Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2ÃÂ± Signaling Cascade
- *Corresponding Author:
- Dr. Hong Yang, MD. or ZhongMao Guo, MD, PhD
Department of Physiology
Meharry Medical College
Nashville, TN 37208
Tel: (615) 327-5772
Fax: (615) 321-2949
E-mail: [email protected], [email protected]
Received Date: September 10, 2010; Accepted Date: October 06, 2010; Published Date: October 06, 2010
Citation: Zhao Y, Guo Z, Lin X, Zhou L, Okoro EU, et al. (2010) Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERKEIF- 2a Signaling Cascade. J Bioanal Biomed 2:113-120. doi:10.4172/1948-593X.1000033
Copyright: © 2010 Zhao Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Transformation of macrophages into foam cells by apolipoprotein (Apo) E-de fi cient, ApoB48-containing (E ÃÂ¾ /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 ÃÂ¾ /B48 lipoproteins. E ÃÂ¾ /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 ÃÂ¾ /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 ÃÂ¾ /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 ÃÂ¾ /B48 lipoproteins down-regulate lysosomal hydrolase synthesis, inhibit lysosomal lipoprotein degradation, and increase intracellular lipoprotein and cholesterol ester accumulation, resulting in foam cell formation.