Modified LDL can also provoke stress of the ER or, in other words, unfolded protein response or just UPR by exceeded free cholesterol accumulation.

In general, activation of the UPR is mediated by three transmembrane proteins, namely inositol-requiring protein-1 (IRE1), activating transcription factor-6 (ATF6), and protein kinase RNA (PKR)-like ER kinase (PERK).IRE1 and PERK are involved in foam cell formation, whereas ATF6 involvement in foam cell formation is controversial.

Prolonged ER stress observed in atherosclerotic lesions is an important contributor to proatherogenic progression.

So ERstress plays an important role in cell foam formation and progression of atherosclerosis.

However,despite of all findings,  the underlying genes and the exact mechanism of cholesterol accumulation remain poorly studied.

(ER stress was found in all major cell type in atherosclerosis including macrophages, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs).