Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine
Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine
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DOI：
10.1194/jlr.m600020-jlr200
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发表时间：
2006-06-01
影响因子：
6.5
通讯作者：
Issandou, Marc
中科院分区：
文献类型：
--
作者：
Brusq, Jean-Marie;Ancellin, Nicolas;Issandou, Marc
生物碱类药物小檗碱（BBR）最近被描述为通过增加肝脏低密度脂蛋白受体（LDLR）的表达来降低高胆固醇血症患者的血浆胆固醇和甘油三酯（TG）。使用HepG 2人肝癌细胞，我们发现BBR抑制胆固醇和TG合成的方式类似于AMP激活的蛋白激酶（AMPK）激活剂5-氨基咪唑-4-甲酰胺1-β-呋喃核糖苷（AICAR）。当细胞与BBR孵育时，观察到AMPK磷酸化和AMPK活性的显著增加。AMPK的激活也通过测量与随后的脂肪酸氧化增加相关的AMPK底物乙酰辅酶A羧化酶的磷酸化来证明。所有这些作用都被丝裂原活化蛋白激酶抑制剂PD 98059所消除。用BBR治疗高脂血症仓鼠可降低血浆LDL胆固醇，并显著减少肝脏中的脂肪储存。这些发现表明，除了上调LDLR外，BBR还通过激活AMPK抑制人肝细胞中的脂质合成。这些作用可以解释在临床试验中观察到的该药物的血浆TG的强烈降低。
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.