CHOLESTEROL-LOWERING IN LOW-DENSITY-LIPOPROTEIN RECEPTOR KNOCKOUT MICE OVEREXPRESSING APOLIPOPROTEIN-E

Apo E is a key molecule in the lipoprotein metabolism; thus, genetic m anipulation of apo E may prove useful in the treatment of hypercholest erolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene (ETg(+/+):LDLRKO), and compared their plasma lipo protein profiles with those of nonexpressing LDLR knockout mice (ETg(- /-):LDLRKO), On a normal chow diet, the mean plasma cholesterol level of ETg(+/+):LDLRKO mice was significantly lower than that of ETg(-/-): LDLRKO mice (189 versus 240 mg/dl, P < 0.01), The LDL fraction was sel ectively reduced in the ETg(+/+):LDLRKO mice. Despite the challenge wi th an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppr essed in the mice overexpressing apo E. These results imply that stimu lation of hepatic production of apo E may be used as a promising adjun ctive therapy for homozygous familial hypercholesterolemia.