CCN family member 1 deregulates cholesterol metabolism and aggravates atherosclerosis
Journal
Acta Physiologica
Journal Volume
225
Journal Issue
3
Pages
e13209
Date Issued
2019
Author(s)
Abstract
Aim: CCN family member 1 (CCN1) is an extracellular matrix cytokine and appears in atherosclerotic lesions. However, we have no evidence to support the role of CCN1 in regulating cholesterol metabolism and atherosclerosis. Methods: Apolipoprotein E-deficient (apoE ?/? ) mice were used as in vivo model. Oxidized low-density lipoprotein (oxLDL)-induced macrophage-foam cells were used as in vitro model. RT-PCR and western blot analysis were used for evaluating gene and protein expression, respectively. Conventional assay kits were used for assessing the levels of cholesterol, triglycerides, and cytokines. Results: We show predominant expression of CCN1 in foamy macrophages in atherosclerotic aortas of apoE ?/? mice. In apoE ?/? mice, CCN1 treatment worsened hyperlipidaemia, systemic inflammation, and the progression of atherosclerosis. In addition, CCN1 decreased the capacity of reverse cholesterol transport and downregulated the protein expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in atherosclerotic aortas. Notably, CCN1 decreased the protein expression of cholesterol clearance-related proteins, including ABCG5, ABCG8, liver X receptor α (LXRα), cholesterol 7α-hydrolase and LDL receptor in liver, and exacerbated hepatic lipid accumulation. In macrophages, treatment with oxLDL increased CCN1 expression. Inhibition of CCN1 activity by neutralizing antibody or small interfering RNA attenuated the oxLDL-induced lipid accumulation. In contrast, cotreatment with CCN1 or overexpression of CCN1 augmented oxLDL-induced lipid accumulation by impairing apolipoprotein AI- and high-density lipoprotein-dependent cholesterol efflux, which was attributed to downregulation of LXRα-dependent expression of ABCA1 and ABCG1. Conclusion: Our findings suggest that CCN1 plays a pivotal role in regulating cholesterol metabolism and the development of atherosclerosis. ? 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd
Subjects
atherosclerosis; CCN1; cholesterol metabolism; hepatosteatosis; inflammation
SDGs
Other Subjects
ABC transporter A1; ABC transporter G1; ABC transporter G5; ABC transporter G8; apolipoprotein E; ccn family member 1; CCN protein; cholesterol 7alpha monooxygenase; high density lipoprotein cholesterol; liver X receptor alpha; low density lipoprotein receptor; neutralizing antibody; oxidized low density lipoprotein; recombinant cytokine; small interfering RNA; unclassified drug; ABC transporter A1; ABCA1 protein, human; ABCG1 protein, human; apolipoprotein E; cholesterol; cysteine rich protein 61; animal cell; animal experiment; animal model; animal tissue; Article; atherosclerosis; cholesterol level; cholesterol metabolism; disease course; down regulation; foam cell; gene expression; hyperlipidemia; in vitro study; in vivo study; lipid storage; macrophage; male; mouse; nonhuman; priority journal; protein expression; regulatory mechanism; reverse transcription polymerase chain reaction; triacylglycerol level; Western blotting; animal; atherosclerosis; cytology; genetics; human; knockout mouse; lipid metabolism; metabolism; Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; Cholesterol; Cysteine-Rich Protein 61; Foam Cells; Humans; Lipid Metabolism; Macrophages; Mice, Knockout
Publisher
Blackwell Publishing Ltd
Type
journal article