Transcriptomics and metabolomics analysis of the pathogenesis of a novel hyperlipidemia-susceptible rat strain

Abstract

Wistar-SD Hypercholesterolemia (WSHc) Rat is a novel hyperlipidemia-susceptible rat that we discovered and bred earlier, which can be used as an ideal animal model for the study of non-alcoholic fatty liver disease (NAFLD). However, its pathogenesis of hyperlipidemia and genetic and biological characteristics need to be further investigated. In the current study, WSHc rats were fed a high-fat diet (HFD) and standard chow (SC), with age-matched Wistar rats as the control group undergoing the same treatment, followed by serum lipid level measurement. It was found that HFD-fed WSHc rats developed dyslipidemia. Transcriptomic analysis was performed to detect genes associated with cholesterol metabolism in the liver, and 119 differentially expressed genes were discovered through bioinformatics analysis and molecular biology verification. Additionally, Srebf1 was identified as a HUB gene and Nr1d1 as an independent key gene using the protein-protein interaction network and one-cluster clustering analysis. The two genes had also been further validated in molecular biology experiments and were consistent with transcriptomic results. Serum lipid metabolomics analysis identified 7 lipid subclasses and 84 lipid molecules using UHPLC-Q-TOF/MS. There were 62 and 70 lipid molecules with significant differences in the metabolic profiles of serum lipid mediators in the WSHc+HFD group compared to the WSHc+SC and Wistar+HFD groups, respectively, and the differential metabolites were mainly produced via sphingolipid and glycerophospholipid metabolism. In sum, the hypercholesterolemia model can be established with WSHc rats after the HFD induction, and the pathogenesis involves the Srebf1 and Nr1d1 genes and the sphingolipid and glycerophospholipid metabolism pathways.