Dietary lipids affect more than genotype hepatic and intestinal miRNome: a study in mouse models with different lipid profiles

Aim. To generate an atlas of miRNA expression levels in liver and small intestine of mice characterized by a different lipoprotein metabolism.Materials and Methods. C57BL/6J, Ldlr-KO and Pcsk9-KO male mice (n=3/group) were fed a Chow diet or a Western diet for 16weeks. Plasma lipids as well as miRNomes of liver, duodenum, jejunum and ileum were assessed.Results. Cholesterolemia and triglyceridemia were higher in Ldlr-KO than in the other genotypes, under both Chow and Western.On Chow diet, C57BL/6J were characterized by higher cholesterolemia and triglyceridemia than Pcsk9-KO, but no differences were observed between the two genotypes on Western diet. In each genotype, Western diet-fed mice had higher cholesterolemia and triglyceridemia than Chow-fed mice. In the liver, the expression of 11miRNAs varied significantly in all genotypes when comparing Chow and Western diets (miR-7a-5p, miR-381-3p, miR-96-5p, miR136-5p, miR-434-3p, miR-409-3p, miR-300-3p, miR-127-3p, miR-4315p, miR-582-5p, miR-34a-5p). Ninety-two out of their 7944 predicted target genes were related to lipid/lipoprotein metabolism. Several among these miRNAs were capable of synergistic action against their targets: 41 lipid-related genes were targeted by at least 3 diet-modulated miRNAs. Of note, Zbtb20, a gene involved in hepatic de novo lipogenesis, appeared to be simultaneously modulated by9 miRNAs. The intestinal segments responded differently to the dietary treatments and did not share any differentially expressed miRNA in duodenum and jejunum. In the ileum, the expression of4 miRNAs varied significantly in all genotypes when comparing Chow and Western diets (miR-29a-5p, miR-223-3p, miR-98-3p, miR467d-5p). Among the 583 predicted target genes, 22 transcripts were related to intestinal lipid/lipoprotein metabolism and were all modulated by mmu-miR-98-3p.Conclusions. Our study demonstrates that: 1) diet and genotype-determined dyslipidemic conditions impact on the miRNome in an organ-specific manner; 2) dietary lipids represent a much more effective driver than genotype in altering miRNA expression