Novel interactomics approach identifies ABCA1 as direct target of evodiamine, which increases macrophage cholesterol efflux

Abstract

Evodiamine, a bioactive alkaloid from the fruits of the traditional Chinese medicine Evodia rutaecarpa (Juss.) Benth. (Fructus Evodiae, Wuzhuyu), recently gained attention as a dietary supplement for weight loss and optimization of lipid metabolism. In light of its use by patients and consumers, there is an urgent need to elucidate the molecular targets affected by this natural product. Using a novel interactomics approach, the Nematic Protein Organisation Technique (NPOT), we report the identification of ATP-binding cassette transporter A1 (ABCA1), a key membrane transporter contributing to cholesterol efflux (ChE), as a direct binding target of evodiamine. The binding of evodiamine to ABCA1 is confirmed by surface plasmon resonance (SPR) experiments. Examining the functional consequences of ABCA1 binding reveals that evodiamine treatment results in increased ABCA1 stability, elevated cellular ABCA1 protein levels, and ultimately increased ChE from THP-1-derived human macrophages. The protein levels of other relevant cholesterol transporters, ABCG1 and SR-B1, remain unaffected in the presence of evodiamine, and the ABCA1 mRNA level is also not altered.

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

“…Increased cholesterol efflux from THP-1derived macrophages by directly binding to ABCA1 and thereby increasing ABCA1 stability (Wang et al, 2018c).…”

“…Evodiamine, an indoloquinazoline alkaloid, is present in the traditional Chinese medicine Fructus Evodiae (Chinese name: Wuzhuyu) (Shoji et al, 1986;Wagner et al, 2011). Evodiamine (3-20 mM) increased cholesterol efflux from THP-1-derived human macrophages significantly by directly binding to ABCA1 and thereby increasing ABCA1 stability and protein level (Wang et al, 2018c). Moreover, treatment of evodiamine (10 mg/kg body weight) for 4 weeks decreased the size of atherosclerotic lesions and alleviated the hyperlipidemia, as well as hepatic macrovesicular steatosis in ApoE 2/2 mice, probably through transient receptor potential vanilloid type 1 (TRPV1) pathway (Su et al, 2014).…”

Regulation mechanism of silkworm pupa oil PUFAs on cholesterol metabolism in hepatic cell L‐02

“…Transcription of membrane transporter ABCA1 is under the control of LXR. ABCG1 is another member of the ATP‐binding cassette transporter superfamily, which reportedly contributes to HDL2‐ and HDL3‐dependent cellular cholesterol efflux . The activation of LXR could increase the expression of ABCG1 transcripts .…”

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

“…Evodiamine has been traditionally used to cure headache, amenorrhea, postpartum hemorrhage and gastrointestinal disorders. The biological activities of evodiamine have been widely investigated, including anti-obesity [ 13 , 14 ], anti-inflammatory [ 15 , 16 ], anti-atherosclerotic [ 17 ], neuroprotective [ 18 , 19 ], anti-gastrointestinal motility [ 20 ], and antiproliferative effects [ 21 ]. Among them, the antiproliferative activity of the multitargeting molecule evodiamine is attractive.…”