Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells
Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells
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DOI：
10.1074/jbc.m007273200
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发表时间：
2001-02-09
影响因子：
4.8
通讯作者：
Brown, MS
中科院分区：
文献类型：
--
作者：
Hannah, VC;Ou, JF;Brown, MS
固醇调节元件结合蛋白（SREBP）是一种膜结合转录因子，在动物细胞中增加脂肪酸和胆固醇的合成。所有三种SREBP亚型（SREBP-1a，-1c和-2）都受到胆固醇的反馈调节，胆固醇阻止它们从膜上的蛋白水解释放。以前的数据表明，SREBPs也受到不饱和脂肪酸的负调控，但其机制尚不清楚。在目前的实验中，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，但不降低SREBP-2。不饱和脂肪酸的效价随着链长和不饱和度的增加而增加，油酸、亚油酸和花生四烯酸都有效，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显著减少，这些SREBP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，不饱和脂肪酸减少核SREBP-1a而不影响mRNA水平。当cDNA编码非膜结合的截短形式时，没有效果。当一起施用时，甾醇和不饱和脂肪酸在减少核SREBP-1方面相互增强。在不存在脂肪酸的情况下，甾醇不引起核SREBP-1的持续减少，但它们确实减少核SREBP-2。我们得出结论，不饱和脂肪酸以及甾醇，可以下调核SREBP，不饱和脂肪酸对SREBP-1a和SREBP-1c具有最大的抑制作用，而甾醇对SREBP-2具有最大的抑制作用。
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, Downregulation 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 downregulate 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.