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* Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141–9100
Cardiovascular Research Institute, University of California, San Francisco, CA 94141–9100
Department of Pathology, University of California, San Francisco, CA 94141–9100
1 To whom correspondence should be addressed. e-mail: rpitas{at}gladstone.ucsf.edu
We present a murine model that examines the effects of macrophage-produced apolipoprotein E3 (apoE3) and apoE4 on VLDL and high density lipoprotein (HDL) metabolism. Mice expressing apoE3 on the Apoe-/- background had substantially lower VLDL levels than mice expressing apoE4. In addition, there were differences between the HDL of apoE3- and apoE4-expressing mice. Apoe-/- mice have low levels of HDL. Low level expression of either apoE3 or apoE4 was able to restore near-normal HDL levels, which increased dramatically when the mice were challenged with a high-fat diet. ApoE4-expressing mice had smaller HDL than apoE3-expressing mice on both chow and high-fat diets. In addition, plasma from apoE4-expressing mice was less efficient at transferring apoA-I from VLDL to HDL and at generating HDL in vitro than that from apoE3-expressing mice.
Thus, we present experimental evidence for differential effects of apoE3 and apoE4 on HDL metabolism that supports epidemiological observations made in humans, which suggested that individual homozygous for the 
4 allele had lower HDL than others.
Abbreviations: apo, apolipoprotein; apoE3+/- and apoE4+/- mice, Apoe-/- mice hemizygous for the visna virus long terminal repeat-driven expression of human apoE3 or apoE4; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TRL, triglyceride-rich lipoprotein(s)
Supplementary key words apolipoprotein AI • apolipoprotein E • chylomicron metabolism • HDL metabolism
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