title: Purple perilla extracts allay ER stress in lipid-laden macrophages.
abstract: There is a growing body of evidence that excess lipids, hypoxic stress and other inflammatory signals can stimulate endoplasmic reticulum (ER) stress in metabolic diseases. However, the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. The current study investigated that 50 ng/ml oxidized LDL promoted unfolded protein response (UPR) and ER stress in J774A1 murine macrophages, which was blocked by extracts (PPE) of purple Perilla frutescens, a plant of the mint family Lamiaceae. The ER stressor tunicamycin was employed as a positive control. Treating 1-10 µg/ml oxidized LDL for 24 h elicited lipotoxic apoptosis in macrophages with obvious nuclear condensation and DNA fragmentation, which was inhibited by PPE. Tunicamycin and oxidized LDL activated and induced the UPR components of activating transcription factor 6 and ER resident chaperone BiP/Grp78 in temporal manners and such effects were blocked by ≥5 µg/ml PPE. In addition, PPE suppressed the enhanced mRNA transcription and splicing of X-box binding protein 1 (XBP1) by tunicamycin and oxidized LDL. The protein induction and nuclear translocation of XBP1 were deterred in PPE-treated macrophages under ER stress. The induction of ATP-binding cassette transporter A1 (ABCA1), scavenger receptor-B1 (SR-B1) and intracellular adhesion molecule-1 (ICAM-1) was abolished by the ER stressor in activated macrophages. The protein induction of ABCA1 and ICAM1 but not SR-B1 was retrieved by adding 10 µg/ml PPE to cells. These results demonstrate that PPE inhibited lipotoxic apoptosis and demoted the induction and activation of UPR components in macrophages. PPE restored normal proteostasis in activated macrophages oxidized LDL. Therefore, PPE was a potent agent antagonizing macrophage ER stress due to lipotoxic signals associated with atherosclerosis.
authors.affiliation: Department of Food science and Nutrition, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.
authors.forename: Sin-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Food science and Nutrition, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.
authors.forename: Daekeun
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Food science and Nutrition, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.
authors.forename: Soon Sung
authors.initials: SS
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Food science and Nutrition, Hallym University, Chuncheon, Kangwon-do, Republic of Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000096:biosynthesis; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D031343:Perilla / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D017510:Protein Folding; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008077:Lipoproteins, LDL; D010936:Plant Extracts; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C099252:oxidized low density lipoprotein