Present study explores the role of liver lipidome in driving T2D-associated metabolic changes. Elevated liver triacylglycerols, reduced PUFAs, and 86 differentially abundant lipid species were identified in diabetes-prone mice. Of these altered lipid species, 82 markedly overlap with human plasma lipids associated with T2D/CVD risk. Pathway enrichment highlighted sphingolipid metabolism, however, only five of all genes involved in the pathway were differentially expressed in the liver. Interestingly, overlap with adipose tissue transcriptome was much higher (57 genes), pointing toward an active adipose-liver interaction. Next, the integration of liver lipidome and transcriptome identified strongly correlated lipid-gene networks highlighting ceramide [Cer(22:0)], dihydroceramide(24:1), and triacylglycerol(58:6) playing a central role in transcriptional regulation. Putative molecular targets of Cer(22:0) were altered (Cyp3a44, Tgf-β1) in primary mouse hepatocytes treated with Cer(22:0). Early alteration of liver lipidome markedly depends on adipose tissue expression pattern and provides substantial evidence linking early liver lipidome alterations and risk of T2D.
