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Papers In Press, published online ahead of print August 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800172-JLR200

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Journal of Lipid Research, Vol. 49, 1782-1793, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors^*,

Li Li, Patricia A. Thompson and Richard L. Kitchens¹

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX

^* This work was supported by National Institutes of Health Grant AI-45896 from the National Institute of Allergy and Infectious Diseases.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table and four figures.

Published, JLR Papers in Press, May 24, 2008.

¹ To whom correspondence should be addressed. e-mail: richard.kitchens{at}utsouthwestern.edu

Apolipoprotein E (apoE) plays important roles in lipid homeostasis, anti-inflammation, and host defense. Since tissue apoE mRNA levels have been reported to decrease during inflammatory responses, we were surprised to find that plasma apoE levels were significantly elevated during septic infections in both humans and mice. This apparent paradox was also observed during lipopolysaccharide-induced acute inflammation in mice: plasma levels of apoE increased up to 4-fold despite sharply decreased apoE gene expression in the liver, macrophages, and extrahepatic tissues. We hypothesized that apoE levels were augmented by decreased plasma clearance. Our analysis revealed that apoE associated principally with HDL in mice and that apoE was cleared from the circulation principally via LDL receptors. The acute inflammatory response decreased LDL receptor expression in the liver and significantly reduced the rate of apoE clearance. In contrast, the same inflammatory stimuli increased LDL receptor expression in macrophages. Our results define a novel acute phase mechanism that increases circulating apoE levels as apoE production decreases. Diminished hepatic LDL receptor expression may thus cooperate with elevated LDL receptor expression in macrophages to facilitate the forward transport of apoE and its associated lipids to these key defense cells.

Supplementary key words sepsis • acute inflammation • lipopolysaccharide • high density lipoprotein • low density lipoprotein

Abbreviations: ALT, alanine aminotransferase; apoE, apolipoprotein E; AST, aspartate aminotransferase; HSPG, heparan sulfate proteoglycan; LDLR^–/–, LDL receptor knockout; LRP, LDL receptor-related protein; LPS, lipopolysaccharide; PCSK9, proprotein convertase subtilisin-like kexin type 9; SR-BI, scavenger receptor class B type I; WT, wild-type

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