LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis

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.

Evaluation of Therapeutic Agents for Idiopathic Pulmonary Fibrosis Based on Mendelian Analysis of Two Sample Sets: Potential Merits and Disadvantages of Utilization

“…Previous studies have found that reducing the content of lipoprotein in plasma can reduce oxidative stress, release of proin ammatory factors, and maintain the steady state of matrix metalloproteinases (MMP), thus alleviating the occurrence and development of pulmonary interstitial diseases. [10,11]. Ezetimibe, as a lipid-lowering drug, can also prevent the occurrence and development of pulmonary brosis in our study.…”

Feeding foliar nano-selenium biofortified panax notoginseng could reduce the occurrence of glycolipid metabolism disorder in mice caused by high-fat diets

“…MCAD and LCAD catalyze the first step of fatty acid oxidation and determine the lipid used for the TCA cycle ( 38 , 39 ). Low-density lipoprotein receptor (LDLR) can bind to LDL and reduce LDL contents in serum ( 40 ). Subtilisin 9 ( PCSK9 ) can negatively regulate the expression of LDLR , resulting in hypercholesterolemia ( 41 ).…”

Targeted delivery of ZNF416 siRNA-loaded liposomes attenuates experimental pulmonary fibrosis

“…Pulmonary fibrosis is an advanced interstitial lung disease characterized by excessive ECM deposition with poor prognosis [ 15 , 16 ], including silicosis and IPF. Despite the current approved two antifibrotic medicine (nintedanib and pirfenidone) having been shown to reduce lung function decline, there is not enough to postpone fibrosis [ 17 ].…”