LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis.

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.

Citation

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. LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis. Clinical and translational medicine. 2022 Jan;12(1):e711

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PMID: 35083881

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