Hannah V C, Ou J, Luong A, Goldstein J L, Brown M S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
J Biol Chem. 2001 Feb 9;276(6):4365-72. doi: 10.1074/jbc.M007273200. Epub 2000 Nov 20.
Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that increase the synthesis of fatty acids as well as cholesterol in animal cells. All three SREBP isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their proteolytic release from membranes. Previous data indicate that the SREBPs are also negatively regulated by unsaturated fatty acids, but the mechanism is uncertain. In the current experiments, unsaturated fatty acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic kidney (HEK)-293 cells. The potency of unsaturated fatty acids increased with increasing chain length and degree of unsaturation. Oleate, linoleate, and arachidonate were all effective, but the saturated fatty acids palmitate and stearate were not effective. Down-regulation occurred at two levels. The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteolytic processing of these SREBPs was inhibited. When SREBP-1a was produced by a cDNA expressed from an independent promoter, unsaturated fatty acids reduced nuclear SREBP-1a without affecting the mRNA level. There was no effect when the cDNA encoded a truncated version that was not membrane-bound. When administered together, sterols and unsaturated fatty acids potentiated each other in reducing nuclear SREBP-1. In the absence of fatty acids, sterols did not cause a sustained reduction of nuclear SREBP-1, but they did reduce nuclear SREBP-2. We conclude that unsaturated fatty acids, as well as sterols, can down-regulate nuclear SREBPs and that unsaturated fatty acids have their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas sterols have their greatest inhibitory effects on SREBP-2.
固醇调节元件结合蛋白（SREBPs）是膜结合转录因子，可增加动物细胞中脂肪酸和胆固醇的合成。所有三种SREBP异构体（SREBP-1a、-1c和-2）均受到胆固醇的反馈调节，胆固醇会阻止它们从膜上进行蛋白水解释放。先前的数据表明，SREBPs也受到不饱和脂肪酸的负调节，但其机制尚不确定。在当前实验中，不饱和脂肪酸降低了培养的人胚肾（HEK）-293细胞中SREBP-1的核含量，但未降低SREBP-2的核含量。不饱和脂肪酸的效力随着链长和不饱和度的增加而增强。油酸、亚油酸和花生四烯酸均有效，但饱和脂肪酸棕榈酸和硬脂酸无效。下调发生在两个水平。编码SREBP-1a和SREBP-1c的mRNA明显减少，并且这些SREBPs的蛋白水解加工受到抑制。当SREBP-1a由独立启动子表达的cDNA产生时，不饱和脂肪酸降低了核SREBP-1a，而不影响mRNA水平。当cDNA编码一个不与膜结合的截短版本时则没有影响。当固醇和不饱和脂肪酸一起使用时，它们在降低核SREBP-1方面相互增强作用。在没有脂肪酸的情况下，固醇不会导致核SREBP-1持续减少，但它们确实会降低核SREBP-2。我们得出结论，不饱和脂肪酸以及固醇均可下调核SREBPs，并且不饱和脂肪酸对SREBP-1a和SREBP-1c具有最大的抑制作用，而固醇对SREBP-2具有最大的抑制作用。
