Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2α Signaling Cascade
| Autor: | GuoHuang Fan, Raju Ramaswamy, ZhongMao Guo, Emmanuel U. Okoro, Yanfeng Zhao, Xinghua Lin, LiChun Zhou, Hong Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Apolipoprotein E
Apolipoprotein B biology Endoplasmic reticulum Pharmaceutical Science macromolecular substances environment and public health Cathepsin B Article Cell biology enzymes and coenzymes (carbohydrates) biology.protein Unfolded protein response Phosphorylation lipids (amino acids peptides and proteins) Lipoprotein Foam cell |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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