Ma Chun-Yan, Shi Xiao-Yun, Wu Ya-Ru, Zhang Yue, Yao Yu-Hong, Qu Hui-Lin, Zhang Wei, Guo Yuan-Lin, Xu Rui-Xia, Li Jian-Jun
State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Division of Endocrinology, Beijing Chaoyang Integrative Medicine Emergency Medical Center, Beijing, China.
Ann Transl Med. 2021 Oct;9(20):1517. doi: 10.21037/atm-20-8106.
BACKGROUND: It has been demonstrated that berberine (BBR), a kind of alkaloid derived from Chinese herbal medicine, has multiple pharmacological effects on human's diseases including anti-atherosclerosis action. However, although the previous studies showed that the beneficial impact of BBR on atherosclerosis might be associated with proprotein convertase subtilisin/kexin type 9 (PCSK9), the exact underlying mechanism are not fully determined. The present study aimed to investigate potential mechanisms of anti-atherosclerosis by BBR using ApoE mice. METHODS: The eight-week mice were divided into five groups: group 1 (wild type C57BL/6J mice with normal diet), group 2 (ApoE mice with normal diet), group 3 [ApoE mice with high-fat diet (HFD)], group 4 (ApoE mice with HFD, and treatment with low dose BBR of 50 mg/kg/d), and group 5 (ApoE mice with HFD, and treatment with high dose BBR of 100 mg/kg/d). After a 16-week treatment, the blood sample, aorta and liver were collected for lipid analysis, hematoxylin-eosin (HE) or oil red O staining, and Western blotting respectively. Besides, HepG2 Cells were cultured and treated with different concentrations of BBR (0, 5, 25 and 50 µg/mL) for 24 hours. Subsequently, cells were collected for real-time PCR or western blotting assays. Finally, the expression levels of PCSK9, LDL receptor (LDLR), ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) were examined. RESULTS: Fifty mg/kg/d and 100 mg/kg/d of BBR decreased total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) level. Moreover, BBR reduced aorta atherosclerotic plaque, and ameliorated lipid deposition in ApoE mice fed with HFD. Finally, in vitro study showed that BBR promoted intracellular cholesterol efflux, up-regulated LDLR and down-regulated PCSK9 expression via the ERK1/2 pathway in cultured HepG2 cells. CONCLUSIONS: Data indicated that BBR significantly attenuated lipid disorder, reduced aortic plaque formation, and alleviated hepatic lipid accumulation in ApoE mice fed with HFD, which was associated with down-regulation of PCSK9 through ERK1/2 pathway.
背景：已证实黄连素（BBR），一种源自中草药的生物碱，对人类疾病具有多种药理作用，包括抗动脉粥样硬化作用。然而，尽管先前的研究表明BBR对动脉粥样硬化的有益影响可能与前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）有关，但其确切的潜在机制尚未完全明确。本研究旨在利用载脂蛋白E（ApoE）小鼠探讨BBR抗动脉粥样硬化的潜在机制。 方法：将8周龄小鼠分为五组：第1组（正常饮食的野生型C57BL/6J小鼠），第2组（正常饮食的ApoE小鼠），第3组[高脂饮食（HFD）的ApoE小鼠]，第4组（HFD喂养的ApoE小鼠，并用50mg/kg/d的低剂量BBR治疗），以及第5组（HFD喂养的ApoE小鼠，并用100mg/kg/d的高剂量BBR治疗）。经过16周的治疗后，分别采集血液样本、主动脉和肝脏进行脂质分析、苏木精-伊红（HE）或油红O染色以及蛋白质印迹分析。此外，培养HepG2细胞并用不同浓度的BBR（0、5、25和50μg/mL）处理24小时。随后，收集细胞进行实时聚合酶链反应（PCR）或蛋白质印迹分析。最后，检测PCSK9、低密度脂蛋白受体（LDLR）、ATP结合盒转运蛋白A1（ABCA1）、ATP结合盒转运蛋白G1（ABCG1）和I型清道夫受体B（SR-BI）的表达水平。 结果：50mg/kg/d和100mg/kg/d的BBR降低了总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）胆固醇（LDL-C）水平，并提高了高密度脂蛋白胆固醇（HDL-C）水平。此外，BBR减少了主动脉粥样硬化斑块，并改善了HFD喂养的ApoE小鼠的脂质沉积。最后，体外研究表明，BBR通过细胞外信号调节激酶1/2（ERK1/2）途径促进培养的HepG2细胞内胆固醇流出，上调LDLR并下调PCSK9表达。 结论：数据表明，BBR显著减轻了HFD喂养的ApoE小鼠的脂质紊乱，减少了主动脉斑块形成，并减轻了肝脏脂质积累，这与通过ERK1/2途径下调PCSK9有关。
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