Abstract 439: REV-ERB--Mediated Regulation of Cholesterol Biosynthesis and Atherosclerosis
Despite significant research efforts in the field of cardiovascular diseases, atherosclerotic cardiovascular disease remains the leading cause of mortality. Current treatment options available to lower lipids are less than optimal in their ability to alter the progression of atherosclerosis. Therapies that can target both metabolic and inflammatory aspect of this disease have significant potential in the treatment of cardiovascular diseases. Recent work from our lab and others suggests that the nuclear receptor REV-ERB plays important role in regulating both lipid levels and inflammatory processes. We hypothesize that synthetic REV-ERB ligands can be used as tools to investigate the biology of the REV-ERBs in the regulation of cholesterol biosynthesis and that these ligands have therapeutic potential in the treatment of atherosclerosis. Eight week old mice (n=11 per group) with deficient LDL receptor were fed high cholesterol diet and treated with vehicle (15% cremophor) or REV-ERB agonist, SR9009 (100mg/kg, I.P.) for a period of eight weeks. We demonstrate that treatment of ldlr-deficient mice with SR9009 significantly reduces the expression of genes involved in cholesterol synthesis pathway in liver and considerably lowers plasma lipid levels - 45% reduction in LDL and 25% reduction in total cholesterol levels. In differentiating macrophages treated with SR9009, significant changes were observed in expression of genes involved in inflammatory responses. These results suggest that REV-ERBs have important role in the regulation of cholesterol synthesis and macrophage biology with therapeutic potential in the treatment of metabolic disorders, including atherosclerosis.
Author Disclosures: S. Sitaula: None. L. Solt: None. T. Kamenecka: None. T.P. Burris: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.