Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages

Junichi Ishiyama,Ryoko Taguchi,Yunike Akasaka,Saiko Shibata,Minoru Ito,Michiaki Nagasawa,Koji Murakami

doi:10.1194/jlr.m007104

Abstract

Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL (oxLDL), and enhances oxLDL uptake in macrophages. However, the precise underlying mechanism remains to be elucidated. PA is known to induce endoplasmic reticulum (ER) stress in various cell types. Therefore, we investigated whether ER stress is involved in PA-induced LOX-1 upregulation. PA induced ER stress, as determined by phosphorylation of PERK, eIF2α, and JNK, as well as induction of CHOP in macrophage-like THP-1 cells. Inhibitors [4-phenylbutyric acid (PBA), sodium tauroursodeoxycholate (TUDCA), and salubrinal] and small interfering RNA (siRNA) for the ER stress response decreased PA-induced LOX-1 upregulation. Thapsigargin, an ER stress inducer, upregulated LOX-1, which was decreased by PBA and TUDCA. We next examined whether unsaturated FAs could counteract the effect of PA. Both oleic acid (OA) and linoleic acid (LA) suppressed PA-induced LOX-1. Activation of the ER stress response observed in the PA-treated cells was markedly attenuated when the cells were cotreated with OA or LA. In addition, OA and LA suppressed thapsigargin-induced LOX-1 upregulation with reduced activation of ER stress markers. Our results indicate that activation of ER stress is involved in PA-induced LOX-1 upregulation in macrophages, and that OA and LA inhibit LOX-1 induction through suppression of ER stress.

Highlights

Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL, and enhances oxLDL uptake in macrophages
Because we confirmed activation of endoplasmic reticulum (ER) stress response preceding LOX-1 induction, we examined whether alleviation of ER stress could mitigate PA-induced LOX-1 upregulation
Consistent with the inhibitory effects on LOX-1 upregulation, treatment of the cells with phenylbutyric acid (PBA), TUDCA, or salubrinal reduced levels of protein kinase-like ER kinase (PERK) phosphorylation in the PA-treated cells (Fig. 1E). These results indicated that alleviation of ER stress could mitigate PA-induced LOX-1 upregulation

Summary

Introduction

Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL (oxLDL), and enhances oxLDL uptake in macrophages. PA induced ER stress, as determined by phosphorylation of PERK, eIF2␣, and JNK, as well as induction of CHOP in macrophage-like THP-1 cells. We examined whether unsaturated FAs could counteract the effect of PA Both oleic acid (OA) and linoleic acid (LA) suppressed PA-induced LOX-1. OA and LA suppressed thapsigargininduced LOX-1 upregulation with reduced activation of ER stress markers. Our results indicate that activation of ER stress is involved in PA-induced LOX-1 upregulation in macrophages, and that OA and LA inhibit LOX-1 induction through suppression of ER stress.—Ishiyama, J., R. Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages. Under conditions that induce ER stress, the unfolded protein response (UPR) is activated to reduce the level of new protein synthesis, increase folding capacity, and degrade terminally misfolded proteins [6]. In addition to the role of ER stress in the induction of apoptosis, there is evidence showing that ER stress increases expression of the scavenger receptors CD36 and SR-A in macrophages [12, 17], suggesting that ER stress promotes foam cell formation

Methods

Results

Conclusion