Cyanidin, a natural flavonoid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes

Yaoyao Jia, Minh Hien Hoang, Hee Jin Jun, Ji Hae Lee, Sung Joon Lee

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    35 Citations (Scopus)

    Abstract

    Cyanidin, a natural flavonoid abundant in fruits and vegetables, is known to regulate cellular lipid metabolism; however, its underlying mechanism of action and protein targets remain unknown. Here, the ligand binding activity of cyanidin on liver X receptors (LXRs) was investigated utilizing surface plasmon resonance and time-resolved fluorescence energy transfer (TR-FRET) analyses. LXRs are nuclear receptors which function as critical transcription factors in the regulation of cellular lipid and glucose metabolism. This includes the stimulation of high-density-lipoprotein synthesis and activation of reverse cholesterol transport. The present findings show that cyanidin induces the transactivation of LXRs and binds directly to the ligand-binding domain of both LXRα and LXRβ with dissociation constants of 2.2 and 73.2 μM, respectively. Cell-free FRET analysis demonstrated that cyanidin induces the recruitment of co-activator peptide for LXRα and LXRβ with EC 50 of 3.5 μM and 125.2 μM, respectively. In addition, intracellular cholesterol and triglyceride (TG) concentrations were reduced in macrophages following cyanidin stimulation. In cultured hepatocytes, cyanidin mildly induced SREBP1c gene expression but marginally affected cellular TG concentrations as well as reduced cellular cholesterol accumulations which activated the expression of genes for reverse cholesterol transport. Two cyanidin metabolites, procatechic acid and phloroglucinaldehyde, did not directly bind or activate LXRs. These results demonstrate that cyanidin is a direct ligand for both LXRα and LXRβ, suggesting that cyanidin may operate, at least in part, through modulation of cellular LXR activity.

    Original languageEnglish
    Pages (from-to)4185-4190
    Number of pages6
    JournalBioorganic and Medicinal Chemistry Letters
    Volume23
    Issue number14
    DOIs
    Publication statusPublished - 2013 Jul 15

    Bibliographical note

    Funding Information:
    This work was carried out with the support of Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ906950 and PJ00842203) Rural Development Administration, Republic of Korea. SPR instrument was provided by the Korea Basic Science Institute. We thank Professor Hyun-Gyu Song for the advice on FRET analysis.

    Keywords

    • Cyanidin
    • Hepatocyte
    • LXR
    • Ligand
    • Macrophages

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

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