title: Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2α Signaling Cascade.
abstract: Transformation of macrophages into foam cells by apolipoprotein (Apo) E-deficient, ApoB48-containing (E(-)/B48) lipoproteins has been shown to be associated with increased phosphorylation of eukaryotic initiation factor-2α (eIF-2α). The present report examined the causal relationship between eIF-2α phosphorylation and lipid accumulation in macrophages induced by E(-)/B48 lipoproteins. E(-)/B48 lipoproteins increased eIF-2α phosphorylation and cholesterol ester accumulation, while lipoprotein degradation decreased and lysosomal acid lipase and cathepsin B mRNA translation was inhibited in mouse peritoneal macrophages (MPMs). These responses were overcome by overexpression of a nonphosphorylatable eIF-2α mutant in MPMs. Incubation of MPMs with E(-)/B48 lipoproteins also increased the phosphorylation of RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), but not other eIF-2α kinases. Overexpression of a nonphosphorylatable PERK mutant inhibited PERK and eIF-2α phosphorylation, and alleviated cholesterol ester accumulation induced by E(-)/B48 lipoproteins. PERK is an eIF-2α kinase activated by endoplasmic reticulum (ER) stress. Taken together, findings from this report suggest that induction of ER stress, i.e., activation of the PERK-eIF2α signaling cascade, is a mechanism by which E(-)/B48 lipoproteins down-regulate lysosomal hydrolase synthesis, inhibit lysosomal lipoprotein degradation, and increase intracellular lipoprotein and cholesterol ester accumulation, resulting in foam cell formation.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN 37208.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhongmao
authors.initials: Z
authors.lastname: Guo
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lin
authors.forename: Lichun
authors.initials: L
authors.lastname: Zhou
authors.forename: Emmanuel U
authors.initials: EU
authors.lastname: Okoro
authors.forename: Guohuang
authors.initials: G
authors.lastname: Fan
authors.forename: Raju
authors.initials: R
authors.lastname: Ramaswamy
authors.forename: Hong
authors.initials: H
authors.lastname: Yang