Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction

Abstract

Background Obesity has been identified as a risk factor for acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the underlying mechanisms remain elusive. This study aimed to investigate the role of fatty acid synthase (FASN) in lipopolysaccharide (LPS)-induced ALI under obesity. Methods A high-fat diet-induced obese (DIO) mouse model was established and lean mice fed with regular chow diet were served as controls. LPS was intratracheally instilled to reproduce ALI in mice. In vitro, primary mouse lung endothelial cells (MLECs), treated by palmitic acid (PA) or co-cultured with 3T3-L1 adipocytes, were exposed to LPS. Chemical inhibitor C75 or shRNA targeting FASN was used for in vivo and in vitro loss-of-function studies for FASN. Results After LPS instillation, the protein levels of FASN in freshly isolated lung endothelial cells from DIO mice were significantly higher than those from lean mice. MLECs undergoing metabolic stress exhibited increased levels of FASN, decreased levels of VE-cadherin with increased p38 MAPK phosphorylation and NLRP3 expression, mitochondrial dysfunction, and impaired endothelial barrier compared with the control MLECs when exposed to LPS. However, these effects were attenuated by FASN inhibition with C75 or corresponding shRNA. In vivo, LPS-induced ALI, C75 pretreatment remarkably alleviated LPS-induced overproduction of lung inflammatory cytokines TNF-α, IL-6, and IL-1β, and lung vascular hyperpermeability in DIO mice as evidenced by increased VE-cadherin expression in lung endothelial cells and decreased lung vascular leakage. Conclusions Taken together, FASN inhibition alleviated the exacerbation of LPS-induced lung injury under obesity via rescuing lung endothelial dysfunction. Therefore, targeting FASN may be a potential therapeutic target for ameliorating LPS-induced ALI in obese individuals.

The role of fatty acid metabolism in acute lung injury: a special focus on immunometabolism

“…The expression of FASN in pulmonary endothelial cells is up-regulated in LPS-induced ALI mice [ 108 ]. Endothelial dysfunction occurs in the early stage of acute lung injury and plays a pivotal role in its pathogenesis.…”

“…The integrity of the microvascular barrier relies on adherens junction protein located in cell–cell boundaries, while FASN is a key mediator of functional alterations in pulmonary endothelial cells under endotoxin-induced metabolic stress. By activating the p38 MAPK/NLRP3 signaling cascade, FASN inhibits VE-cadherin expression and promotes pulmonary vascular leakage in response to endotoxin stress [ 108 ], while inhibition of FASN facilitated the repairment of pulmonary endothelial cell barrier integrity under metabolic stress, as evidenced by the upregulation of VE-cadherin expression, enhanced trans endothelial electrical resistance (TEER), and reduced permeability following endotoxin stimulation. The palmitoylation process of endothelial nitric oxide synthase relies on FASN activity, which plays a maintaining endothelial function by facilitating eNOS targeting to the plasma membrane [ 109 ].…”

“…Moreover, FASN is up-regulated in pulmonary endothelial cells of LPS-induced ALI mice, which is further enhanced by obesity. Inhibition of FASN in obese mice effectively restores the loss of VE-cadherin in pulmonary endothelial cells and exerted a beneficial effect on reducing pulmonary vascular leakage during ALI [ 108 ]. Conversely, high-fat diet results in the down-regulation of FASN expression in AECs, which is associated with impaired mitochondrial metabolic capacity under stress and more severe lung injury [ 107 ].…”