Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters
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DOI：
10.1194/jlr.m003566
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发表时间：
2010-06-01
影响因子：
6.5
通讯作者：
Liu, Jingwen
中科院分区：
文献类型：
--
作者：
Dong, Bin;Wu, Minhao;Liu, Jingwen
我们研究了前蛋白转换酶枯草杆菌/可信9(PCSK9)在他汀类药物诱导的低密度脂蛋白-胆固醇(LDL-C)抵抗中的作用，以及他汀类药物在体内调节PCSK9基因表达的分子机制。我们利用果糖饮食诱导的高脂仓鼠作为体内模型，观察瑞舒伐他汀对肝脏PCSK9和低密度脂蛋白受体(LDLR)表达及血脂水平的影响。结果表明，瑞舒伐他汀对仓鼠肝脏PCSK9基因的诱导作用强于LDLR基因。最终结果是肝脏低密度脂蛋白受体蛋白水平降低。这与他汀类药物治疗后血清低密度脂蛋白-C的升高密切相关。更重要的是，我们证明，除了增加固醇反应元件结合蛋白2(SREBP2)的表达外，瑞舒伐他汀治疗还增加了肝细胞核因子1α(HNF1α)的表达，HNF1α是新发现的PCSK9基因表达的关键反式激活因子。我们的研究表明，瑞舒伐他汀对HNF1α的诱导作用可能是PCSK9的诱导高于LDLR的一个潜在机制，这是因为PCSK9转录中使用了两个反式激活子(HNF1α和SREBP2)，而LDLR转录中使用的是一个反式激活子(SREBP2)。因此，净平衡有利于PCSK9诱导的低密度脂蛋白受体在仓鼠肝脏中的降解，从而消除了罗舒伐他汀对降低低密度脂蛋白-C的影响。通过HNF1α和SREBP2强诱导PCSK9基因表达：他汀类药物抵抗降脂仓鼠低密度脂蛋白胆固醇作用的机制。J.Lipid Res.2010年。51：1486-1495。
We investigated the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the resistance of dyslipidemic hamsters to statin-induced LDL-cholesterol (LDL-C) reduction and the molecular mechanism by which statins modulated PCSK9 gene expression in vivo. We utilized the fructose diet-induced dyslipidemic hamsters as an in vivo model and rosuvastatin to examine its effects on liver PCSK9 and LDL receptor (LDLR) expression and serum lipid levels. We showed that rosuvastatin induced PCSK9 mRNA to a greater extent than LDLR mRNA in the hamster liver. The net result was that hepatic LDLR protein level was reduced. This correlated closely with an increase in serum LDL-C with statin treatment. More importantly, we demonstrated that in addition to an increase in sterol response element binding protein 2 (SREBP2) expression, rosuvastatin treatment increased the liver expression of hepatocyte nuclear factor 1 alpha (HNF1 alpha), the newly identified key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1 alpha is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1 alpha and SREBP2) in PCSK9 transcription versus one (SREBP2) in LDLR transcription. Thus, the net balance is in favor of PCSK9-induced degradation of LDLR in the hamster liver, abrogating the effect of rosuvastatin on LDL-C lowering.-Dong, B., M. Wu, H. Li, F. B. Kraemer, K. Adeli, N. G. Seidah, S. W. Park, and J. Liu. Strong induction of PCSK9 gene expression through HNF1 alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J. Lipid Res. 2010. 51: 1486-1495.