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 und...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-03-01
|
| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02382-w |
| _version_ | 1827983039786909696 |
|---|---|
| author | Zhuhua Wu Li Zhu Xinran Nie Yingli Liu Xiaoju Zhang Yong Qi |
| author_facet | Zhuhua Wu Li Zhu Xinran Nie Yingli Liu Xiaoju Zhang Yong Qi |
| author_sort | Zhuhua Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T22:41:21Z |
| format | Article |
| id | doaj.art-38962a313bc844d98f92cc573d5d7661 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-09T22:41:21Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-38962a313bc844d98f92cc573d5d76612023-03-22T12:07:50ZengBMCRespiratory Research1465-993X2023-03-0124111810.1186/s12931-023-02382-wInhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunctionZhuhua Wu0Li Zhu1Xinran Nie2Yingli Liu3Xiaoju Zhang4Yong Qi5Department of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalAbstract 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.https://doi.org/10.1186/s12931-023-02382-wObesityFatty acid synthaseAcute lung injuryEndothelial cellsVE-cadherin |
| spellingShingle | Zhuhua Wu Li Zhu Xinran Nie Yingli Liu Xiaoju Zhang Yong Qi Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction Respiratory Research Obesity Fatty acid synthase Acute lung injury Endothelial cells VE-cadherin |
| title | Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| title_full | Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| title_fullStr | Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| title_full_unstemmed | Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| title_short | Inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| title_sort | inhibition of fatty acid synthase protects obese mice from acute lung injury via ameliorating lung endothelial dysfunction |
| topic | Obesity Fatty acid synthase Acute lung injury Endothelial cells VE-cadherin |
| url | https://doi.org/10.1186/s12931-023-02382-w |
| work_keys_str_mv | AT zhuhuawu inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction AT lizhu inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction AT xinrannie inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction AT yingliliu inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction AT xiaojuzhang inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction AT yongqi inhibitionoffattyacidsynthaseprotectsobesemicefromacutelunginjuryviaamelioratinglungendothelialdysfunction |