Clinical and Translational Medicine (Jan 2022)
LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis
- Xiangguang Shi,
- Yahui Chen,
- Qingmei Liu,
- Xueqian Mei,
- Jing Liu,
- Yulong Tang,
- Ruoyu Luo,
- Dayan Sun,
- Yanyun Ma,
- Wenyu Wu,
- Wenzhen Tu,
- Yinhuan Zhao,
- Weihong Xu,
- Yuehai Ke,
- Shuai Jiang,
- Yan Huang,
- Rui Zhang,
- Lei Wang,
- Yuanyuan Chen,
- Jingjing Xia,
- Weilin Pu,
- Honglin Zhu,
- Xiaoxia Zuo,
- Yisha Li,
- Jinhua Xu,
- Fei Gao,
- Dong Wei,
- Jingyu Chen,
- Wenguang Yin,
- Qingwen Wang,
- Huaping Dai,
- Libing Yang,
- Gang Guo,
- Jimin Cui,
- Nana Song,
- Hejian Zou,
- Shimin Zhao,
- Jörg H.W. Distler,
- Li Jin,
- Jiucun Wang
Affiliations
- Xiangguang Shi
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Yahui Chen
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Qingmei Liu
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Xueqian Mei
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Jing Liu
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Yulong Tang
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Ruoyu Luo
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Dayan Sun
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Yanyun Ma
- MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences Fudan University Shanghai P. R. China
- Wenyu Wu
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Wenzhen Tu
- Division of Rheumatology Shanghai TCM‐Integrated Hospital Shanghai P. R. China
- Yinhuan Zhao
- Division of Rheumatology Shanghai TCM‐Integrated Hospital Shanghai P. R. China
- Weihong Xu
- The Clinical Laboratory of Tongren Hosipital Shanghai Jiaotong University Shanghai P. R. China
- Yuehai Ke
- Department of Pathology and Pathophysiology Zhejiang University School of Medicine Hangzhou Zhejiang Province P. R. China
- Shuai Jiang
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Yan Huang
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Rui Zhang
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Lei Wang
- Division of Rheumatology Shanghai TCM‐Integrated Hospital Shanghai P. R. China
- Yuanyuan Chen
- Division of Rheumatology Shanghai TCM‐Integrated Hospital Shanghai P. R. China
- Jingjing Xia
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Weilin Pu
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Honglin Zhu
- Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen Nuremberg Germany
- Xiaoxia Zuo
- Department of Rheumatology, Xiangya Hospital Central South University Changsha Hunan Province P. R. China
- Yisha Li
- Department of Rheumatology, Xiangya Hospital Central South University Changsha Hunan Province P. R. China
- Jinhua Xu
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- Fei Gao
- Wuxi Lung Transplant Center Wuxi People's Hospital affiliated to Nanjing Medical University Wuxi P. R. China
- Dong Wei
- Wuxi Lung Transplant Center Wuxi People's Hospital affiliated to Nanjing Medical University Wuxi P. R. China
- Jingyu Chen
- Wuxi Lung Transplant Center Wuxi People's Hospital affiliated to Nanjing Medical University Wuxi P. R. China
- Wenguang Yin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong P. R. China
- Qingwen Wang
- Rheumatology and Immunology Department Peking University Shenzhen Hospital Shenzhen P. R. China
- Huaping Dai
- Department of Pulmonary and Critical Care Medicine, China‐Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine Chinese Academy of Medical Science Beijing P. R. China
- Libing Yang
- Department of Pulmonary and Critical Care Medicine, China‐Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine Chinese Academy of Medical Science Beijing P. R. China
- Gang Guo
- Department of Rheumatology and Immunology Yiling Hospital Affiliated to Hebei Medical University Shijiazhuang Hebei Province P. R. China
- Jimin Cui
- Department of Rheumatology and Immunology Yiling Hospital Affiliated to Hebei Medical University Shijiazhuang Hebei Province P. R. China
- Nana Song
- Department of Nephrology, Zhongshan Hospital, Fudan University Fudan Zhangjiang Institute Shanghai P. R. China
- Hejian Zou
- Division of Rheumatology Huashan hospital, Fudan University Shanghai P. R. China
- Shimin Zhao
- Institute of Metabolism and Integrative Biology Fudan University Shanghai P. R. China
- Jörg H.W. Distler
- Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen Nuremberg Germany
- Li Jin
- Human Phenome Institute and Collaborative Innovation Center for Genetics and Development Fudan University Shanghai P. R. China
- Jiucun Wang
- Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences Fudan University Shanghai P. R. China
- DOI
- https://doi.org/10.1002/ctm2.711
- Journal volume & issue
-
Vol. 12,
no. 1
pp. n/a – n/a
Abstract
Abstract Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low‐density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis‐related PF (SSc‐PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low‐density lipoprotein (LDL) increased in SSc‐PF and IPF patients. The disrupted LDL–LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr‐deficient (Ldlr−/−) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast‐like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild‐type mice. In vitro experiments revealed that apoptosis and TGF‐β1 production were induced by LDL, while fibroblast‐like cell accumulation and ET‐1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL‐pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL–LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM‐induced LDL elevation, apoptosis, fibroblast‐like cell accumulation and mitigated PF in mice. Therefore, LDL–LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.
Keywords
