Increased expression of ATP-binding cassette transporter A1 (ABCA1) as a possible mechanism for the protective effect of cilostazol against hepatic steatosis

Abstract

ATP-binding cassette transporter A1 (ABCA1), a membrane protein that mediates the transport of cellular cholesterol and phospholipid to lipid-deficient apolipoproteins, is known to play a critical role in the regulation of intracellular cholesterol levels in hepatocytes. In this study, we investigated the effect of cilostazol, a selective inhibitor of phophodiesterase 3 (PDE3), on the expression and function of hepatic ABCA1. Human hepatocarcinoma (HepG2) cell lines were treated with various concentrations of cilostazol. In addition, male C57BL/6 mice were used as a high fat-induced dyslipidemia and fatty liver model and administered cilostazol (30 mg/kg) for nine weeks. The expression and function of ABCA1 in HepG2 cells and liver samples of the mice were analyzed. ABCA1 protein expression increased in HepG2 cells following cilostazol treatment but was lower at a cilostazol concentration of 100 μM than at 30 μM. In addition, cilostazol (30 μM) treatment recovered ABCA1 expression reduced by palmitate. Cilostazol ameliorated lipid accumulation induced by 300 μM palmitate, and this effect was abolished when ABCA1 was silenced by small interference RNA (siRNA) knockdown. Plasma cholesterol level was greater in high-fat diet mice compared to chow diet mice and was slightly lowered with cilostazol treatment. Hepatic ABCA1 was enhanced in mice treated with cilostazol compared to high fat-diet mice. Taken together, our findings indicate that ABCA1 is a novel regulator of lipid metabolism that is increased by cilostazol in HepG2 cells and the liver. Enhancing ABCA1 expression with cilostazol represents a potential therapeutic avenue for treatment of hepatic steatosis.