Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1 Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
J Lipid Res. 2011 Feb;52(2):299-307. doi: 10.1194/jlr.M007104. Epub 2010 Nov 15.
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.
软脂酸 (PA) 上调了氧化型 LDL 受体-1（LOX-1），LOX-1 是一种负责摄取氧化型 LDL（oxLDL）的清道夫受体，并且增强了巨噬细胞对 oxLDL 的摄取。然而，确切的潜在机制仍有待阐明。PA 已知可诱导各种细胞类型的内质网（ER）应激。因此，我们研究了 ER 应激是否参与了 PA 诱导的 LOX-1 上调。PA 诱导了 ER 应激，这可通过 PERK、eIF2α 和 JNK 的磷酸化以及巨噬细胞样 THP-1 细胞中 CHOP 的诱导来确定。抑制剂[4-苯基丁酸（PBA）、牛磺熊脱氧胆酸钠（TUDCA）和 Salubrinal]和针对 ER 应激反应的小干扰 RNA（siRNA）降低了 PA 诱导的 LOX-1 上调。内质网应激诱导剂 thapsigargin 上调了 LOX-1，而 PBA 和 TUDCA 则降低了 LOX-1。接下来，我们研究了不饱和 FAs 是否可以抵消 PA 的作用。油酸（OA）和亚油酸（LA）均抑制了 PA 诱导的 LOX-1。当用 OA 或 LA 共处理用 PA 处理的细胞时，观察到的 PA 处理细胞中的 ER 应激反应明显减弱。此外，OA 和 LA 通过抑制 ER 应激标志物的激活来抑制 thapsigargin 诱导的 LOX-1 上调。我们的结果表明，ER 应激的激活参与了巨噬细胞中 PA 诱导的 LOX-1 上调，OA 和 LA 通过抑制 ER 应激来抑制 LOX-1 的诱导。
