The multi-dimensional regulation of gene expression by fatty acids: polyunsaturated fats as nutrient sensors
The multi-dimensional regulation of gene expression by fatty acids: polyunsaturated fats as nutrient sensors
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DOI：
10.1097/00041433-200402000-00004
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Clarke, SD
中科院分区：
文献类型：
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作者：
Clarke, SD
综述的目的以高度不饱和的20-和22-碳ω-6或ω-3脂肪酸提供2-5%能量的饮食与抑制肝脏脂肪生成、刺激肝脏脂肪酸氧化和因此降低血液甘油三酯水平有关。本文综述了高度不饱和脂肪酸通过在多个水平调节蛋白质表达来调节脂质代谢，包括基因转录、信使RNA加工、mRNA降解和翻译后蛋白质修饰。尽管高度不饱和脂肪酸的细胞内信号转导机制尚不清楚，但本文综述了高度不饱和脂肪酸作为激酶级联激活剂的新知识，并对最近的发现进行了总结。高度不饱和脂肪酸通过降低几种转录因子的DNA结合活性来抑制脂肪基因的转录，特别是固醇调节元件结合蛋白1和核因子Y。高度不饱和脂肪酸通过神经酰胺依赖性信号抑制固醇调节元件结合蛋白1从其膜锚定前体的蛋白水解释放，并赋予核因子Y翻译后修饰。高度不饱和脂肪酸加速固醇调节元件结合蛋白1 mRNA衰变，并可能作为肝受体X的拮抗配体发挥作用，从而干扰肝受体X刺激固醇调节元件结合蛋白1基因转录。过氧化物酶体增殖物激活受体α的高度不饱和脂肪酸激活与其从肝受体X置换氧固醇相结合，可能会将肝受体X“捕获”为转录失活的过氧化物酶体增殖物激活受体α/肝受体X异二聚体。肝脏受体X '捕获'的基因表达的后果可以解释如何饮食高度不饱和脂肪酸导致脂肪酸的重新分配远离存储和走向oxidation.SummaryThe肝脏似乎使用高度不饱和脂肪酸的状态作为营养传感器，以确定是否脂肪酸被存储或氧化。以这种方式，高度不饱和脂肪酸可以作为营养因子，降低发生肝脂毒性和胰岛素抵抗的风险。
Purpose of reviewA diet that provides 2-5% of energy as highly unsaturated 20- and 22-carbon omega-6 or omega-3 fatty acids is associated with an inhibition of hepatic lipogenesis, a stimulation of hepatic fatty acid oxidation, and consequently a lowering of blood triglyceride levels. The purpose of this review is to demonstrate that highly unsaturated fatty acids regulate lipid metabolism by modulating protein expression at many levels including gene transcription, messenger RNA processing, mRNA decay, and post-translational protein modifications. Although the intracellular signaling mechanisms employed by highly unsaturated fatty acids are unknown, this review presents a summary of the emerging knowledge regarding highly unsaturated fatty acids as kinase cascade activators.Recent findingsHighly unsaturated fatty acids suppress lipogenic gene transcription by reducing the DNA binding activity of several transcription factors, notably sterol regulatory-element binding protein 1 and nuclear factor Y. Highly unsaturated fatty acids inhibit the proteolytic release of sterol regulatory-element binding protein 1 from its membrane-anchored precursor through a ceramide-dependent signal, and impart a post-translational modification to nuclear factor Y. Highly unsaturated fatty acids accelerate sterol regulatory-element binding protein 1 mRNA decay and may function as antagonistic ligands for liver receptor X, thereby interfering with the liver receptor X stimulation of sterol regulatory-element binding protein 1 gene transcription. Highly unsaturated fatty acid activation of peroxisome proliferator-activated receptor alpha combined with their displacement of the oxysterol from liver receptor X may 'trap' liver receptor X as transcriptionally inactive peroxisome proliferator-activated receptor alpha/liver receptor X heterodimer. The gene expression consequences of liver receptor X 'trapping' may explain how dietary highly unsaturated fatty acids lead to a repartitioning of fatty acids away from storage and towards oxidation.SummaryThe liver appears to use the highly unsaturated fatty acid status as a nutrient sensor to determine whether fatty acids are to be stored or oxidized. In this way highly unsaturated fatty acids may function as nutritional factors that reduce the risk of developing hepatic lipotoxicity and insulin resistance.