Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

Abstract

Cholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXR) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood. Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXR) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXR and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK. Meanwhile, hesperetin-induced upregulation of LXR expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXR and its target genes, all which were depressed by AMPK1/2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXR and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.