Fatty acid regulation of hepatic gene transcription
Fatty acid regulation of hepatic gene transcription
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DOI：
10.1093/jn/135.11.2503
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发表时间：
2005-11-01
影响因子：
4.2
通讯作者：
Demeure, O
中科院分区：
文献类型：
--
作者：
Jump, DB;Botolin, D;Demeure, O
膳食脂肪通过控制关键转录因子的活性或丰度来调节基因的表达。体外结合和细胞培养研究已证实许多转录因子是脂肪酸调节的潜在靶点，包括过氧化物酶体增殖物激活受体(PPARα、13、Gamma 1和Gamma 2)、类固醇调节元件结合蛋白-1c(SREBP-1c)、肝脏核因子(HNF-4α和Gamma)、维甲酸X受体(RXRα)、肝X受体(LXRα)等。体内研究证实，PPARα和SREBP-1c调节的基因是多不饱和脂肪酸控制肝脏基因表达的关键靶点。多不饱和脂肪酸通过直接结合激活PPARa，导致肝脏脂肪酸氧化。多不饱和脂肪酸通过抑制SREBP-1c的核丰度来抑制肝脏脂肪酸的合成，其机制包括抑制SREBP-1c基因转录，促进蛋白酶体降解和mRNA(SREBP1c)的降解。细胞内非酯化脂肪酸(NEFA)的变化与PPARa活性和mRNA(SREBP)-1c丰度的变化密切相关。几种机制调节细胞内NEFA的组成，包括脂肪酸转运、酰基辅酶A合成酶和硫代酯酶、脂肪酸伸长酶和去饱和酶、中性和极性脂肪酶以及脂肪酸氧化。其中许多机制受PPARα或SREBP-1c调控。这些机制共同控制肝脏的脂肪组成，并影响全身的脂肪组成。
Dietary fat regulates gene expression by controlling the activity or abundance of key transcription factors. In vitro binding and cell culture studies have identified many transcription factors as prospective targets for fatty acid regulation, including peroxisome proliferator-activated receptors (PPAR alpha, 13, gamma 1, and gamma 2), sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4 alpha and gamma), retinoid X receptor (RXR alpha), liver X receptor (LXR alpha), and others. In vivo studies established that PPAR alpha- and SREBP-1c-regulated genes are key targets for PUFA control of hepatic gene expression. PUFA activate PPARa by direct binding, leading to the induction of hepatic fatty acid oxidation. PUFA inhibit hepatic fatty acid synthesis by suppressing SREBP-1c nuclear abundance through several mechanisms, including suppression of SREBP-1c gene transcription and enhancement of proteasomal degradation and mRNA(SREBP1c) decay. Changes in intracellular nonesterified fatty acids (NEFA) correlate well with changes in PPARa activity and mRNA(SREBP)-1c abundance. Several mechanisms regulate intracellular NEFA composition, including fatty acid transport, acyl CoA synthetases and thioesterases, fatty acid elongases and desaturases, neutral and polar lipid lipases, and fatty acid oxidation. Many of these mechanisms are regulated by PPAR alpha or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition.