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J. Biol. Chem., Vol. 279, Issue 44, 45312-45321, October 29, 2004

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The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice^*

Herminia González-Navarro, Zengxuan Nong, Marcelo J. A. Amar, Robert D. Shamburek, Jamila Najib-Fruchart||, Beverly J. Paigen, H. Bryan Brewer, Jr., and Silvia Santamarina-Fojo¶

From the Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the Jackson Laboratory, Bar Harbor, Maine 04609, and ^||Institut Pasteur, Lille 59019, France

To investigate the separate contributions of the lipolytic versus ligand-binding function of hepatic lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO x HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p < 0.01), but only HL-WT decreased high density lipoprotein cholesterol (by 67%) and apoA-I (by 54%). Compared with E-KO x HL-KO mice, both active and inactive HL lowered the pro-atherogenic lipoproteins by enhancing the catabolism of autologous ¹²⁵I-apoB very low density/intermediate density lipoprotein (VLDL/IDL) (fractional catabolic rates of 2.87 ± 0.04/day for E-KO x HL-KO, 3.77 ± 0.03/day for E-KO x HL-WT, and 3.63 ± 0.09/day for E-KO x HL-S145G mice) and ¹²⁵I-apoB-48 low density lipoprotein (LDL) (fractional catabolic rates of 5.67 ± 0.34/day for E-KO x HL-KO, 18.88 ± 1.72/day for E-KO x HL-WT, and 9.01 ± 0.14/day for E-KO x HL-S145G mice). In contrast, the catabolism of apoE-free, ¹³¹I-apoB-100 LDL was not increased by either HL-WT or HL-S145G. Infusion of the receptor-associated protein (RAP), which blocks LDL receptor-related protein function, decreased plasma clearance and hepatic uptake of ¹³¹I-apoB-48 LDL induced by HL-S145G. Despite their similar effects on lowering pro-atherogenic apoB-containing lipoproteins, HL-WT enhanced atherosclerosis by up to 50%, whereas HL-S145G markedly reduced aortic atherosclerosis by up to 96% (p < 0.02) in both male and female E-KO x HL-KO mice. These data identify a major receptor pathway (LDL receptor-related protein) by which the ligand-binding function of HL alters remnant lipoprotein uptake in vivo and delineate the separate contributions of the lipolytic versus ligand-binding function of HL to plasma lipoprotein size and metabolism, identifying an anti-atherogenic role of the ligand-binding function of HL in vivo.

Received for publication, June 10, 2004 , and in revised form, August 2, 2004.

^* 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.

^¶ To whom correspondence should be addressed: Molecular Disease Branch, NHLBI, NIH, Bldg. 10, Rm. 7N115, 10 Center Dr., MSC 1666, Bethesda, MD 20892. Tel.: 301-496-5095; Fax: 301-402-0190; E-mail: silvia{at}mdb.nhlbi.nih.gov.

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