Ao Yichan, Ma Jingyue, Hou Xiangyu, Li Hongbin, Wang Zhiqiao, Wang Hanbing, He Jianyu, Luo Siqing, Duan Zikun, Liu Ling, Wei Ke
Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
Cell Mol Life Sci. 2025 Jun 19;82(1):242. doi: 10.1007/s00018-025-05706-9.
Obesity is an independent risk factor for acute respiratory distress syndrome (ARDS). However, the precise pathway through which obesity amplifies the severity of ARDS remains elusive. Our study embarked on a comprehensive analysis focusing on alterations in the proteomic and metabolomic landscapes of lung tissue extracted from high-fat diet (HFD) mice afflicted with lipopolysaccharide-induced lung injury. This approach was designed to shed light on the molecular mechanisms underlying the exacerbated pulmonary response in obesity-related ARDS. Bioinformatics analysis revealed that dysregulation of sphingolipid metabolism may be involved in the exacerbation of lung injury associated with obesity. Specifically, pulmonary ceramide transfer protein (CERT) expressions were reduced in patients with obesity and HFD mice, while Cer levels were increased. Similarly, co-culture with 3T3-L1 cells reduced CERT expression and increased ceramide (Cer) levels in MH-S cells. Furthermore, overexpression of CERT in vivo and in vitro enhanced Cer transport, leading to reduced Cer levels and, subsequently, a decrease in reactive oxygen species (ROS) production and inflammatory damage in mouse lung tissues and alveolar macrophages. Conversely, CERT knockdown yielded the opposite effect. Moreover, exogenous ceramide supplementation reversed these protective effects conferred by CERT overexpression. In vivo and in vitro studies indicated that obesity-induced downregulation of CERT reduced Cer transport, increased Cer levels, and aggravated ARDS through elevated ROS production and apoptosis. Taken together, these results highlight CERT may represent a promising therapeutic target for managing ARDS in individuals with obesity.
肥胖是急性呼吸窘迫综合征（ARDS）的独立危险因素。然而，肥胖加剧ARDS严重程度的确切途径仍不清楚。我们的研究对高脂饮食（HFD）诱导的脂多糖肺损伤小鼠肺组织的蛋白质组学和代谢组学变化进行了全面分析。该方法旨在揭示肥胖相关ARDS中肺部反应加剧的分子机制。生物信息学分析表明，鞘脂代谢失调可能与肥胖相关的肺损伤加剧有关。具体而言，肥胖患者和HFD小鼠的肺神经酰胺转运蛋白（CERT）表达降低，而神经酰胺（Cer）水平升高。同样，与3T3-L1细胞共培养可降低MH-S细胞中CERT的表达并增加神经酰胺（Cer）水平。此外，体内和体外过表达CERT均可增强Cer转运，从而降低Cer水平，进而减少小鼠肺组织和肺泡巨噬细胞中的活性氧（ROS）产生和炎症损伤。相反，敲低CERT则产生相反的效果。此外，外源性神经酰胺补充可逆转CERT过表达所赋予的这些保护作用。体内和体外研究表明，肥胖诱导的CERT下调会减少Cer转运，增加Cer水平，并通过升高ROS产生和细胞凋亡加重ARDS。综上所述，这些结果表明CERT可能是治疗肥胖患者ARDS的一个有前景的治疗靶点。
