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J. Biol. Chem., Vol. 279, Issue 41, 42403-42409, October 8, 2004

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Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan^*

Robert J. Brown¶, André Gauthier||, Robin J. Parks**, Ruth McPherson, Daniel L. Sparks¶¶, Joshua R. Schultz, and Zemin Yao||||

From the Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada, the ^**Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada, and the Departments of Biochemistry, Microbiology, and Immunology, Medicine, and Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Unlike human hepatic lipase (hHL) that is mainly cell surface-anchored via binding to heparan sulfate proteoglycans (HSPG), mouse HL (mHL) has a low affinity to HSPG and thus is largely blood-borne. The reduced HSPG binding of mHL is attributable to the C-terminal amino acids. To determine the functions of HSPG binding of hHL in vivo, we created adenovirus vectors encoding hHL or a chimeric protein (designated hHLmt) in which the C-terminal HSPG-binding sequences were replaced with the corresponding mouse sequences. Injecting hHLmt-expressing virus into C57BL/6J mice (1.8 x 10¹⁰ virus particles/mouse) resulted in a 3-fold increase in pre-heparin HL activity, whereas infection with an identical dose of hHL virus did not change pre-heparin HL activity. In hHLmt-expressing mice, the concentration of total cholesterol and phospholipids was inversely related to the hHL activity in pre-heparin plasma in a dose- and time-dependent manner, and the decrease was mainly attributable to high density lipoproteins (HDL) cholesterol and HDL phospholipids. The expression of hHL exhibited no change in plasma total cholesterol or phospholipid levels as compared with control mice infected with luciferase or injected with saline. The reduced HDL lipids in the hHLmt-expressing mice were accompanied by markedly decreased plasma and hepatic apolipoprotein (apo) A-I. In primary hepatocytes isolated from hHLmt-expressing mice, the concentration of cell-associated and secreted apoA-I was decreased by 2–3-fold as compared with hepatocytes isolated from control mice, whereas the levels of apoB and apoE were unaltered. Infection of primary hepatocytes with hHLmt virus ex vivo also resulted in reduced apoA-I secretion but had no effect on cell-associated apoA-I. These results suggest that expression of HSPG binding-deficient hHL has a profound HDL-lowering effect.

Received for publication, July 9, 2004 , and in revised form, July 26, 2004.

^* This work was supported by Grant-in Aids of the Heart and Stroke Foundation of Ontario (to Z. Y.). Portions of this work were presented at the 5th Conference on Arteriosclerosis, Thrombosis, and Vascular Biology of the American Heart Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A recipient of a studentship from the Heart and Stroke Foundation of Canada.

^|| A recipient of a studentship from the Ontario Graduate Scholarship.

^¶¶ A recipient of the Career Investigator Award from the Heart and Stroke Foundation of Canada.

^|||| A Career Investigator of the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed. Tel.: 613-798-5555 (ext. 18711); Fax: 613-761-5281; E-mail: zyao{at}ottawaheart.ca.

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