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, Acat1 and Olr1 were 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.

MicroRNA（miRNA）在翻译抑制和转录后调节中的关键作用有助于调节肠道脂质代谢。尽管已经阐明了它们在不同代谢组织中的作用，但它们的肠道活性尚不清楚。我们旨在通过创建肠道特异性Dicer1基因敲除（Int-Dicer1 KO）小鼠模型来研究肠道miRNA调控的脂质代谢相关基因，而该模型在肠上皮细胞中耗竭了微RNA。在基线和口服脂质攻击后2小时，评估了Int-Dicer1 KO和野生型C57BL / 6（WT）同窝仔小鼠的肠粘膜中83种与胆固醇和脂蛋白代谢相关的基因的水平。在选择用于进一步验证的18个基因中，Hmgcs2， 阿卡特1号 和 奥尔1被发现是肠细胞和肠类器官中受miRNA调节的强候选基因。此外，我们报告肠道miRNA有助于肠道上皮分化的调节。分析了在肠中发现的29种常见miRNA，它们有可能靶向Caco-2细胞中通过miRNA转染测定发现并验证的三个候选基因中的任何一种。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节因子。我们的数据提供了有关肠道miRNA作为脂质代谢相关病理学治疗靶标潜力的新证据。