Silencing the Very Low-density Lipoprotein Receptor (VLDLR) Prevents Obesity Associated with Excess Lipid Deposition (P21-040-19)

Abstract

ObjectivesObesity is associated with an insulin resistant state, characterized by abnormalities in lipid metabolism, a leading cause of morbidity and mortality in cardiovascular diseases (CVD). Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of apolipoprotein E triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity associated lipotoxicity is not well understood. MethodsIn the current study, lean WT, VLDLR-deficient (VLDLR−/−), genetically obese leptin-deficient (Lepob/ob), and leptin–VLDLR double-null (Lepob/ob/VLDLR−/−) mice were used to determine the impact of VLDLR deficiency on obesity-induced cardiac lipotoxicity. ResultsThe results showed that insulin sensitivity and glucose uptake were reduced in the hearts of Lepob/ob mice, and at the same time, VLDLR expression was upregulated and associated with increased VLDL uptake resulting in excess lipid deposition. These changes were accompanied by upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in Lepob/ob mice reduced VLDL uptake and prevented excess lipid deposition. Moreover, VLDLR deficiency reduced superoxide overproduction and normalized glucose uptake. In isolated cardiomyocytes, VLDLR deficiency prevented VLDL-mediated induction of NOx activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. An important observation showed that Lepob/ob/VLDLR−/− mice compared to Lepob/ob mice, had significantly improved heart performance and energetic reserves. ConclusionsThese findings suggest that that when VLDLR is silenced (deficiency), lipid deposition is also reduced, preventing cardiac lipotoxicity in obesity. In addition, the effects may be linked to the role of VLDLR on VLDL uptake, which triggers a cascade of events leading to insulin resistance and superoxide overproduction. Funding SourcesInstitutional Support.Howard University, Washington DC 20059Hackensack University Medical Center, NJ 07601