Overexpression of human hepatic lipase and ApoE in transgenic rabbits attenuates response to dietary cholesterol and alters lipoprotein subclass distributions

The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholestero l was compared with the response of nontransgenic control rabbits. Suppleme ntation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 we eks resulted in markedly increased levels of plasma cholesterol and VLDL an d IDL in control rabbits as expected. Expression of either HL or apoE reduc ed plasma cholesterol response by 75% and 60%, respectively. The HL transge nic rabbits had substantial reductions in medium and small VLDL and IDL fra ctions but not in larger VLDL. LDL levels were also reduced, with a shift f rom larger, more buoyant to smaller, denser particles. In contrast, apoE tr ansgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expressio n of apoE and HL led to dramatic reductions of total cholesterol (85% versu s controls) and of total VLDL+IDL+LDL (87% versus controls). HDL subclasses were remodeled by the expression of either transgene and accompanied by a decrease in HDL cholesterol compared with controls. HL expression reduced a ll subclasses except for HDL2b and HDL2a, and expression of apoE reduced la rge HDL1 and HDL2b. Extreme HDL reductions (92% versus controls) were obser ved in the combined HL+apoE transgenic rabbits. These results demonstrate t hat human HL and apoE have complementary and synergistic functions in plasm a cholesterol and lipoprotein metabolism.