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Journal of Lipid Research, Vol. 46, 27-35, January 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Removal of chylomicron remnants in transgenic mice overexpressing normal and membrane-anchored hepatic lipase

Sung-Joon Lee^,, Sujata Kadambi^*, Kenneth C-W. Yu^1,*, Christopher David^*, Salman Azhar^**, Allen D. Cooper^*, and Sungshin Y. Choi^2,*

^* Research Institute, Palo Alto Medical Foundation, Palo Alto, CA
Department of Medicine, Stanford University, Stanford, CA
Division of Food Sciences, Korea University, Seoul, Korea
^** Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA

² To whom correspondence should be addressed. e-mail: chois{at}pamfri.org

The LDL receptor and the LDL receptor-related protein (LRP) mediate the removal of chylomicron remnants. The LRP pathway involves sequestration of particles in the space of Disse. It has been proposed that either alone or in combination with other factors, such as apolipoprotein E and proteoglycans, hepatic lipase (HL) may contribute to the sequestration of chylomicron remnants. To test this hypothesis, we generated two lines of transgenic mice producing rat HL as a native or as a membrane-anchored form. These animals express HL at levels similar to normal rat. Chylomicron remnants were perfused in a single nonrecirculating pass into the livers of the rat HL transgenic, HL-deficient, and wild-type (WT) mice for 20 min, and the rate of chylomicron remnant removal was measured. Chylomicron remnants were removed at a rate of 50% per pass in WT mice. It was slightly increased in both transgenic mice and reduced in HL-deficient mice compared with the WT mice. Confocal microscopy of liver sections showed that a modest amount of HL colocalized with chylomicron remnant clusters in the transgenic mice, suggesting that HL is a component of the LRP-proteoglycan clusters.

These data suggest that HL helps to direct cholesterol to the tissues in which it is localized by a nonenzymatic mechanism.

Abbreviations: apoB, apolipoprotein B; DiD, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine percholate; GPI, glycophosphatidylinositol; HSPG, heparan sulfate proteoglycan; LRP, low density lipoprotein receptor-related protein; OG, Oregon Green; RAP, receptor-associated protein; WT, wild-type

Supplementary key words liver perfusion • in vivo • glycophosphatidylinositol • immunohistochemistry • low density lipoprotein receptor • low density lipoprotein receptor-related protein

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