Genistein upregulates LDLR levels via JNK-mediated activation of SREBP-2

Medicia Kartawijaya, Hye Won Han, Yunhye Kim, Seung Min Lee

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Genistein has been proved in vitro and in vivo to lower LDLR level. It is also widely consumed and implicated for its anti-atherogenic effects. However, the molecular mechanism by which genistein lowers the LDL level is still unknown. Objective: To understand the anti-atherogenic molecular mechanism of action, genistein was investigated for its impact on the expression of LDLR, the receptor for LDL cholesterol, and related signaling pathways in a human hepatoma cell line. Design: HepG2 cell was used for the experiments. Genistein with different concentrations was diluted in media and was incubated for 24 h or more as indicated. Protein levels were measured by western blotting, and mRNA expression was detected by RT-qPCR. Chromatin immunoprecipitation assay (CHIP) assay was used to determine protein binding levels, and luciferase assay was used to measure promoter activity. Result: Genistein increased the mRNA and protein levels of LDLR in a time-dependent manner. Genistein increased the transcriptional activity of the LDLR promoter containing the reporter gene (pLDLR-luc, 805 to 50). But the sterol regulatory element deletion mutant construct failed to be activated by genistein. Genistein increased the nuclear fraction of SREBP-2 and the DNA-binding activity of SREBP-2 to LDLR promoter, as assessed by CHIP. The genistein-phosphorylated JNK inhibitor (SP600126) abolished the genistein-stimulated levels of LDLR and the nuclear SREBP-2. The addition of cholesterol up to 5 mg/mL for 24 h did not affect the effect of genistein on LDLR protein expression. Even the addition of 40 mM genistein increased the cholesterol uptake by more than 10% in the human hepatoma cell line. Conclusion: Our data support the idea that genistein may have anti-atherogenic effects by activating JNK signals and SREBP-2 processing, which is followed by the upregulation of LDLR.

Original languageEnglish
Article number31120
JournalFood and Nutrition Research
Volume60
DOIs
Publication statusPublished - 2016 May 20

All Science Journal Classification (ASJC) codes

  • Food Science
  • Nutrition and Dietetics
  • Public Health, Environmental and Occupational Health

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