Hepatic expression of apolipoprotein E inhibits progression of atherosclerosis without reducing cholesterol levels in LDL receptor-deficient mice

Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liv er and by tissue macrophages. Plasma apoE (derived primarily from the liver ) regulates plasma lipoprotein metabolism, but macrophage-derived apoE was shown to slow the progression of atherosclerosis independent of plasma lipi d levels. We utilized liver-directed gene transfer to test the hypothesis t hat hepatic expression of human apoE would inhibit atherogenesis even in a model in which apoE expression has little effect on plasma lipoproteins. LD L receptor-deficient mice fed a western-type diet for 5 weeks were injected with a second-generation recombinant adenovirus encoding human apoE3 or co ntrol virus. Plasma cholesterol levels were not significantly different in the two groups of mice after virus injection. Four weeks after injection, a therosclerosis was examined using three independent assays. Expression of a poE was associated with significantly reduced atherosclerosis compared with control mice in both the aortic arch (decreased by 43%) and the aortic roo t (decreased by 59%). In summary, hepatic overexpression of apoE inhibited progression of atherosclerosis in LDL receptor-deficient mice without reduc ing plasma cholesterol levels. This finding indicates that liver-derived pl asma apoE can influence early atherogenesis through mechanisms other than m odulation of lipoprotein metabolism and that liver-directed gene transfer a nd overexpression of apoE may be a therapeutic approach to atherosclerosis.