Guangdong Provincial Key Laboratory of Marine Biotechnology and Research Center for Nutrition, Feed and Healthy Breeding of Aquatic Animals of Guangdong Province, Shantou University, Shantou, China.
College of Marine Sciences of South China Agricultural University and Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.
J Biol Chem. 2020 Oct 2;295(40):13875-13886. doi: 10.1074/jbc.RA120.014858. Epub 2020 Aug 5.
MicroRNAs have been recently shown to be important regulators of lipid metabolism. However, the mechanisms of microRNA-mediated regulation of long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis in vertebrates remain largely unknown. Herein, we for the first time addressed the role of miR-26a in LC-PUFA biosynthesis in the marine rabbitfish The results showed that miR-26a was significantly down-regulated in liver of rabbitfish reared in brackish water and in hepatocyte line (SCHL) incubated with the LC-PUFA precursor α-linolenic acid, suggesting that miR-26a may be involved in LC-PUFA biosynthesis because of its abundance being regulated by factors affecting LC-PUFA biosynthesis. Opposite patterns were observed in the expression of liver X receptor α (α) and sterol regulatory element-binding protein-1 (), as well as the LC-PUFA biosynthesis-related genes (Δ4 , Δ6Δ5 , and ) in SCHL cells incubated with α-linolenic acid. Luciferase reporter assays revealed rabbitfish α as a target of miR-26a, and overexpression of miR-26a in SCHL cells markedly reduced protein levels of Lxrα, Srebp1, and Δ6Δ5 Fads2 induced by the agonist T0901317. Moreover, increasing endogenous Lxrα by knockdown of miR-26a facilitated Srebp1 activation and concomitant increased expression of genes involved in LC-PUFA biosynthesis and consequently promoted LC-PUFA biosynthesis both and These results indicate a critical role of miR-26a in regulating LC-PUFA biosynthesis through targeting the Lxrα-Srebp1 pathway and provide new insights into the regulatory network controlling LC-PUFA biosynthesis and accumulation in vertebrates.
微 RNA 最近被证明是脂质代谢的重要调节因子。然而，miRNA 介导的脊椎动物长链多不饱和脂肪酸（LC-PUFA）生物合成的调控机制在很大程度上仍然未知。在此，我们首次研究了 miR-26a 在海洋兔鱼 LC-PUFA 生物合成中的作用。结果表明，在低盐水中饲养的兔鱼肝和用 LC-PUFA 前体α-亚麻酸孵育的肝细胞系（SCHL）中，miR-26a 的表达显著下调，这表明 miR-26a 可能参与 LC-PUFA 生物合成，因为其丰度受影响 LC-PUFA 生物合成的因素调节。在用α-亚麻酸孵育的 SCHL 细胞中，观察到 LXRα 和固醇调节元件结合蛋白-1（SREBP1）以及 LC-PUFA 生物合成相关基因（Δ4、Δ6Δ5 和 Fads2）的表达呈相反模式。荧光素酶报告基因测定显示兔鱼 LXRα 是 miR-26a 的靶标，SCHL 细胞中 miR-26a 的过表达显著降低了激动剂 T0901317 诱导的 Lxrα、Srebp1 和 Δ6Δ5 Fads2 的蛋白水平。此外，通过敲低 miR-26a 增加内源性 Lxrα 促进了 Srebp1 的激活以及与 LC-PUFA 生物合成相关基因的表达增加，从而促进了 LC-PUFA 生物合成 both 和。这些结果表明 miR-26a 通过靶向 Lxrα-Srebp1 途径在调节 LC-PUFA 生物合成中起关键作用，并为控制脊椎动物 LC-PUFA 生物合成和积累的调控网络提供了新的见解。
