RNAseq analysis of liver transcriptomes from wild-type and MLL4SETf/fHSA-Cre mice

Evidence is emerging that skeletal muscle metabolic reprogramming could be a modifier of hepatic steatosis. Skeletal muscle-specific Mll4-knockout (MLL4SETf/fHSA-Cre) and wild-type (WT) littermates were placed on HFD (60% kcal from fat). Interestingly, muscle MLL4 deficiency prevents HFD-induced hepatic steatosis. To gain insight into the liver metabolic reprogramming in MLL4SETf/fHSA-Cre mice, we performed RNA-Seq analysis on mRNA isolated from liver of the MLL4SETf/fHSA-Cre mice and littermate controls. Gene ontology (GO) analysis of down-regulated genes revealed significant enrichment in lipid metabolic process, inflammatory response as well as collagen fibril organization. Conversely, pathways of oxidation-reduction and epoxygenase P450 were significantly enriched in the upregulated gene set. Gene expression validation studies demonstrated that the expression of the gene encoding lipid uptake and de novo lipogenesis was reduced in HFD-fed MLL4SETf/fHSA-Cre liver, concomitant with an increased in the expression of the oxidation-reduction genes. These findings suggest that MLL4 deletion in skeletal muscle decreases lipid uptake and denovo lipogenesis in the liver, leading to protection from HFD-induced hepatic steatosis. Overall design: Liver mRNA profiles of 20-week-old WT and MLL4SETf/fHSA-Cre mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq 6000.