title: Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages.
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.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1 Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ishiyama
authors.forename: Ryoko
authors.initials: R
authors.lastname: Taguchi
authors.forename: Yunike
authors.initials: Y
authors.lastname: Akasaka
authors.forename: Saiko
authors.initials: S
authors.lastname: Shibata
authors.forename: Minoru
authors.initials: M
authors.lastname: Ito
authors.forename: Michiaki
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D019308:Palmitic Acid / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051131:Receptors, Oxidized LDL / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D005231:Fatty Acids, Unsaturated; D010654:Phenylbutyrates; D034741:RNA, Small Interfering; D051131:Receptors, Oxidized LDL; D019308:Palmitic Acid; D019284:Thapsigargin; C075773:4-phenylbutyric acid