INRA, Univ Pau & Pays Adour, E2S UPPA, UMR 1419, Nutrition Métabolisme Aquaculture, Saint Pée sur Nivelle, France.
PLoS One. 2020 Feb 28;15(2):e0223813. doi: 10.1371/journal.pone.0223813. eCollection 2020.
Cholesterol metabolism is greatly affected in fish fed plant-based diet. The regulation of cholesterol metabolism is mediated by both transcriptional factors such as sterol regulatory element-binding proteins (SREBPs) and liver X receptors (LXRs), and posttranscriptional factors including miRNAs. In mammals, SREBP-2 and LXRα are involved in the transcriptional regulation of cholesterol synthesis and elimination, respectively. In mammals, miR-33a is reported to directly target genes involved in cholesterol catabolism. The present study aims to investigate the regulation of cholesterol metabolism by SREBP-2 and LXRα and miR-33a in rainbow trout using in vivo and in vitro approaches. In vivo, juvenile rainbow trout of ~72 g initial body weight were fed a total plant-based diet (V) or a marine diet (M) containing fishmeal and fish oil. In vitro, primary cell culture hepatocytes were stimulated by graded concentrations of 25-hydroxycholesterol (25-HC). The hepatic expression of cholesterol synthetic genes, srebp-2 and miR-33a as well as miR-33a level in plasma were increased in fish fed the plant-based diet, reversely, their expression in hepatocytes were inhibited with the increasing 25-HC in vitro. However, lxrα was not affected neither in vivo nor in vitro. Our results suggest that SREBP-2 and miR-33a synergistically enhance the expression of cholesterol synthetic genes but do not support the involvement of LXRα in the regulation of cholesterol elimination. As plasma level of miR-33a appears as potential indicator of cholesterol synthetic capacities, this study also highlights circulating miRNAs as promising noninvasive biomarker in aquaculture.
鱼类的胆固醇代谢在食用植物性饲料后会受到很大影响。胆固醇代谢的调节是由转录因子（如固醇调节元件结合蛋白（SREBPs）和肝 X 受体（LXRs））和转录后因子（包括 miRNA）介导的。在哺乳动物中，SREBP-2 和 LXRα 分别参与胆固醇合成和消除的转录调控。在哺乳动物中，miR-33a 被报道可直接靶向参与胆固醇分解代谢的基因。本研究旨在通过体内和体外方法研究 SREBP-2、LXRα 和 miR-33a 在虹鳟鱼中对胆固醇代谢的调节作用。在体内，初始体重约为 72g 的幼龄虹鳟鱼被喂食全植物性饲料（V）或含有鱼粉和鱼油的海洋性饲料（M）。在体外，用不同浓度的 25-羟胆固醇（25-HC）刺激原代肝细胞培养物。在食用植物性饲料的鱼类中，肝脏中胆固醇合成基因 srebp-2 和 miR-33a 的表达以及血浆中 miR-33a 的水平增加，相反，体外随着 25-HC 的增加，其在肝细胞中的表达受到抑制。然而，LXRα 无论是在体内还是在体外都不受影响。我们的研究结果表明，SREBP-2 和 miR-33a 协同增强胆固醇合成基因的表达，但不支持 LXRα 参与胆固醇消除的调节。由于血浆中 miR-33a 的水平似乎是胆固醇合成能力的潜在指标，因此本研究还强调了循环 miRNA 作为水产养殖中很有前途的非侵入性生物标志物。
