LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis

Clin Transl Med. 2022 Jan;12(1):e711. doi: 10.1002/ctm2.711.


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: LDL; LDLR; apoptosis; combination treatment; pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Lipoproteins, LDL / drug effects
  • Lipoproteins, LDL / genetics*
  • Mice
  • Mice, Inbred C57BL / genetics
  • Mice, Inbred C57BL / metabolism
  • Pulmonary Fibrosis / etiology*
  • Pulmonary Fibrosis / genetics
  • Receptors, LDL / metabolism*


  • LDLR protein, human
  • Lipoproteins, LDL
  • Receptors, LDL