Role of Hyaluronic Acid on Apolipoprotein A1 and HDL-Mediated Cholesterol Efflux in Macrophages

Abstract

Diabetic macroangiopathy are characterized by increased arterial stiffness and hyaluronic acid (HA) deposition in the large elastic arteries. It is noteworthy that systemic inhibition of HA synthesis by 4-methylumbelliferone interferes with the protective function of the endothelial glycocalyx, thereby facilitating leukocyte adhesion, inflammation, and progression of atherosclerosis. Apolipoprotein A1 (ApoA1) and High-density lipoprotein (HDL) mediates cholesterol efflux, which is the initial and rate-limiting step of reverse cholesterol transport preventing from atherosclerosis. The aim of the present study was to investigate the role of HA on ApoA1 and HDL-mediated cholesterol efflux in macrophages. Murine J774.1 macrophages and human THP-1 macrophages were labeled with 3H-cholesterol and incubated with ApoA1 (10 μg/ml) for 24 hours or HDL (50 μg/ml) for 4 hours. The percentage cholesterol efflux was calculated by dividing the media-derived radioactivity by the sum of the radioactivity in the media and the cells. The effect of HA on the cholesterol efflux was studied, adding that into the medium before the analysis of the cholesterol efflux. Under the existence of medium molecular weight HA (75-350 kDa), the HDL-mediated cholesterol efflux had significantly increased by 10.9% (n=4, p<0.01) in J774.1 macrophages. We also researched the relationship between HA and ATP-binding cassette transporter G1 (ABCG1), because expression of ABCG1 enhances cholesterol efflux to HDL. Predictably, HA significantly increased ABCG1 mRNA expression in macrophage (n=4, p<0.01), determined by Real-time Quantitative RT-PCR. These data suggest that HA increases HDL-mediated cholesterol efflux via ABCG1 in macrophages and the difference of molecular weight on HA may influence ApoA1 and HDL-mediated cholesterol efflux. The relationship between HA and cholesterol efflux might be one of the important mechanisms to prevent progression of atherosclerosis and diabetic macroangiopathy. Disclosure K. Matsuki: None. M. Ogura: None. M. Harada-Shiba: Advisory Panel; Self; Aegerion Pharmaceuticals. Speaker's Bureau; Self; Amgen Inc., Astellas Pharma US, Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Daiichi Sankyo Company, Limited, MSD K.K.. Research Support; Self; Sanofi, Aegerion Pharmaceuticals, Kowa Pharmaceuticals America, Inc..