CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXR\u03b1 pathway

Jiao-Jiao Chen,Gang Wang,Wen-Yi Deng,Shan-Hui Yin,Xiao-Hua Yu,Kun Ren

doi:10.1038/s41419-021-03544-8

Abstract

C1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

Highlights

Atherosclerosis, the pathological basis of most cardiovascular disease, is a chronic vascular inflammatory disease characterized by dysregulated lipid homeostasis[1]
We demonstrated for the first time that C1q tumor necrosis factor-related protein 12 (CTRP12) mitigates atherosclerosis by promoting ATP binding cassette transporter A1 (ABCA1)/ABCG1-dependent cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/ liver X receptor α (LXRα) signaling pathway, thereby providing a novel target for the prevention and treatment of atherosclerotic cardiovascular disease
In comparison with unloaded cells, THP-1 macrophagederived foam cells displayed a significant increase in intracellular total cholesterol (TC), free cholesterol (FC), CE, and TG contents, and this increase was attenuated by LV-CTRP12 treatment (Fig. 1B, C)

Summary

Introduction

Atherosclerosis, the pathological basis of most cardiovascular disease, is a chronic vascular inflammatory disease characterized by dysregulated lipid homeostasis[1]. As a major cell type in the atherosclerotic lesions, macrophages play a central role in the occurrence and development of atherosclerosis. Official journal of the Cell Death Differentiation Association. ABCA1 and ABCG1 are regulated by a variety of bioactive molecules. Liver X receptor α (LXRα, encoded by the NR1H3 gene), a nuclear hormone receptor, is thought to be the most important transcription factor to induce ABCA1 and ABCG1 expression[9]. We and others previously reported that administration of leonurine, kuwanon G or dihydromyricetin inhibits lipid accumulation in THP-1 macrophages and protects against atherosclerosis in mice by activating the LXRα-ABCA1/ ABCG1 signaling pathways[10,11,12]. In addition to its role in the regulation of lipid metabolism, activation of LXRα can suppress inflammatory signaling in macrophages[13]

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