was obtained. Compared with the common single-gene knockout mice, the time required to form atherosclerosis was significantly shortened, and the blood lipid and body weight were abnormal. Second, we found that the level of APOA4 in the liver of ob/ob mice was abnormally elevated by detecting the mouse model of ob/ob APOE-r-double gene knockout induced by HFD-induced atherosclerosis. The results suggested that there might be a relationship between the two, so we specifically knock down APOA4 in the liver of model mice, detect the level of blood lipid and body weight, and observe the formation of atherosclerosis. The results showed that APOA4 could regulate plasma TG level, but had no significant effect on atherosclerosis. Third, in order to explore the relationship between APOA4 in liver and liver injury, we established a model of acute liver injury induced by CCl4, and found that acute liver injury induced by CCl4 could cause abnormal increase of APOA4 level in liver of mice. The results suggest that the abnormal increase of APOA4 may be involved in CCL 4 induced liver injury. To sum up, a HFD-induced ob/ob APOE-P-double knockout atherosclerosis model was established in this study. APOA4 could decrease plasma TG level, but had no significant effect on atherosclerosis. At the same time, liver injury can cause abnormal increase of APOA4 level in liver of mice, which suggests that APOA4 may regulate liver injury.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R575

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