Horton J D, Bashmakov Y, Shimomura I, Shimano H
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Room L5-238, Dallas, TX 75235-9046, USA.
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5987-92. doi: 10.1073/pnas.95.11.5987.
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.
已知肝脏脂质合成受食物摄入的调节。在啮齿动物中，禁食会降低胆固醇以及脂肪酸的合成。重新喂食高碳水化合物/低脂肪饮食会使脂肪酸合成比进食状态增强5至20倍，而胆固醇合成仅恢复到禁食前水平。固醇调节元件结合蛋白（SREBPs）是调节参与胆固醇和脂肪酸合成的基因的转录因子。在此，我们表明禁食显著降低了小鼠肝细胞核中SREBP-1和-2的含量，同时SREBP激活的靶基因的mRNA相应减少。重新喂食高碳水化合物/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比非禁食水平增加了5至10倍，这一模式与核SREBP-1的变化平行。参与胆固醇合成的酶的肝脏mRNA恢复到非禁食水平，紧密跟随核SREBP-2的调节模式。过量产生核SREBP-1c的转基因小鼠在禁食时肝脏中胆固醇和脂肪酸合成酶的mRNA水平未能显示出正常下降。我们得出结论，SREBPs在小鼠肝脏中受食物摄入调节，禁食时核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。
