Increasing intake of long-chain n-3 PUFA enhances lipoperoxidation and modulates hepatic gene expression in a dose-dependent manner
Increasing intake of long-chain n-3 PUFA enhances lipoperoxidation and modulates hepatic gene expression in a dose-dependent manner
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DOI：
10.1017/s0007114511004259
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发表时间：
2012-05-01
影响因子：
3.6
通讯作者：
Comte, Blandine
中科院分区：
文献类型：
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作者：
Gladine, Cecile;Roy, Nicole C.;Comte, Blandine
长链（LC）n-3 PUFA具有广泛的生物学特性，可以在基因表达水平上实现。这已经在肝脏中得到了很好的描述，其中LC n-3 PUFA调节与脂质代谢相关的基因的表达。然而，生物途径调节的复杂性和生物活性分子的性质仍在研究中。本研究旨在研究LC n-3 PUFA对过氧化代谢产物（作为潜在的生物活性分子）的产生以及对肝脏中全局基因表达的剂量反应效应。高胆固醇血症家兔每日经口给予（7周）富含油酸的油或提供0.1、0.5或1%（分别为第1、2和3组）能量（以DHA计）的油混合物。通过GC/MS/MS在肝脏中平行于转录谱测定了LC n-3 PUFA产生的特定过氧化代谢产物（即4-羟基己烯醛（4-HHE）-蛋白加合物）的水平。摄入LC n-3 PUFA以剂量依赖性方式增加肝脏4-HHE的产生。在最高剂量下，LC n-3 PUFA引起TAG在肝脏中的积累，这可能与脂蛋白肝受体（LDL受体和VLDL受体）的mRNA水平增加直接相关。在第1组和第2组中，微粒体TAG转移蛋白的mRNA水平降低，提示可能存在减少VLDL分泌的新机制。这些与脂蛋白代谢相关的基因的调节独立于PPAR α信号传导，但可能与LC n-3 PUFA和/或其代谢产物（如HHE）激活法尼醇X受体途径有关。
Long-chain (LC) n-3 PUFA have a broad range of biological properties that can be achieved at the gene expression level. This has been well described in liver, where LC n-3 PUFA modulate the expression of genes related to lipid metabolism. However, the complexity of biological pathway modulations and the nature of bioactive molecules are still under investigation. The present study aimed to investigate the dose-response effects of LC n-3 PUFA on the production of peroxidised metabolites, as potential bioactive molecules, and on global gene expression in liver. Hypercholesterolaemic rabbits received by daily oral administration (7 weeks) either oleic acid-rich oil or a mixture of oils providing 0.1, 0.5 or 1% (groups 1, 2 and 3 respectively) of energy as DHA. Levels of specific peroxidised metabolites, namely 4-hydroxyhexenal (4-HHE)-protein adducts, issued from LC n-3 PUFA were measured by GC/MS/MS in liver in parallel to transcription profiling. The intake of LC n-3 PUFA increased, in a dose-dependent manner, the hepatic production of 4-HHE. At the highest dose, LC n-3 PUFA provoked an accumulation of TAG in liver, which can be directly linked to increased mRNA levels of lipoprotein hepatic receptors (LDL-receptor and VLDL-receptor). In groups 1 and 2, the mRNA levels of microsomal TAG transfer protein decreased, suggesting a possible new mechanism to reduce VLDL secretion. These modulations of genes related to lipoprotein metabolism were independent of PPAR alpha signalling but were probably linked to the activation of the farnesol X receptor pathway by LC n-3 PUFA and/or their metabolites such as HHE.