Abstract
ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.
Highlights
Publisher’s Note: MDPI stays neutral2-Methoxyestradiol (2-ME2 ) is a main metabolite of estradiol and is generated by a sequential process: 17β-estradiol (E2) produces 2-hydroxyestradiol (2HE) via the enzyme cytochrome P450 isoform 1A1, and 2HE generates 2-ME2 by a conjugation reaction catalyzed via the enzyme catechol-O-methyltransferase (COMT) [1]
The results showed that the phosphorylation of FoxO1 was stimulated by 2-ME2 from
A specific hepatic ATP-binding cassette transporter A1 (ABCA1) knockout decreases the generation of heterogeneoussized nascent high-density lipoprotein (HDL) particles in vivo, leading to large TG-rich very low-density lipoprotein (VLDL) accumulation in the liver [22]
Summary
2-Methoxyestradiol (2-ME2 ) is a main metabolite of estradiol and is generated by a sequential process: 17β-estradiol (E2) produces 2-hydroxyestradiol (2HE) via the enzyme cytochrome P450 isoform 1A1, and 2HE generates 2-ME2 by a conjugation reaction catalyzed via the enzyme catechol-O-methyltransferase (COMT) [1]. Estrogen protects women from NAFLD before menopause by reducing the TG accumulation in the liver via the activation of the estrogen receptor (ER), which is the main receptor of E2, or the G protein-coupled estrogen receptor (GPER or Gpr30), a receptor of 2-ME2 [2]. As an important lipid transporter, ATP-binding cassette transporter A1 (ABCA1) is a. 254-kD membrane protein to transport cholesterol from the cytoplasm to apolipoproteins, and it plays a critical role in the process of reverse cholesterol transport [5]. ABCA1 is firstly detected as a mutated molecule in patients with Tangier disease, and the reduction of ABCA1 results in a severe deficiency of high-density lipoprotein (HDL) and cholesterol with regard to jurisdictional claims in published maps and institutional affiliations.
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