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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:625-632.)
© 1999 American Heart Association, Inc.

Original Contributions

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

Carlo M. Barbagallo; Jianglin Fan; Patricia J. Blanche; Manfredi Rizzo; John M. Taylor; Ronald M. Krauss

From the Istituto di Medicina Interna e Geriatria (C.M.B.), Universitá degli Studi di Palermo, Italy; the Gladstone Institute of Cardiovascular Disease (J.F., J.M.T.), University of California, San Francisco; and the Life Sciences Division (C.M.B., P.J.B., M.R., R.M.K.), Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley.

Correspondence to Ronald M. Krauss, MD, Lawrence Berkeley National Laboratory, Donner Laboratory, Room 459, University of California, One Cyclotron Road, Berkeley, CA 94720. E-mail rmkrauss{at}lbl.gov

Abstract—The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expression of apoE and HL led to dramatic reductions of total cholesterol (85% versus 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 all subclasses except for HDL_2b and HDL_2a, and expression of apoE reduced large HDL₁ and HDL_2b. Extreme HDL reductions (92% versus controls) were observed in the combined HL+apoE transgenic rabbits. These results demonstrate that human HL and apoE have complementary and synergistic functions in plasma cholesterol and lipoprotein metabolism.

Key Words: lipoproteins • apoE • hepatic lipase • rabbits • transgene

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