title: PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages.
abstract: BACKGROUND
  Clinical trials have shown that treatment of patients with type 2 diabetes with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, reduces cardiovascular events. However, the effect of PPARγ agonists on endoplasmic reticulum (ER) stress that plays an important role in the progression of atherosclerosis has not been determined. We sought to determine the effect of PPARγ agonists on ER stress induced by palmitate, the most abundant saturated fatty acid in the serum.
  
  
  RESULTS
  Protein expression of ER stress marker was evaluated by Western blot analysis and stearoyl-CoA desaturase1 (SCD-1) mRNA expression was evaluated by qRT-PCR. Macrophage apoptosis was detected by flowcytometry. Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK, a marker of ER stress, in RAW264.7, a murine macrophage cell line. Pioglitazone also suppressed palmitate-induced apoptosis in association with inhibition of CHOP expression, JNK phosphorylation and cleavage of caspase-3. These effects of pioglitazone were reversed by GW9662, a PPARγ antagonist, indicating that PPARγ is involved in this process. PPARγ agonists increased expression of SCD-1 that introduces a double bond on the acyl chain of long-chain fatty acid. 4-(2-Chlorophenoxy)-N-(3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide, an inhibitor of SCD-1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone. These results suggest that PPARγ agonists attenuate palmitate-induced ER stress and apoptosis through SCD-1 induction. Up-regulation of SCD-1 may contribute to the reduction of cardiovascular events by treatment with PPARγ agonists.
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ikeda
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahara
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Chikahiro
authors.initials: C
authors.lastname: Sankoda
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Tomotake
authors.initials: T
authors.lastname: Tokunou
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D010168:Palmitates / Q000633:toxicity*; D000077205:Pioglitazone; D000077154:Rosiglitazone; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D047495:PPAR gamma; D010168:Palmitates; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D000077205:Pioglitazone