Palmitic Acid-Rich High-Fat Diet Exacerbates Experimental Pulmonary Fibrosis by Modulating Endoplasmic Reticulum Stress
Palmitic Acid-Rich High-Fat Diet Exacerbates Experimental Pulmonary Fibrosis by Modulating Endoplasmic Reticulum Stress
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DOI：
10.1165/rcmb.2018-0324oc
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发表时间：
2019-12-01
影响因子：
6.4
通讯作者：
Rosas, Ivan O.
中科院分区：
文献类型：
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作者：
Chu, Sarah G.;Villalba, Julian A.;Rosas, Ivan O.
脂毒性对肺纤维化发展的影响尚不清楚。饱和脂肪酸，如棕榈酸（PA），激活内质网（ER）应激，一种与特发性肺纤维化（IPF）发展相关的细胞应激反应。我们检验了PA通过调节ER应激增加肺上皮细胞死亡和实验性纤维化易感性的假设。采用全液相色谱法和质谱法测定IPF肺中的脂肪酸含量。给野生型小鼠喂食富含PA的高脂饮食（HFD）或标准饮食，并使其遭受博莱霉素诱导的肺损伤。以羟脯氨酸含量测定肺纤维化程度。用PA处理小鼠肺上皮细胞。Western blotting、TUNEL染色和细胞活力测定检测ER应激和细胞死亡。与对照组相比，IPF肺的PA水平较高。与喂食标准饮食的小鼠相比，喂食HFD的博莱霉素暴露小鼠的肺纤维化显著增加，与细胞死亡和ER应激增加相关。PA增加肺上皮细胞的凋亡和未折叠蛋白反应的激活。这是衰减的遗传缺失和化学抑制CD36，脂肪酸转运蛋白。总之，食用富含饱和脂肪的HFD增加了对肺纤维化和ER应激的易感性，PA通过CD36介导肺上皮细胞死亡和ER应激。这些发现表明，脂毒性可能通过增强促死亡ER应激途径对肺损伤和纤维化的发展产生显著影响。
The impact of lipotoxicity on the development of lung fibrosis is unclear. Saturated fatty acids, such as palmitic acid (PA), activate endoplasmic reticulum (ER) stress, a cellular stress response associated with the development of idiopathic pulmonary fibrosis (IPF). We tested the hypothesis that PA increases susceptibility to lung epithelial cell death and experimental fibrosis by modulating ER stress. Total liquid chromatography and mass spectrometry were used to measure fatty acid content in IPF lungs. Wild-type mice were fed a high-fat diet (HFD) rich in PA or a standard diet and subjected to bleomycin-induced lung injury. Lung fibrosis was determined by hydroxyproline content. Mouse lung epithelial cells were treated with PA. ER stress and cell death were assessed byWestern blotting, TUNEL staining, and cell viability assays. IPF lungs had a higher level of PA compared with controls. Bleomycin-exposed mice fed an HFD had significantly increased pulmonary fibrosis associated with increased cell death and ER stress compared with those fed a standard diet. PA increased apoptosis and activation of the unfolded protein response in lung epithelial cells. This was attenuated by genetic deletion and chemical inhibition of CD36, a fatty acid transporter. In conclusion, consumption of an HFD rich in saturated fat increases susceptibility to lung fibrosis and ER stress, and PA mediates lung epithelial cell death and ER stress via CD36. These findings demonstrate that lipotoxicity may have a significant impact on the development of lung injury and fibrosis by enhancing pro-death ER stress pathways.