Novel ABC transporters promote cholesterol efflux to HDL
Lead Inventors: Alan R. Tall, M.D.Problem or Unmet Need:Altered lipid metabolism is associated with coronary cardiovascular disease and Alzheimer's disease. Accumulated evidence suggests that cholesterol and cholesterol-loaded macrophage foam cells play a critical role in the development of these disorders. The cause of cholesterol accumulation in macrophage foam cells is not completely understood, but likely a result of imbalanced cholesterol transport into and out of the macrophage. High density lipoprotein (HDL) accounts for the major proportion of the capacity of cholesterol efflux due to its high plasma concentrations. However the molecular mechanism for HDL mediated cholesterol efflux and its regulation is poorly understand. This technology discovered novel ATP-binding cassette (ABC) transporter that enhance cellular cholesterol efflux to HDL, representing a novel therapeutic approach to atherosclerotic cardiovascular disease and Alzheimer's disease. The technology identified ATP-binding cassette transporter G1 (ABCG1) and ATP-binding cassette transporter G4 (ABCG4) play a major role in promoting macrophage cholesterol efflux to HDL. Therefore, it suggested that the enhancement of ABCG1 and ABCG4 activity by increasing gene expression, decreasing protein turnover or by altered post-transcriptional modification of the protein could increase cholesterol efflux to HDL in vivo. In blood vessel wall, increased ABCG1 or ABCG4 activities would increase cholesterol efflux to HDL, which decrease cholesterol accumulation in macrophages, leading to decreased macrophage death and decreased atherosclerotic lesion progress. In brain increased ABCG1 or ABCG4 activity would increase cholesterol efflux from neuronal cells to HDL in cerebrospinal fluid, leading to retarded or reversed development of Alzheimer's disease.
Effective: The technology discovered the major molecular pathway in cholesterol efflux, would lead to the development of more effective cholesterol therapy Specific: The targets are natural transporters in vivo, presenting a specific therapeutic strategy with fewer side effects
Drug target: Enhancement of ABCG1 and ABCG4 activity by increasing gene expression in somatic cells, decreasing protein turnover or by altered post-transcriptional modification of the protein could increase cholesterol efflux to HDL in vivo, offering a protective therapy against atherosclerotic cardiovascular disease and Alzheimer's disease. Diagnostic marker: ABCG1 and ABCG4 activities could be used as novel markers for clinic diagnosis. Others: The non-macrophage cell having an expression vector encoding ABCG1 or ABCG4 can be used in preparing a composition for treating atherosclerotic cardiovascular disease and Alzheimer's disease.
The technology identified ATP-binding cassette transporter G1 (ABCG1) and ATP-binding cassette transporter G4 (ABCG4) play a major role in promoting macrophage cholesterol efflux to HDL. Therefore, it suggested that the enhancement of ABCG1 and...
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