LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis

Shi X, Chen Y, Liu Q, Mei X, Liu J, Tang Y, Luo R, Sun D, Ma Y, Wu W, Tu W, Zhao Y, Xu W, Ke Y, Jiang S, Huang Y, Zhang R, Wang L, Chen Y, Xia J, Pu W, Zhu H, Zuo X, Li Y, Xu J, Gao F, Wei D, Chen J, Yin W, Wang Q, Dai H, Yang L, Guo G, Cui J, Song N, Zou H, Zhao S, Distler J, Jin L, Wang J (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Clinical and Translational Medicine Wiley

Book Volume: 12

Journal Issue: 1

DOI: 10.1002/ctm2.711

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-beta 1 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.

Authors with CRIS profile

Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Involved external institutions

Peking University (PKU) / 北京大学 CN China (CN) Shanghai University of Traditional Chinese Medicine (SHUTCM) / 上海中医药大学 CN China (CN) Fudan University / 复旦大学 CN China (CN) Huashan Hospital CN China (CN) Chinese Academy of Medical Sciences (CAMS) CN China (CN) Guangzhou Medical University (GMU) / 广州医科大学 CN China (CN) Nanjing Medical University / 南京医科大学 CN China (CN) Hebei Medical University / 河北医科大学 CN China (CN) Shanghai Jiao Tong University / 上海交通大学 CN China (CN) Central South University CN China (CN) Xiangya Hospital Central South University / 中南大学湘雅医院 CN China (CN) Zhejiang University CN China (CN)

How to cite

APA:

Shi, X., Chen, Y., Liu, Q., Mei, X., Liu, J., Tang, Y.,... Wang, J. (2022). LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis. Clinical and Translational Medicine, 12(1). https://doi.org/10.1002/ctm2.711

MLA:

Shi, Xiangguang, et al. "LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis." Clinical and Translational Medicine 12.1 (2022).

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