基于脂质代谢组学研究羟基红花黄色素A治疗高脂血症LDLR-/-小鼠的作用机制

To investigate the mechanism of Hydroxysafflor yellow A in the treatment of hyperlipidemia in LDLR-/- mice based on lipid metabolomics

关键词:  羟基红花黄色素A  高脂血症  脂质组学  脂代谢

Key words:  Hydroxysafflor yellow A  hyperlipidemia  lipidomics  metabolism of lipid

摘要:

[目的] 基于脂质代谢组学方法考察羟基红花黄色素A（HSYA）对高脂饲料诱导的LDLR^-/-小鼠高脂血症脂质代谢的影响及其机制。[方法] 将28只雄性LDLR^-/-小鼠分为对照组与高脂组。对照组喂养普通饲料，高脂组喂养高脂饲料，6周后，高脂组按照血清中低密度脂蛋白胆固醇（LDL-C）含量平均分为4组：模型组、辛伐他汀组、HSYA（3.8 mg/kg）低剂量组、HSYA（7.6 mg/kg）高剂量组。给药11周，给药期间同时给予高脂饲料饲养。全自动生化仪检测小鼠血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、三酰甘油（TG）、总胆固醇（TC）、LDL-C含量，苏木精-伊红（HE）染色观察肝组织病理形态，油红O染色观察小鼠肝脏组织脂肪蓄积情况，采用靶向脂质组学技术对LDLR^-/-小鼠血清中脂质进行测定。[结果] 与对照组比较，模型组小鼠血清中LDL-C、TC、TG、AST、ALT含量升高（P<0.05），肝组织出现大小不等的脂滴浸润，肝细胞排列紊乱，大量脂质蓄积。与模型组比较，HSYA两组小鼠血清中LDL-C、TC、TG、AST、ALT含量降低（P<0.05），肝脏的脂肪变性、脂质蓄积等病理情况得到改善。脂质组学检测结果显示，模型组和对照组之间具有差异的脂质分子共有14种（VIP>1，P<0.05）。HSYA两组与模型组比较，17种脂质分子呈现相反的趋势并具有差异，分别为PE（18∶0/18∶1）、PE（18∶0/18∶2）、PE（18∶0/20∶3）、PE（18∶0/20∶4）、PE（O-18∶0/18∶1）、PE（O-18∶0/20∶4）、LPE（18∶1）、LPE（20∶4）、FFA（22∶4）、PI（18∶0/18∶2）、PI（16∶0/18∶1）、PI（18∶1/18∶1）、LPI（18∶0）、PG（18∶1/16∶1）、PG（18∶1/18∶1）、PG（18∶1/18∶2）、PA（18∶1/18∶1）（VIP>1，P<0.05）。[结论] 研究利用脂质组学技术，发现HSYA可以通过调节高脂血症LDLR^-/-小鼠血清中脂质代谢水平，发挥治疗高脂血症的作用，为临床应用HSYA提供了新的参考依据。

Abstract:

[Objective] To investigate the effect and mechanism of Hydroxysafflor yellow A(HSYA) on lipid metabolism in LDLR^-/- mice with hyperlipidemia induced by high-fat diet based on lipid metabolomics. [Methods] Twenty-eight male LDLR^-/- mice were divided into control group and high-fat diet group. The control group was fed with normal diet, and the high-fat group was fed with high-fat diet. After 6 weeks, according to the content of LDL-C, the mice were divided into four groups[model group, simvastatin group, low dose HSYA(3.8 mg/kg) and high dose HSYA(7.6 mg/kg)]. The drug was administered for 11 weeks, and high-fat diet was given simultaneously during the drug administration. The content of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglyceride(TG), total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-C) in serum of mice were detected by automatic biochemical instrument, the pathological morphology of liver histology was observed by hematoxylin-eosin staining, and the fat deposition of liver tissues of mice was observed by oil red O staining, and lipids in the serum of LDLR^-/- mice were measured by targeted lipidomic technology. [Results] Compared with the control group, the serum content of LDL-C, TC, TG, AST and ALT in the model group were increased(P<0.05). The liver tissue showed infiltration of lipid droplets of different sizes, disorderly arrangement of hepatocytes, and a large number of lipid deposits. Compared with the model group, the serum content of LDL-C, TC, TG, AST and ALT in the HSYA group were decreased(P<0.05), liver steatosis, lipid deposition and other pathological conditions were improved. The results of lipid profiling showed that there were 14 different lipid molecules(VIP>1, P<0.05). Compared with the model group, 17 lipid molecules in the HSYA group showed the opposite trend and had differences, Respectively PE(18:0/18:1), PE(18:0/18:2), PE(18:0/20:3), PE(18:0/20:4), PE(O-18:0/18:1), PE(O-18:0/20:4), LPE(18:1), LPE(20:4), FFA(22:4), PI(18:0/18:2), PI(16:0/18:1), PI(18:1/18:1), LPI(18:0), PG(18:1/16:1), PG(18:1/18:1), PG(18:1/18:2), PA(18:1/18:1)(VIP>1, P<0.05). [Conclusion] Using lipidomics technology, this study found that HSYA could play a role in the treatment of hyperlipidemia by regulating lipid metabolism in the serum of hyperlipidemia LDLR^-/- mice, and provided a new reference for its clinical application.