Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells.
Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells.
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DOI：
10.3892/mmr.2017.7141
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发表时间：
2017-10
影响因子：
3.4
通讯作者：
Tatsuno I
中科院分区：
文献类型：
--
作者：
Ishihara N;Suzuki S;Tanaka S;Watanabe Y;Nagayama D;Saiki A;Tanaka T;Tatsuno I
许多临床研究报告，他汀类药物可增加花生四烯酸（一种ω-6长链多不饱和脂肪酸（LCPUFA））的血浆浓度，并降低二十碳五烯酸和二十二碳六烯酸（一种ω-3 LCPUFA）的浓度。这些结果表明，他汀类药物可能会影响LCPUFA的内源性合成，这是由脂肪酸去饱和酶（FADS）和极长链脂肪酸蛋白（CNOVL）的延长调节。本研究的目的是调查的作用，内在甲羟戊酸级联和Rho依赖性途径在他汀类药物诱导的调节这些去饱和酶和延长酶，以及使用小鼠3 T3-L1细胞的细胞活力。用定量聚合酶链反应分析mRNA表达。用阿托伐他汀处理以剂量依赖性方式降低细胞活力并增加Fads 1、Fads 2和FadsVL脂肪酸延伸酶5（Elovl 5）的mRNA表达水平。甲羟戊酸和香叶基香叶基焦磷酸（GGPP），而不是胆固醇，完全逆转阿托伐他汀诱导的细胞活力下调和基因表达上调;然而，甲羟戊酸本身不影响细胞活力和基因表达。Rho相关蛋白激酶抑制剂Y-27632抑制甲羟戊酸和GDPP介导的阿托伐他汀诱导的Fads 1、Fads 2和Elov 15上调的逆转。这些结果表明，他汀类药物可能通过调节小鼠3 T3-L1细胞中Fads 1、Fads 2和Elovl 5基因的表达来影响LCPUFAs的内源性合成。
Numerous clinical studies have reported that statins increase the plasma concentration of arachidonic acid, which is an ω-6 long-chain polyunsaturated fatty acid (LCPUFA), and decrease the concentrations of eicosapentaenoic acid and docosahexaenoic acid, which are ω-3 LCPUFAs. These findings indicate that statins may affect the endogenous synthesis of LCPUFAs, which is regulated by fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids proteins (ELOVLs). The present study aimed to investigate the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in statin-induced regulation of these desaturases and elongases, as well as cell viability using mouse 3T3-L1 cells. mRNA expression was analyzed by quantitative polymerase chain reaction. Treatment with atorvastatin decreased cell viability and increased the mRNA expression levels of Fads1, Fads2 and ELOVL fatty acid elongase 5 (Elovl5) in a dose-dependent manner. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, fully reversed the atorvastatin-induced downregulation of cell viability and upregulation of gene expression; however, mevalonate itself did not affect cell viability and gene expression. The Rho-associated protein kinase inhibitor Y-27632 inhibited the mevalonate- and GGPP-mediated reversal of atorvastatin-induced upregulation of Fads1, Fads2 and Elovl5. These findings indicated that statins may affect the endogenous synthesis of LCPUFAs by regulating Fads1, Fads2 and Elovl5 gene expression via the GGPP-dependent Rho kinase pathway in mouse 3T3-L1 cells.
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影响因子：
5.6
作者：
Hrboticky, N;Zimmer, B;Weber, PC
通讯作者：
Weber, PC
影响因子：
1.5
作者：
Kurisu, Satoshi;Ishibashi, Ken;Kihara, Yasuki
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Michishita, Ichiro
影响因子：
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作者：
Fulcher, Jordan;O'Connell, Rachel;Reith, C.
通讯作者：
Reith, C.
影响因子：
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作者：
Sampson, Uchechukwu K.;Fazio, Sergio;Linton, MacRae F.
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Linton, MacRae F.