Dicer1 Lipid metabolism Small intestine microRNA Organoids Hmgcs2 Acat1 Olr1
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Ruíz-Roso, M.B. (María Belén); Gil-Zamorano, J. (Judit); Lopez-de-las-Hazas, M.C. (María-Carmen); et al. "Intestinal Lipid Metabolism Genes Regulated by miRNAs". Frontiers in Genetics. 11 (707), 2020,
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, miR99b-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.