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首页> 外文期刊>Cellular Physiology and Biochemistry >C. Elegans Fatty Acid Two-Hydroxylase Regulates Intestinal Homeostasis by Affecting Heptadecenoic Acid Production
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C. Elegans Fatty Acid Two-Hydroxylase Regulates Intestinal Homeostasis by Affecting Heptadecenoic Acid Production

机译：C. Elegans脂肪酸二羟化酶通过影响庚二烯酸的产生来调节肠道稳态

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Background/Aims 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. Methods 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. Results 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. Conclusion 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.
机译：背景/目的脂肪酸在C-2位置的羟基化是脂肪酸α-氧化的第一步，并生成含有2-羟基脂肪酰基部分的鞘脂。脂肪酸2-羟化酶（FA2H）酶催化脂肪酸2-羟化。但是，FA2H和脂肪酸2-羟基化在全细胞稳态中的确切作用仍不清楚。方法在此我们以秀丽隐杆线虫为模型，系统地研究了FATH-1 / C25A1.5的生理功能，FATH-1 / C25A1.5是哺乳动物FA2H酶的高度保守的蠕虫同源物。免疫染色，染料染色和翻译融合报告基因被用于可视化FATH-1蛋白和多种亚细胞结构。使用“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敲低实验以失活FATH-1功能。 Fath-1缺陷型突变体的脂质分析通过质谱进行。结果秀丽隐杆线虫FATH-1在大多数发育阶段和大多数组织中表达。 fath-1表达的丧失会导致严重的生长迟缓和寿命缩短。 FATH-1功能在肠道中至关重要，但不是具有立体特异性的表皮。 “点击化学”标记技术表明，FATH-1代谢产物主要富集于肠细胞顶侧的膜结构。在亚细胞水平，我们发现fath-1表达的丧失会抑制脂质液滴的形成，并选择性地破坏过氧化物酶体和根尖内体。对fath-1缺乏动物的血脂分析显示，庚二烯酸的含量显着降低，而其他主要FA仍不受影响。饲喂外源的庚二烯酸（C17 1），而不是油酸（C18 1），可以拯救fath-1敲除蠕虫的整体和亚细胞缺陷。结论我们的研究表明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的合成和功能如此出乎意料的特异性有助于调节蛋白质的转运和脂肪代谢，从而维持肠道细胞的细胞稳态。这些发现可能有助于我们了解跨物种的FA2H功能，并为治疗FA2H相关疾病提供潜在的治疗靶点。

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