PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages.
PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages.
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DOI：
10.1371/journal.pone.0128546
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sunagawa K
中科院分区：
文献类型：
--
作者：
Ikeda J;Ichiki T;Takahara Y;Kojima H;Sankoda C;Kitamoto S;Tokunou T;Sunagawa K
临床试验表明，使用吡格列酮（一种过氧化物酶体增殖物激活受体 (PPAR)γ 激动剂）治疗 2 型糖尿病患者可减少心血管事件。然而，PPARγ激动剂对内质网（ER）应激的影响尚未确定，而内质网应激在动脉粥样硬化的进展中起着重要作用。我们试图确定 PPARγ 激动剂对棕榈酸（血清中最丰富的饱和脂肪酸）诱导的 ER 应激的影响。通过蛋白质印迹分析评估 ER 应激标记物的蛋白表达，并通过 qRT-PCR 评估硬脂酰辅酶 A 去饱和酶 1 (SCD-1) mRNA 表达。流式细胞术检测巨噬细胞凋亡。在小鼠巨噬细胞系 RAW264.7 中，吡格列酮和罗格列酮降低了棕榈酸盐诱导的 PERK 磷酸化（ER 应激标志物）。吡格列酮还抑制棕榈酸诱导的细胞凋亡，这与抑制 CHOP 表达、JNK 磷酸化和 caspase-3 裂解有关。吡格列酮的这些作用被 PPARγ 拮抗剂 GW9662 逆转，表明 PPARγ 参与了这一过程。 PPARγ 激动剂增加 SCD-1 的表达，SCD-1 在长链脂肪酸的酰基链上引入双键。 4-(2-氯苯氧基)-N-(3-(3-甲基氨基甲酰基)苯基)哌啶-1-甲酰胺是一种 SCD-1 抑制剂，可消除吡格列酮的抗 ER 应激和抗细胞凋亡作用。这些结果表明 PPARγ 激动剂通过 SCD-1 诱导减弱棕榈酸诱导的 ER 应激和细胞凋亡。 SCD-1 的上调可能有助于 PPARγ 激动剂治疗减少心血管事件。
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. 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.
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影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
7.7
作者：
Kurebayashi, S;Hirose, T;Kishimoto, T
通讯作者：
Kishimoto, T
影响因子：
2
作者：
Yoshiuchi, Kazutomi;Kaneto, Hideaki;Matsuhisa, Munehide
通讯作者：
Matsuhisa, Munehide
影响因子：
4.5
作者：
Quan, Jinxing;Liu, Jing;Wang, Baoli
通讯作者：
Wang, Baoli
影响因子：
64.5
作者：
Hotamisligil GS
通讯作者：
Hotamisligil GS