Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids
Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids
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DOI：
10.1042/bj20040933
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发表时间：
2005-02-01
影响因子：
4.1
通讯作者：
Bournot, P
中科院分区：
文献类型：
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作者：
Le Jossic-Corcos, C;Gonthier, C;Bournot, P
富含多不饱和脂肪酸(多不饱和脂肪酸)的饮食植物油和鱼油对啮齿动物具有降胆固醇和降甘油三酯的作用。多不饱和脂肪酸的降胆固醇作用部分归因于降低胆固醇合成和限速酶HMG-CoA还原酶(3-羟基-3-甲基戊二酰辅酶A还原酶)的活性。为了更好地了解其中涉及的机制，我们研究了金枪鱼油和单个n-3和n-6多不饱和脂肪酸如何影响肝脏FPP合成酶(FAMESTYL二磷酸合成酶)的表达，FPP合成酶是一种受甾醇负反馈调节的SREBP(类固醇调节元件结合蛋白)靶标酶，与HMG-CCA还原酶协同作用。给小鼠喂食金枪鱼油两周后，小鼠的血清胆固醇和三酰甘油水平分别降低了50%和60%。肝脏FPP合成酶和HMG-CCA还原酶mRNAs水平也分别下降了70%和40%。单独的n-3和n-6多不饱和脂肪酸降低H4IIEC3大鼠肝癌细胞FPP合成酶和HMG-CoA还原酶mRNA水平的程度大于硬脂酸盐和油酸盐，其中最大的抑制作用发生在花生四烯酸、EPA(二十碳五烯酸)和DHA(二十二碳六烯酸)。我们观察到了类似的对FPP合成酶蛋白水平的抑制作用。PUFA对FPP合成酶mRNA水平的抑制作用不是由于降低了mRNA的稳定性，而是通过抑制转录而实现的。此外，在经阿糖胞苷、EPA或DHA处理的HepG2人肝母细胞瘤细胞中，观察到SREBP-1和SREBP-2成熟形式的核可利用性较低。综上所述，这些数据表明，PUFA可以通过抑制HMG-CoA还原酶和FPP合成酶来下调肝脏胆固醇的合成，至少部分是通过抑制SREBP途径。
Dietary vegetable oils and fish oils rich in PUFA (polyunsaturated fatty acids exert hypocholesterolaemic and hypotriglyceridaemic effects in rodents. The plasma cholesterol-lowering properties of PUFA are due partly to a diminution of cholesterol synthesis and of the activity of the rate-limiting enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase). To better understand the mechanisms involved, we examined how tuna fish oil and individual n - 3 and n - 6 PUFA affect the expression of hepatic FPP synthase (famesyl diphosphate synthase), a SREBP (sterol regulatory element-binding protein) target enzyme that is subject to negative-feedback regulation by sterols, in co-ordination with HMG-CcA reductase. Feeding mice on a tuna fish oil diet for 2 weeks decreased serum cholesterol and triacylglycerol levels, by 50 % and 60 % respectively. Hepatic levels of FPP synthase and HMG-CcA reductase mRNAs were also decreased, by 70% and 40 % respectively. Individual n - 3 and n - 6 PUFA lowered FPP synthase and HMG-CoA reductase mRNA levels in H4IIEC3 rat hepatoma, cells to a greater extent than did stearate and oleate, with the largest inhibitory effects occurring with arachidonate, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). We observed a similar inhibitory effect on protein levels of FPP synthase. The suppressive effect of PUFA on the FPP synthase mRNA level was not due to a decrease in mRNA stability, but to transcription inhibition. Moreover, a lower nuclear availability of both SREBP-1 and SREBP-2 mature forms was observed in HepG2 human hepatoblastoma cells treated with arachiclonate, EPA or DHA. Taken together, these data suggest that PUFA can down-regulate hepatic cholesterol synthesis through inhibition of HMG-CoA reductase and FPP synthase, at least in part through impainnent of the SREBP pathway.