A relative newcomer to the LDL receptor family is a protein with 11 receptor ligand binding repeats called LR11. This receptor is predominantly expressed in brain tissues and has been implicated to protect against Alzheimer's disease. Recent data showed that LR11 is also expressed in liver, vessel wall, and in adipose tissues, but not in the heart nor in skeletal muscle. This project has produced LR11-knockout mice to address the role of this novel receptor in lipid metabolism and arteriosclerosis. Preliminary Results showed that the LR11-null mice displayed higher fasting plasma triglyceride levels and increased postprandial hyperlipidemia compared to their wild type littermates. In vitro cell culture studies also showed that over- expression of LR11 induces urokinase-type plasminogen activator (uPA) receptor expression in smooth muscle cells, increasing their migration and invasion activities by inhibiting uPAR internalization and retaining uPA at the cell surface. The first goal of this study will test the hypothesis that LR11 expression in the liver and adipose tissues plays an important role in plasma lipid assimilation by these tissues and the lack of LR11 will result in hyperlipidemia, but possibly protection against diet-induced obesity and diabetes. The second goal of this project is to identify the role of LR11 in vascular cell homeostasis by comparing diet- induced atherosclerosis and injury-induced neointimal hyperplasia between LR11(+/+) and LR11(-/-) mice.
Specific Aim 1 will identify the difference in lipid metabolism, tissue-specific partitioning of dietary lipids, and compare susceptibility to diet-induced obesity and diabetes between LR11 (+/+) and LR11 (-/-) mice.
In Specific Aim 2, the LR11-null mice will be crossed with LDL receptor-null mice, and atherosclerosis progression in the double receptor-knockout mice will be compared to that observed in LDL receptor-null mice to assess the role of LR11 in foam cell formation and deposition in response to high fat/high cholesterol feeding.
Specific Aim 3 will identify the role of LR11 in vascular smooth muscle cell hyperplasia in response to vascular injury, by comparing LR11-null mice with their wild type littermates in neointimal formation after mechanical denudation of the endothelium in their carotid arteries. Results obtained from this study, if supportive of our proposed hypotheses, will offer a novel therapeutic target, namely the inhibition of LR11, to reduce the debilitating metabolic diseases associated with high fat/high cholesterol intake. ? ? ?
