Effect of diet and genotype on the hepatic and intestinal mirnomes of genetically modified mice with altered lipoprotein metabolism

Aim. To generate an atlas of miRNA expression levels in liver and small intestine of mice characterized by a different lipoprotein metabolism. Methods. Normolipidemic C57BL/6J male mice, hyperlipidemic Ldlr-KO, and hypolipidemic Pcsk9- KO male mice (n=3 per group) were fed a Chow diet or a Western diet for 16 weeks. miRNome profiles of liver, duodenum, jejunum and ileum were assessed. Results. In the liver, the expression of 11 miRNAs varied significantly in all genotypes when comparing Chow and Western diets (miR-7a-5p, miR-381-3p, miR-96-5p, miR-136-5p, miR-434-3p, miR-409-3p, miR-300-3p, miR-127-3p, miR-431-5p, 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 by 9 miRNAs. The intestinal segments of the three genotypes responded differently to the dietary treatments and did not share any differentially expressed miRNA in duodenum and jejunum. In the ileum, the expression of 4 miRNAs varied significantly in all genotypes when comparing Chow and Western diets (miR-29a-5p, miR-223-3p, miR-98-3p, miR-467d-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: i) diet- and genotype-determined dyslipidemic conditions impact on the miRNome in an organ-specific manner; ii) dietary lipids represent a much more effective driver than genotype in altering miRNA expression.