Acceleration of HDL-mediated cellular cholesterol efflux alleviates periodontitis

ABSTRACT Periodontitis (PD) is a common inflammatory disease known to be closely associated with metabolic disorders, particularly hyperlipidemia. However, direct evidence is lacking, and the molecular mechanism is yet to be examined. In the current study, we demonstrated that hypercholesterolemia is a causative factor in the development of PD. Logistic regression analysis revealed a strong positive correlation between PD and dyslipidemia. Data from in vivo (PD mouse model subjected to a high cholesterol diet) and in vitro (cholesterol treatment of periodontal cells) experiments showed that excess cholesterol influx into periodontal cells potentially contributes to periodontal inflammation and subsequently, alveolar bone erosion. Additionally, we compared the protective efficacies of cholesterol-lowering drugs with their different modes of action against PD pathogenesis in mice. Among the cholesterol-lowering drugs we tested, fenofibrate exerted the most protective effect against PD pathogenesis, due to an increased level of high-density lipoprotein cholesterol, a lipoprotein involved in cholesterol efflux from cells and reverse cholesterol transport. Indeed, cholesterol efflux was suppressed during PD progression by downregulation of the apoA-I binding protein (APOA1BP) expression in inflamed gingival fibroblasts and periodontal ligament cells. We also demonstrated that the overexpression of APOA1BP efficiently regulated periodontal inflammation and the subsequent alveolar bone loss by inducing cholesterol efflux. Our collective findings highlight the potential utility of currently available cholesterol-lowering medications for the mitigation of PD pathogenesis. By targeting the acceleration of high-density lipoprotein (HDL)-mediated cellular cholesterol efflux, a new therapeutic approach for PD may become possible.