Effects of cholesterol in chylomicron remnant models of lipid emulsions on apoE-mediated uptake and cytotoxicity of macrophages.
Chylomicron remnants have been suggested to be involved in the development of atherosclerosis. To investigate the mechanisms of chylomicron remnant-induced atherosclerosis, we prepared cholesterol (Chol)-containing emulsion particles as models for chylomicron remnants. Chol markedly increased the apolipoprotein E (apoE) binding maximum of emulsions without changing the binding affinity and thereby promoted emulsion uptake by J774 macrophages. Fluorescence measurements showed that Chol increased acyl chain order and head group hydration of the surface phospholipid (PL) layer of emulsions. The binding maximum of apoE was closely correlated with the hydration and the increase in the PL head group separation at the emulsion surface. From experiments using inhibitors for lipoprotein receptors, heparan sulfate proteoglycans and low density lipoprotein receptor-related protein were found to be the major contributors to the uptake of Chol-containing emulsions. Trypan blue dye exclusion revealed that the uptake of Chol-containing emulsions induced cytotoxicity to J774 macrophages. This study proposes a mechanism of atherosclerosis induced by chylomicron remnants.
Sakurai
Atsushi
A
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Morita
Shin-Ya
SY
Wakita
Kyoko
K
Deharu
Yuko
Y
Nakano
Minoru
M
Handa
Tetsurou
T
D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry / Q000494:pharmacology*; D053298:Chylomicron Remnants; D002914:Chylomicrons / Q000378:metabolism / Q000494:pharmacology*; D004655:Emulsions; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D013499:Surface Properties
D001057:Apolipoproteins E; D053298:Chylomicron Remnants; D002914:Chylomicrons; D004655:Emulsions; D019812:Heparan Sulfate Proteoglycans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D002784:Cholesterol