Intestinal Lipid Metabolism Genes Regulated by miRNAs
Intestinal Lipid Metabolism Genes Regulated by miRNAs
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DOI：
10.3389/fgene.2020.00707
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发表时间：
2020-07-10
影响因子：
3.7
通讯作者：
Davalos, Alberto
中科院分区：
文献类型：
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作者：
Belen Ruiz-Roso, Maria;Gil-Zamorano, Judit;Davalos, Alberto
microrna （mirna）在翻译抑制和转录后调节中起着至关重要的作用，有助于调节肠道脂质代谢。尽管它们在不同代谢组织中的作用已被阐明，但它们的肠道活性尚不清楚。我们旨在通过建立肠道特异性Dicer1敲除（Int-Dicer1 KO）小鼠模型，研究肠道mirna调节的脂质代谢相关基因，并在肠细胞中缺失microrna。研究人员对Int-Dicer1 KO和野生型C57BL/6 （WT）幼崽小鼠肠黏膜在基线和口服脂质刺激后2小时的83种胆固醇和脂蛋白代谢相关基因水平进行了评估。在选择进一步验证的18个基因中，Hmgcs2、acat1和olr1被发现是肠细胞和肠道类器官中mirna调节的强候选基因。此外，我们报道了肠道mirna有助于肠上皮分化的调节。研究人员分析了在肠道中发现的29种常见mirna，以确定其靶向Caco-2细胞中发现的三种候选基因中的任何一种的潜力。MiR-31-5p、miR-99b-5p、miR-200a-5p、miR-200b-5p和miR-425-5p是这些脂质代谢相关基因的主要调控因子。我们的数据为肠道mirna作为脂质代谢相关病理的治疗靶点的潜力提供了新的证据。
MicroRNAs (miRNAs) crucial roles in translation repression and post-transcriptional adjustments contribute to regulate intestinal lipid metabolism. Even though their actions in different metabolic tissues have been elucidated, their intestinal activity is yet unclear. We aimed to investigate intestinal miRNA-regulated lipid metabolism-related genes, by creating an intestinal-specific Dicer1 knockout (Int-Dicer1 KO) mouse model, with a depletion of microRNAs in enterocytes. The levels of 83 cholesterol and lipoprotein metabolism-related genes were assessed in the intestinal mucosa of Int-Dicer1 KO and Wild Type C57BL/6 (WT) littermates mice at baseline and 2 h after an oral lipid challenge. Among the 18 genes selected for further validation,Hmgcs2,Acat1andOlr1were found to be strong candidates to be modulated by miRNAs in enterocytes and intestinal organoids. Moreover, we report that intestinal miRNAs contribute to the regulation of intestinal epithelial differentiation. Twenty-nine common miRNAs found in the intestines were analyzed for their potential to target any of the three candidate genes found and validated by miRNA-transfection assays in Caco-2 cells. MiR-31-5p, miR-99b-5p, miR-200a-5p, miR-200b-5p and miR-425-5p are major regulators of these lipid metabolism-related genes. Our data provide new evidence on the potential of intestinal miRNAs as therapeutic targets in lipid metabolism-associated pathologies.