Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice
Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice
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DOI：
10.1073/pnas.95.11.5987
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Shimano, H
中科院分区：
文献类型：
--
作者：
Horton, JD;Bashmakov, Y;Shimano, H
已知肝脏脂质合成受食物消耗的调节。在啮齿类动物中，禁食会降低胆固醇和脂肪酸的合成。高碳水化合物/低脂肪饮食的再喂养使脂肪酸合成比进食状态高5至20倍，而胆固醇合成仅恢复到禁食前的水平。固醇调节元件结合蛋白（SREBP）是调节胆固醇和脂肪酸合成相关基因的转录因子。在这里，我们发现禁食显著降低了小鼠肝细胞核中SREBP-1和-2的数量，同时SREBP激活的靶基因的mRNA也相应减少。高碳水化合物/低脂肪饮食导致核SREBP-1比非禁食水平增加4至5倍，而核SREBP-2蛋白仅恢复到非禁食水平。脂肪酸生物合成酶的肝脏mRNA比非禁食水平增加5至10倍，这一模式证实了核SREBP-1的变化。参与胆固醇合成的酶的肝脏mRNA恢复到非禁食水平，密切遵循核SREBP-2调节的模式。过量产生核SREBP-1c的转基因小鼠在禁食后未能显示胆固醇和脂肪酸合成酶的肝脏mRNA水平的正常降低。我们得出结论，SREBP受小鼠肝脏中食物消耗的调节，并且禁食后核SREBP-1c的下降可能部分解释了脂肪酸生物合成途径中编码酶的mRNA的减少。
Hepatic lipid synthesis is known to be regulated by food consumption. In rodents fasting decreases the synthesis of cholesterol as well as fatty acids. Refeeding a high carbohydrate/low fat diet enhances fatty acid synthesis by 5- to 20-fold above the fed state, whereas cholesterol synthesis returns only to the prefasted level. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate genes involved in cholesterol and fatty acid synthesis. Here, we show that fasting markedly reduces the amounts of SREBP-1 and -2 in mouse liver nuclei, with corresponding decreases in the mRNAs for SREBP-activated target genes. Refeeding a high carbohydrate/low fat diet resulted in a 4- to 5-fold increase of nuclear SREBP-1 above nonfasted levels, whereas nuclear SREBP-2 protein returned only to the nonfasted level, The hepatic mRNAs for fatty acid biosynthetic enzymes increased 5- to 10-fold above nonfasted levels, a pattern that paralleled the changes in nuclear SREBP-1. The hepatic mRNAs for enzymes involved in cholesterol synthesis returned to the nonfasted level, closely following the pattern of nuclear SREBP-2 regulation. Transgenic mice that overproduce nuclear SREBP-1c failed to show the normal decrease in hepatic mRNA levels for cholesterol and fatty acid synthetic enzymes upon fasting, We conclude that SREBPs are regulated by food consumption in the mouse liver and that the decline in nuclear SREBP-1c upon fasting may explain in part the decrease in mRNAs encoding enzymes of the fatty acid biosynthetic pathway.