Differential gene expression in FXR-null mice and relevance to cardiovascular disease.

Atherosclerotic cardiovascular disease is the major cause of death in Western societies. Disruption of the hepatic elimination of cholesterol favours the deposition of cholesterol within the arterial wall and thereby contributes to atherosclerosis. The farnesoid X-receptor FXR, is a nuclear hormone receptor that regulates cholesterol conversion to bile acids and, thereby cholesterol elimination from the liver. Mice with a disrupted FXR gene exhibit profound defects in lipid metabolism as indicated by elevated plasma and hepatic levels of cholesterol, triglycerides and phospholipids which are known risk factors for the development of atherosclerosis in humans. Using microarray analysis we have identified a novel mouse gene retinoic acid responder 2 (RARRES2) of unknown function with reduced expression in the FXR-null compared to FXR wild-type mice. Preliminary studies of RARRES2 in humans suggests that the aberrant regulation of that gene could be important in lipid accumulation and/or the macrophage recruitment and inflammation that is associated with atherosclerotic disease. The proposed experiments will characterize the tissue expression and the regulation of mouse and human RARRES2 by FXR. Once the regulatory properties of RARRES2 have been elucidated we will be able to devise strategies to determine how changes in the expression of that gene effects the development of pathology associated with atherosclerosis. Increased knowledge of the genetic determinants of atherosclerosis allows identification of individuals at high risk for the development of this disease. Forearmed with this information, it may be possible to design specific preventative measures for these individuals, or to devise therapies when prevention is no longer an option.