Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling
Abstract Background Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial...
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.902 |
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| author | Liyang Li Yifei Liu Xuanqi Liu Nannan Zheng Yutong Gu Yuanlin Song Xiangdong Wang |
| author_facet | Liyang Li Yifei Liu Xuanqi Liu Nannan Zheng Yutong Gu Yuanlin Song Xiangdong Wang |
| author_sort | Liyang Li |
| collection | DOAJ |
| description | Abstract Background Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. Methods Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR. Results We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. Conclusions Our data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes. |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-12T17:10:48Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-b16f00e4921d4815ad8d335ed3c424ad2022-12-22T00:17:53ZengWileyClinical and Translational Medicine2001-13262022-06-01126n/an/a10.1002/ctm2.902Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signallingLiyang Li0Yifei Liu1Xuanqi Liu2Nannan Zheng3Yutong Gu4Yuanlin Song5Xiangdong Wang6Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital Fudan University Shanghai Medical College Shanghai ChinaCenter of Molecular Diagnosis and Therapy The Second Hospital of Fujian Medical University Quanzhou Fujian ChinaShanghai Institute of Clinical Bioinformatics Shanghai ChinaDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital Fudan University Shanghai Medical College Shanghai ChinaDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital Fudan University Shanghai Medical College Shanghai ChinaDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital Fudan University Shanghai Medical College Shanghai ChinaDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital Fudan University Shanghai Medical College Shanghai ChinaAbstract Background Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. Methods Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR. Results We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. Conclusions Our data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.https://doi.org/10.1002/ctm2.902airway epitheliacholesterolCOPDMFN2mitochondriaSTARD3 |
| spellingShingle | Liyang Li Yifei Liu Xuanqi Liu Nannan Zheng Yutong Gu Yuanlin Song Xiangdong Wang Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling Clinical and Translational Medicine airway epithelia cholesterol COPD MFN2 mitochondria STARD3 |
| title | Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling |
| title_full | Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling |
| title_fullStr | Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling |
| title_full_unstemmed | Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling |
| title_short | Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling |
| title_sort | regulatory roles of external cholesterol in human airway epithelial mitochondrial function through stard3 signalling |
| topic | airway epithelia cholesterol COPD MFN2 mitochondria STARD3 |
| url | https://doi.org/10.1002/ctm2.902 |
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