Abstract
ATP binding cassette transporter A1 (ABCA1) plays a key role in atherogenesis. Hydrogen sulfide (H2S), a gasotransmitter, has been reported to play an anti-atherosclerotic role. However, the underlying mechanisms are largely unknown. In this study we examined whether and how H2S regulates ABCA1 expression. The effect of H2S on ABCA1 expression and lipid metabolism were assessed in vitro by cultured human hepatoma cell line HepG2, and in vivo by ApoE−/− mice with a high-cholesterol diet. NaHS (an exogenous H2S donor) treatment significantly increased the expression of ABCA1, ApoA1, and ApoA2 and ameliorated intracellular lipid accumulation in HepG2 cells. Depletion of the endogenous H2S generator cystathionine γ-lyase (CSE) by small RNA interference (siRNA) significantly decreased the expression of ABCA1 and resulted in the accumulation of lipids in HepG2 cells. In vivo NaHS treatment significantly reduced the serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL), diminished atherosclerotic plaque size, and increased hepatic ABCA1 expression in fat-fed ApoE−/− mice. Further study revealed that NaHS upregulated ABCA1 expression by promoting peroxisome proliferator-activated receptor α (PPARα) nuclear translocation. H2S up-regulates the expression of ABCA1 by promoting the nuclear translocation of PPARα, providing a fundamental mechanism for the anti-atherogenic activity of H2S. H2S may be a promising potential drug candidate for the treatment of atherosclerosis.
Highlights
High-density lipoproteins (HDLs) are known to protect against atherogenesis by transporting excess cholesterol out of macrophages through the adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)-mediated reverse cholesterol transport [1]
Our results indicate that H2S upregulated ATP-binding cassette transporter A1 (ABCA1) expression through the promotion of peroxisome proliferator-activated receptor α (PPARα) nuclear translocation
We investigated the dose-dependent effect of NaHS on ABCA1 expression
Summary
High-density lipoproteins (HDLs) are known to protect against atherogenesis by transporting excess cholesterol out of macrophages through the ATP-binding cassette transporter A1 (ABCA1)-mediated reverse cholesterol transport [1]. There is plentiful evidence indicating that H2S has an anti-atherosclerosis property, the underlying mechanisms are largely unknown [12,13,14,15,16,17,18]. Both of ABCA1 and H2S were shown to play a significant role in atherogenesis, there is no information about the correlation between them. Our results indicate that H2S upregulated ABCA1 expression through the promotion of PPARα nuclear translocation
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