Abstract 355: Dyslipidemia, Obesity, Insulin Resistance and Atherosclerosis in LDL-Receptor Deficient Rats

Abstract

The LDL-receptor (LDLR) plays a major role in removing circulating LDL. Deletion of the receptor in mice results in profound dyslipidemia and atherosclerotic lesion formation. We established a new LDLR deficient (KO) rat model of atherosclerosis. When maintained on normal chow (NC), the KO rats displayed a 2.5-fold increase in plasma total cholesterol and 1.5 to 2.0- fold increase in triglycerides levels than corresponding WT rats. Lipidomics analysis of the plasma showed that deficiency of LDLR significantly (P<0.05) affected the abundance of 65 lipids. On normal chow, KO rats gained more weight and were more glucose intolerant than WT rats. Plasma leptin levels were higher and adiponectin levels were lower in KO than WT rats. Untargeted metabolomics analysis of polar extracts of plasma revealed that deficiency of LDLR differentially regulated the abundance of 20 metabolites (P<0.05). Measurement of circulating micro RNAs showed differential regulation of 35 micro RNAs, several of which are associated with obesity, insulin resistance and dyslipidemia. On Western diet (WD), the KO rats displayed exaggerated obesity and age-dependent increase in glucose intolerance. Their plasma levels of adiponectin and leptin were lower in comparison with WT rats. Lipidomics and metabolomics analyses of plasma showed differential regulation of 53 lipids (P<0.05) and 9 polar metabolites (P<0.05) as compared with WT rats maintained on WD. No appreciable aortic lesions were observed in KO rats fed NC for 64 weeks or WD for 16 weeks; however after 34-52 weeks of Western diet, the KO rats developed exuberant atherosclerotic lesions in the aortic arch and throughout the abdominal aorta. Several microRNAs associated with atherosclerosis, insulin resistance and obesity were also differentially regulated in the KO rats maintained on WD. These data suggest that LDLR-KO rat may be a useful model for studying obesity, insulin resistance, and atherosclerosis; and a panel of signature plasma lipids, polar metabolites and circulating microRNAs may serve as biomarkers of atherosclerosis and its risk factors.