Astaxanthin Enhances ATP-Binding Cassette Transporter A1/G1 Expressions and Cholesterol Efflux from Macrophages

Abstract

Summary ATP-binding cassette transporters (ABC) A1 and G1 are key molecules in cholesterol efflux from macrophages, which is an initial step of reverse cholesterol transport (RCT), a major anti-atherogenic property of high-density lipoprotein (HDL). Astaxanthin is one of the naturally occurring carotenoids responsible for the pink-red pigmentation in a variety of living organisms. Although astaxanthin is known to be a strong antioxidant, it remains unclear through what mechanism of action it affects cholesterol homeostasis in macrophages. We therefore investigated the effects of astaxanthin on cholesterol efflux and ABCA1/G1 expressions in macrophages. Astaxanthin enhanced both apolipoprotein (apo) A-I-and HDL-mediated cholesterol efflux from RAW264.7 cells. In supporting these enhanced cholesterol efflux mechanisms, astaxanthin promoted ABCA1/G1 expression in various macrophages. In contrast, peroxisome proliferator-activated receptor ␥ , liver X receptor (LXR) ␣ and LXR ␤ levels remained unchanged by astaxanthin. An experiment using actinomycin D demonstrated that astaxanthin transcriptionally induced ABCA1/G1 expression, and oxysterol depletion caused by overexpression of cholesterol sulfotransferase further revealed that these inductions in ABCA1/G1 were independent of LXR-mediated pathways. Finally, we performed luciferase assays using human ABCA1/G1 promoterreporter constructs to reveal that astaxanthin activated both promoters irrespective of the presence or absence of LXR-responsive elements, indicating LXR-independence of these activations. In conclusion, astaxanthin increased ABCA1/G1 expression, thereby enhancing apoA-I/HDL-mediated cholesterol efflux from the macrophages in an LXR-independent manner. In addition to the anti-oxidative properties, the potential cardioprotective properties of astaxanthin might therefore be associated with an enhanced anti-atherogenic function of HDL.

Curcumin Enhanced Cholesterol Efflux by Upregulating ABCA1 Expression Through AMPK-SIRT1-LXRα Signaling in THP-1 Macrophage-Derived Foam Cells

“…Previous studies demonstrated that ABCA1 is a key player in macrophage reverse cholesterol transport (RCT) and is critical for regulating cellular cholesterol homeostasis during transformation of foam cells (Iizuka et al, 2012;Yu et al, 2013). To study whether ABCA1 is involved in the effect of curcumin on cellular cholesterol levels, we investigated the impacts of curcumin on the mRNA and protein levels of ABCA1.…”

Homocysteine-mediated cholesterol efflux via <italic>ABCA1</italic> and <italic>ACAT1</italic> DNA methylation in THP-1 monocyte-derived foam cells

“…In macrophages, the effects of ABCA1 on cholesterol efflux may be critical for protecting the artery wall from atherosclerotic lesion formation [34]. ACAT1 is expressed at high levels by macrophage-derived foam cells in atherosclerotic lesions [35], and ACAT1 influences the efflux of both cellular and lipoprotein-derived cholesterol [36].…”

The Target of Regulating The ATP-binding Cassette A1 Protein (ABCA1): Promoting ABCA1-Mediated Cholesterol Efflux in Different Cells

“…Niacin, the most effective agent clinically available to raise HDL, increases apoA-I lipidation by enhancing lipid efflux through the LXR /DR4-dependent transcription of ABCA1 in HepG2 cells [34]. In addition, agonists of peroxisome proliferator activated receptors (PPARs), which lack a corresponding response element in the ABCA1 promoter, including pioglitazone, fibrates and astaxanthin, can upregulate ABCA1 gene expression dependent on or independent of the PPARs/LXR pathway for activating ABCA1 transcription [35][36][37][38]. Statins also induce the accumulation of ABCA1 mRNA dependent on PPARs/LXR .…”