Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Regulates AMPK, SREBP-2, HMGCR, and INSIG-1 Signaling and Cholesterol Metabolism In Vitro and In Vivo
Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Regulates AMPK, SREBP-2, HMGCR, and INSIG-1 Signaling and Cholesterol Metabolism In Vitro and In Vivo
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DOI：
10.3390/nu12030610
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发表时间：
2020-03-01
期刊：
影响因子：
5.9
通讯作者：
Kim, Sunoh
中科院分区：
文献类型：
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作者：
Lee, Ki Hoon;Jeong, Eui-Seon;Kim, Sunoh
我们前期的研究表明，未成熟的朝鲜莓5%乙醇提取物（5-uRCK）具有降胆固醇和抗肥胖的活性。然而，其作用的分子机制的特点是很差的。我们假设5-uRCK及其主要生物活性化合物之一鞣花酸可降低细胞和血浆胆固醇水平。因此，我们研究了5-uRCK在肝细胞和高胆固醇饮食（HCD）诱导的大鼠模型中的降胆固醇活性和机制。5-uRCK和鞣花酸显著降低肝脏和血清中的胆固醇。5-uRCK提取物和鞣花酸均降低了HMG-CoA和CETP的肝脏活性，并增加了LCAT的肝脏活性，这也引起了组织学改善。灌胃5-uRCK或鞣花酸后，主动脉和血清中MDA含量显著降低。进一步的免疫印迹分析表明，5-uRCK和鞣花酸诱导肝脏中AMPK磷酸化，从而激活AMPK，通过抑制磷酸化抑制HMGCR的活性。与此相反，5-uRCK和鞣花酸抑制核转位和激活SREBP-2，这是一个关键的转录因子在胆固醇生物合成。总之，我们的研究结果表明，5-uRCK及其生物活性化合物，鞣花酸，是有用的替代治疗剂，以调节血液胆固醇。
Our previous study demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) has hypo-cholesterolemic and anti-obesity activity. However, the molecular mechanisms of its effects are poorly characterized. We hypothesized that 5-uRCK and one of its major bioactive compounds, ellagic acid, decrease cellular and plasma cholesterol levels. Thus, we investigated the hypocholesterolemic activity and mechanism of 5-uRCK in both hepatocytes and a high-cholesterol diet (HCD)-induced rat model. Cholesterol in the liver and serum was significantly reduced by 5-uRCK and ellagic acid. The hepatic activities of HMG-CoA and CETP were reduced, and the hepatic activity of LCAT was increased by both 5-uRCK extract and ellagic acid, which also caused histological improvements. The MDA content in the aorta and serum was significantly decreased after oral administration of 5-uRCK or ellagic acid. Further immunoblotting analysis showed that AMPK phosphorylation in the liver was induced by 5-uRCK and ellagic acid, which activated AMPK, inhibiting the activity of HMGCR by inhibitory phosphorylation. In contrast, 5-uRCK and ellagic acid suppressed the nuclear translocation and activation of SREBP-2, which is a key transcription factor in cholesterol biosynthesis. In conclusion, our results suggest that 5-uRCK and its bioactive compound, ellagic acid, are useful alternative therapeutic agents to regulate blood cholesterol.