Obesity promotes ARDS by modulating ceramide transfer protein-ceramide pathway and exacerbating oxidative stress/apoptosis in alveolar macrophages

作者：Yichan Ao, Jingyue Ma, Xiang‐Yu Hou, Hongbin Li, Zhiqiao Wang, Hanbing Wang, Jianyu He, Siqing Luo, Zikun Duan, Ling Liu, Ke Wei · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05706-9 · 被引用次数：4 · 研究领域：Sphingolipid Metabolism and Signaling、Respiratory Support and Mechanisms、Immune cells in cancer

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 trans...