Circulating Levels of CILP2 Are Elevated in Coronary Heart Disease and Associated with Atherosclerosis.

Wenjing Hu,Yongsheng Liu,Mengliu Yang,Shangcheng Xu,Shan Geng,Hua Liu,Baoyong Zhou,Ke Li,Xiaoyun Fan,Gangyi Yang,Hongdong Han,Jos P Andrade

doi:10.1155/2020/1871984

Abstract

Methods and Results Circulating CILP2 levels (measured by ELISA) were compared to various insulin resistance- and atherosclerosis-related parameters in normal subjects and newly diagnosed CHD patients. THP-1 cells were cultured and treated with indicated stimulators. Western blots and RT-PCR were performed to examine protein and mRNA expressions. The results showed that there were significantly higher circulating CILP2 levels in CHD patients relative to healthy controls. Circulating CILP2 correlated positively with waist-hip ratio (WHR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HbA1c, homeostasis model assessment of insulin resistance (HOMA-IR), and Gensini scores. In an in vitro study, we found that CILP2 increased oxidatively modified LDL-stimulated lipid accumulation in THP-1 macrophages via the upregulation of CD36 expression. Inhibition of PPARγ signaling eliminated the CILP2 regulation of CD36 expression in THP-1 macrophages. CILP2 positively regulated CD36 transcription through PPARγ-mediated action on two peroxisome-proliferator-responsive elements (PPREs) binding sites of CD36 promoter, PPRE-G, and PPRE-J. Conclusions Our findings have uncovered a novel role for CILP2 in lipid uptake and foam cell formation. This role is mediated by CD36 through the activation of PPARγ pathway.

Highlights

Coronary heart disease (CHD) is a complex disease caused by multiple factors, including heredity and environment
We found that circulating cartilage intermediate layer protein 2 (CILP2) levels had a progressive increase from normal to impaired glucose tolerance (IGT) and to diabetes, which was correlated with insulin resistance (IR) and obesity [10]
Site-directed mutation in two peroxisome-proliferator-responsive elements (PPREs) binding sites (-120 to 108 bp for PPRE-J and -245 bp to -233 bp for PPRE-G,) resulted in the significant decrease of CILP2-induced CD36 transcriptional activity (Figure 5(c)). These results showed that PPRE-G and PPRE-J binding sites were necessary for the CILP2 regulation of CD36 promoter activity

Summary

Introduction

Coronary heart disease (CHD) is a complex disease caused by multiple factors, including heredity and environment. Genome-wide association studies (GWAS) of different races have identified more than 30 loci associated with CHD [1]. One of these newly identified single nucleotide polymorphisms (SNPs) is rs16996148 SNP in the NCAN/cartilage intermediate layer protein 2 (CILP2)/PBX4. The CILP2 expression was found in skeletal muscle and the myocardium. We reported that CILP2 was a secreted protein that existed in circulating blood in humans and animals [10]. To further understand the relationship between CILP2 and cholesterol metabolism and atherosclerosis, we reported serum CILP2 concentrations in CHD patients and normal adults. We identified a direct interaction between CILP2 and CD36 in the regulation of cholesterol metabolism

Materials and Methods

Results

Discussion

Conflicts of Interest