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LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis.

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机构： [1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China. [2]Human Phenome Institute and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P. R. China. [3]Division of Rheumatology, Huashan hospital, Fudan University, Shanghai, P. R. China. [4]MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China. [5]Institute for Six-sector Economy, Fudan University, Shanghai, P. R. China. [6]Division of Rheumatology, Shanghai TCM-Integrated Hospital, Shanghai, P. R. China. [7]The Clinical Laboratory of Tongren Hosipital, Shanghai Jiaotong University, Shanghai, P. R. China. [8]Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, P. R. China. [9]Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Nuremberg, Germany. [10]Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, P. R. China. [11]Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, P. R. China. [12]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. [13]Rheumatology and Immunology Department, Peking University Shenzhen Hospital, Shenzhen, P. R. China. [14]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. [15]School of Medicine, Tsinghua University, Beijing, P. R. China. [16]Department of Rheumatology and Immunology, Yiling Hospital Affiliated to Hebei Medical University, Shijiazhuang, Hebei Province, P. R. China. [17]Department of Nephrology, Zhongshan Hospital, Fudan University, Fudan Zhangjiang Institute, Shanghai, P. R. China. [18]Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, P. R. China. [19]Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, P. R. China. [20]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, P. R. China.

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关键词： apoptosis combination treatment LDL LDLR pulmonary fibrosis

摘要：

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.© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

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出版当年[2021]版：

大类 | 2 区医学

小类 | 2 区医学：研究与实验 3 区肿瘤学

最新[2025]版：

大类 | 2 区

医学

小类 | 2 区医学：研究与实验 2 区肿瘤学

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出版当年[2020]版：

Q1 ONCOLOGY Q1 MEDICINE, RESEARCH & EXPERIMENTAL

最新[2023]版：

Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q1 ONCOLOGY

影响因子： 7.9 最新[2023版] 8 最新五年平均 11.492 出版当年[2020版] 8.601 出版当年五年平均 7.919 出版前一年[2019版] 8.554 出版后一年[2021版]

第一作者：

第一作者机构： [1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.

通讯作者：

通讯机构： [1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China. [2]Human Phenome Institute and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P. R. China. [18]Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, P. R. China. [20]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, P. R. China. [*1]Department ofDermatology, HuashanHospital, and StateKey Laboratory of GeneticEngineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.

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LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis.

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