Cardiovascular disease (CVD) is the leading cause of death in the United States. Patients who inherit a mutation in the low density lipoprotein receptor related protein 6 (LRP6) developed CVD at a very early age due to metabolic syndrome (a constellation of symptoms which includes high serum levels of LDL and triglycerides, hypertension, and diabetes). This knowledge increases opportunities to better understand the factors that lead to the development of metabolic syndrome. Using novel mouse models, we seek to identify which cell type(s) are affected by reduced LRP6 function to cause metabolic syndrome. Two potential sources for the primary cell type affected by this mutation are the adipocytes and hepatocytes. To examine Lrp6 function in these cells, we will create and characterize mice carrying hepatocyte- or adipocyte-specific deletions of Lrp6. In Specific Aim 1, Lrp6-flox mice will be crossed to a strain expressing cre recombinase under the control of the albumin promoter (Albumin-cre). This will direct expression specifically and with high penetrance to the liver. Albumin-cre;Lrp6-flox/flox mice and littermate controls maintained on low- and high-fat diets will be evaluated for changes in liver function, as well as alterations in serum levels of components relevant to metabolic syndrome (with an emphasis on serum levels of LDL and triglycerides). We hypothesize that these mice will develop elevated levels of serum LDL and triglycerides when fed a high fat diet. We further predict that this will predispose these mice to the development of atherosclerosis. In Specific Aim 2, Lrp6-flox mice will be crossed to a strain expressing cre recombinase under the control of the 5.4 kb promoter fragment of the Fatty acid binding protein 4 gene (FABP4-cre). FABP4-cre mice express cre exclusively in adipocytes with virtually full penetrance. FABP4-cre;Lrp6-flox/flox mice and littermate controls maintained on low- and high-fat diets will be evaluated for changes in fat deposition and alterations in serum levels of components relevant to metabolic syndrome. We hypothesize that these mice with adipocyte-specific deletion of Lrp6 will display defects in adipocyte function which will eventually induce systemic changes in the mice, including the development of diabetes. PUBLIC HEALTH RELEVANCE: People who inherit a mutation in the low-density lipoprotein receptor 6 (LRP6) genes are dramatically predisposed to metabolic syndrome (a constellation of symptoms including high serum LDL and triglyceride levels, hypertension, and diabetes that dramatically increases the risk of cardiovascular disease). We will create mice carrying liver- or adipocyte-specific inactivating mutations in Lrp6 to gain insight into the tissue type(s) affected and to develop a mouse model of metabolic syndrome that can be used to test therapeutic interventions. Given that cardiovascular disease is the leading killer in the United States, this work will be very significant in gaining a better understanding of the underlying causes of this disease.