Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2α Signaling Cascade.

Transformation of macrophages into foam cells by apolipoprotein (Apo) E-de fi cient, ApoB48-containing (E O¾ /B48) lipoproteins has been shown to be associated with increased phosphorylation of eukaryotic initiation factor-2 α (eIF- 2 α ). The present report examined the causal relationship between eIF-2 α phosphorylation and lipid accumulation in macrophages induced by E O¾ /B48 lipoproteins. E O¾ /B48 lipoproteins increased eIF-2 α 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-2 α mutant in MPMs. Incubation of MPMs with E O¾ /B48 lipoproteins also increased the phosphorylation of RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), but not other eIF-2 α kinases. Overexpression of a nonphosphorylatable PERK mutant inhibited PERK and eIF-2 α phosphorylation, and alleviated cholesterol ester accumulation induced by E O¾ /B48 lipoproteins. PERK is an eIF-2 α kinase activated by endoplasmic reticulum (ER) stress. Taken together, fi ndings from this report suggest that induction of ER stress, i.e ., activation of the PERK-eIF2 α signaling cascade, is a mechanism by which E O¾ /B48 lipoproteins down-regulate lysosomal hydrolase synthesis, inhibit lysosomal lipoprotein degradation, and increase intracellular lipoprotein and cholesterol ester accumulation, resulting in foam cell formation.