C. Elegans Fatty Acid Two-Hydroxylase Regulates Intestinal Homeostasis by Affecting Heptadecenoic Acid Production.
C. Elegans Fatty Acid Two-Hydroxylase Regulates Intestinal Homeostasis by Affecting Heptadecenoic Acid Production.
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C-Elegans 脂肪酸二羟化酶通过影响十七碳烯酸的产生来调节肠道稳态
DOI：
10.1159/000493226
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Li Y;Wang C;Huang Y;Fu R;Zheng H;Zhu Y;Shi X;Padakanti PK;Tu Z;Su X;Zhang H
脂肪酸在C-2位的羟基化是脂肪酸α-氧化的第一步，生成含有2-羟基脂肪酰基部分的鞘脂。脂肪酸2-羟基化由脂肪酸2-羟基化酶（FA 2 H）催化。然而，FA 2 H和脂肪酸2-羟基化在全细胞内稳态中的确切作用仍然不清楚。本文以秀丽隐杆线虫为模型，系统研究了FATH-1/C25A1.5的生理功能。免疫染色，染料染色和翻译融合报告被用来可视化FATH-1蛋白和各种亚细胞结构。采用“点击化学”方法在体内标记2-OH脂肪酸。进行全局和组织特异性RNAi敲低实验以抑制FATH-1功能。通过质谱法实现了β-l缺陷突变体的脂质分析。C.秀丽线虫FATH-1在大多数发育阶段和大多数组织中表达。β-1表达的缺失导致严重的生长迟缓和寿命缩短。FATH-1功能在肠中是至关重要的，但在具有立体特异性的表皮中不是。“点击化学”标记技术表明，FATH-1代谢产物主要富集在肠细胞顶侧的膜结构中。在亚细胞水平上，我们发现，损失的ESTA-1表达抑制脂滴的形成，以及选择性地破坏过氧化物酶体和顶端内体。脂质分析显示，在十七碳烯酸的含量显着减少，而其他主要的脂肪酸保持不受影响的ESTA-1缺陷的动物。喂食外源性十七碳烯酸（C17：1），而不是油酸（C18：1），挽救了全球和亚细胞的缺陷，β-1敲低蠕虫。我们的研究表明，FATH-1及其催化产物在手性，C链长度，空间分布以及它们影响的细胞器类型方面具有高度特异性。对羟基化FA的合成和功能的这种意想不到的特异性程度有助于调节蛋白质转运和脂肪代谢，因此维持肠细胞的细胞稳态。这些发现可能有助于我们了解FA 2 H在不同物种中的功能，并为治疗FA 2 H相关疾病提供潜在的治疗靶点。
The hydroxylation of fatty acids at the C-2 position is the first step of fatty acid α-oxidation and generates sphingolipids containing 2-hydroxy fatty acyl moieties. Fatty acid 2-hydroxylation is catalyzed by Fatty acid 2-hydroxylase (FA2H) enzyme. However, the precise roles of FA2H and fatty acid 2-hydroxylation in whole cell homeostasis still remain unclear. Here we utilize Caenorhabditis elegans as the model and systemically investigate the physiological functions of FATH-1/C25A1.5, the highly conserved worm homolog for mammalian FA2H enzyme. Immunostaining, dye-staining and translational fusion reporters were used to visualize FATH-1 protein and a variety of subcellular structures. The “click chemistry” method was employed to label 2-OH fatty acid in vivo. Global and tissue-specific RNAi knockdown experiments were performed to inactivate FATH-1 function. Lipid analysis of the fath-1 deficient mutants was achieved by mass spectrometry. C. elegans FATH-1 is expressed at most developmental stages and in most tissues. Loss of fath-1 expression results in severe growth retardation and shortened lifespan. FATH-1 function is crucially required in the intestine but not the epidermis with stereospecificity. The “click chemistry” labeling technique showed that the FATH-1 metabolites are mainly enriched in membrane structures preferable to the apical side of the intestinal cells. At the subcellular level, we found that loss of fath-1 expression inhibits lipid droplets formation, as well as selectively disrupts peroxisomes and apical endosomes. Lipid analysis of the fath-1 deficient animals revealed a significant reduction in the content of heptadecenoic acid, while other major FAs remain unaffected. Feeding of exogenous heptadecenoic acid (C17:1), but not oleic acid (C18:1), rescues the global and subcellular defects of fath-1 knockdown worms. Our study revealed that FATH-1 and its catalytic products are highly specific in the context of chirality, C-chain length, spatial distribution, as well as the types of cellular organelles they affect. Such an unexpected degree of specificity for the synthesis and functions of hydroxylated FAs helps to regulate protein transport and fat metabolism, therefore maintaining the cellular homeostasis of the intestinal cells. These findings may help our understanding of FA2H functions across species, and offer potential therapeutical targets for treating FA2H-related diseases.
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影响因子：
13.9
作者：
Blackstone C
通讯作者：
Blackstone C
影响因子：
6.5
作者：
Guo, Lin;Zhang, Xu;Su, Xiong
通讯作者：
Su, Xiong
DOI：
10.1073/pnas.0409009101
发表时间：
2005-03-01
影响因子：
11.1
作者：
Gray, JM;Hill, JJ;Bargmann, CI
通讯作者：
Bargmann, CI
影响因子：
6.7
作者：
Pukkila-Worley R;Feinbaum RL;McEwan DL;Conery AL;Ausubel FM
通讯作者：
Ausubel FM
影响因子：
4.5
作者：
Chen B;Jiang Y;Zeng S;Yan J;Li X;Zhang Y;Zou W;Wang X
通讯作者：
Wang X