title: Hydrogen Sulfide Up-Regulates the Expression of ATP-Binding Cassette Transporter A1 via Promoting Nuclear Translocation of PPARα.
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.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. itstiming@outlook.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201210, China. xqh.841011@163.com.|Improvinglife Biological Technology (Shanghai) Co., Ltd., Shanghai 201210, China. xqh.841011@163.com.
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Xiong
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. pengj56@mail2.sysu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201210, China. weiweide420@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. lwz531lwz@163.com.
authors.forename: Wanzhen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201210, China. YZZhu2013@163.com.
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. shxiaoy@fudan.edu.cn.|Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201210, China. shxiaoy@fudan.edu.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D056945:Hep G2 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000517:prevention & control; D034622:RNA Interference; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D001057:Apolipoproteins E; D047493:PPAR alpha; D014280:Triglycerides; D002784:Cholesterol; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: ABCA1; PPARα; atherosclerosis; hydrogen sulfide