激活PPARγ通过抑制内质网应激和促进线粒体生物发生保护肥胖小鼠急性肺损伤。

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL PPAR Research Pub Date : 2022-09-28 eCollection Date: 2022-01-01 DOI:10.1155/2022/7888937
Yin Tang, Ke Wei, Ling Liu, Jingyue Ma, Siqi Wu, Wenjing Tang
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引用次数: 0

摘要

目的:肥胖引起的内质网应激与急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)易感性增加有关。过氧化物酶体增殖物激活受体-γ (PPARγ)的激活与肺保护有关,并可有效改善内质网应激和线粒体功能障碍。本研究旨在研究肥胖小鼠肺组织中PPARγ的表达,探讨PPARγ依赖通路是否通过调节内质网应激和线粒体生物发生介导ALI/ARDS的减少。方法:测定正常和肥胖小鼠肺组织中PPARγ的表达。使用肺泡上皮细胞和肥胖小鼠的ALI模型,并使用PPARγ激活剂罗格列酮(RSG)或PPARγ抑制剂GW9662治疗。收集肺组织和细胞样本,评估肺部炎症和凋亡,检测内质网应激和线粒体生物发生。结果:肥胖小鼠肺组织中PPARγ的表达明显低于正常小鼠。体内和体外研究均表明,激活PPARγ可导致内质网应激标记蛋白78-kDa葡萄糖调节蛋白(GRP78)、C/EBP同源蛋白(CHOP)和Caspase12的表达降低。相反,线粒体生物发生相关蛋白过氧化物酶体增殖物激活受体γ共激活因子1 (PGC-1α)、核呼吸因子-1 (NRF-1)和线粒体转录因子A (TFAM)的表达增加。此外,PPARγ的激活与肺炎症和上皮细胞凋亡水平的降低以及脂联素(APN)和丝裂酶2 (MFN2)表达的增加有关。GW9662与PPARγ结合,阻断其转录活性,降低PPARγ对肺组织的保护作用。结论:PPARγ激活通过减轻内质网应激和促进线粒体生物发生,在肺泡上皮中发挥抗炎作用。因此,肥胖小鼠肺组织中PPARγ水平降低可能导致ALI易感性增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Activation of PPARγ Protects Obese Mice from Acute Lung Injury by Inhibiting Endoplasmic Reticulum Stress and Promoting Mitochondrial Biogenesis.

Objective: Obesity-induced endoplasmic reticulum (ER) stress plays a role in increased susceptibility to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The activation of peroxisome proliferator-activated receptor-γ (PPARγ) is associated with lung protection and is effective in ameliorating ER stress and mitochondrial dysfunction. The aim of this study was to investigate the expression of PPARγ in the lung tissues of obese mice and explore whether the PPARγ-dependent pathway could mediate decreased ALI/ARDS by regulating ER stress and mitochondrial biogenesis.

Methods: We determined PPARγ expression in the lung tissues of normal and obese mice. ALI models of alveolar epithelial cells and of obese mice were used and treated with either PPARγ activator rosiglitazone (RSG) or PPARγ inhibitor GW9662. Lung tissue and cell samples were collected to assess lung inflammation and apoptosis, and ER stress and mitochondrial biogenesis were detected.

Results: PPARγ expression was significantly decreased in the lung tissue of obese mice compared with that in normal mice. Both in vivo and in vitro studies have shown that activation of PPARγ leads to reduced expression of the ER stress marker proteins 78-kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), and Caspase12. Conversely, expression of the mitochondrial biogenesis-related proteins peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) increased. Furthermore, activation of PPARγ is associated with decreased levels of lung inflammation and epithelial apoptosis and increased expression of adiponectin (APN) and mitofusin2 (MFN2). GW9662 bound to PPARγ and blocked its transcriptional activity and then diminished the protective effect of PPARγ on lung tissues.

Conclusions: PPARγ activation exerts anti-inflammation effects in alveolar epithelia by alleviating ER stress and promoting mitochondrial biogenesis. Therefore, lower levels of PPARγ in the lung tissues of obese mice may lead to an increased susceptibility to ALI.

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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
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