Rosa rugosa flavonoids exhibited PPARα agonist-like effects on genetic severe hypertriglyceridemia of mice
Rosa rugosa flavonoids exhibited PPARα agonist-like effects on genetic severe hypertriglyceridemia of mice
复制标题
玫瑰黄酮类化合物对小鼠遗传性重度高甘油三酯血症表现出 PPAR α 激动剂样作用
DOI：
10.1016/j.jep.2019.111952
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发表时间：
2019-08-10
影响因子：
5.4
通讯作者：
Qi, Rong
中科院分区：
文献类型：
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作者：
Baiyisaiti, Asiya;Wang, Yuhui;Qi, Rong
民族药理学相关性：玫瑰rugosa Thunb。是一种传统中药，用于治疗心血管疾病和相关危险因素，如糖尿病，高脂血症，高血压和炎症。玫瑰黄酮类化合物（Rosa rugosa flavonoids，RRFs）是玫瑰中的主要成分。研究表明，RRFs具有调节血脂的作用，但其作用机制尚未完全阐明，本研究旨在探讨RRFs对甘油三酯代谢的影响及其机制。使用表达人载脂蛋白C3（ApoC 3）的转基因小鼠作为高脂血症的小鼠模型。以PPARa激动剂非诺贝特（FNB）作为降高甘油三酯的阳性对照药。FNB（100 mg/kg）或RRF（300 mg/kg）每天通过管饲法给予小鼠。给药2周后，用市售试剂盒测定小鼠血脂水平的变化，用口服脂肪负荷试验评价甘油三酯的清除率，用真实的时间PCR检测小鼠肝脏脂质β-氧化合成相关基因的表达。研究发现，RRF和FNB在给药两周后可显著降低ApoC 3转基因小鼠的血浆甘油三酯（TG）水平。RRF可提高小鼠血浆脂质清除率，降低肝脏脂质含量。RRF处理上调PPARa及其下游基因ACOX的mRNA表达，同时下调与脂肪酸合成相关的基因（FREB、SREBP-1c和ACC 1）的mRNA表达。结论：RRFs可通过抑制ApoC 3的表达，诱导LPL的表达，从而降低TG水平。RRF还可以通过增加β-氧化和减少脂质合成来降低肝细胞中的甘油三酯。这些发现显示了RRF作为治疗心血管疾病的降血脂药物的进一步临床应用潜力。
Ethnopharmacological relevance: Rosa rugosa Thunb. is a traditional Chinese medicine that was used in the treatment of cardiovascular diseases and relative risk factors such as diabetes, hyperlipidemia, hypertension, and inflammation. Rosa rugosa flavonoids (RRFs) are the main components in Rosa rugosa Thunb. Several studies have demonstrated that RRFs can regulate plasma lipid contents, but the related mechanism of which has not yet been elucidated clearly.Aim of the study: The goal of this study was to clarify the effects of RRFs on triglyceride metabolism and its related mechanisms.Materials and methods: RRFs were obtained by ethanol extraction from Rosa rugosa Thunb.. Transgenic mice expressing human Apolipoprotein C3 (ApoC3) were used as a mouse model of hypertriglyceridemia. Fenofibrate (FNB), a PPARa agonist, was used as a positive control drug of decreasing high triglyceride. FNB (100 mg/kg) or RRFs (300 mg/kg) were given to the mice by gavage daily. Two weeks later, the changes of plasma lipid levels in the mice were measured by commercial kits, the clearance of triglyceride was evaluated by oral fat load test, and expression of the genes related to lipid beta-oxidation and synthesis was detected in the mice livers by real time PCR.Results: RRFs, as well as FNB, were found to significantly reduce plasma triglyceride (TG) levels in ApoC3 transgenic mice after administration of the drug for two weeks. Plasma lipid clearance rate was increased and lipid content in the mice livers was reduced after administration of RRF. Treatment with RRFs up-regulated mRNA expression of PPARa and its downstream gene of ACOX, while down-regulated mRNA expression of the genes related to fatty acid synthesis (FASN, SREBP-1c, and ACC1). The expression of LPL was raised, while the expression of ApoC3 was decreased, and Foxo1 was inhibited by RRFs in the mice livers.Conclusion: RRFs can reduce plasma TG levels by repressing the expression of ApoC3 and inducing the expression of LPL in liver. RRFs could also reduce triglyceride in hepatocytes through increasing beta-oxidation and decreasing synthesis of the lipids. These findings show the potency of further clinical application of RRFs as a hypolipidemic drug for treatment of cardiovascular diseases.