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

  • Medicia Kartawijaya Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
  • Hye Won Han Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
  • Yunhye Kim Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
  • Seung-Min Lee Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea

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 µg/mL for 24 h did not affect the effect of genistein on LDLR protein expression. Even the addition of 40 µM 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.

Keywords: genistein; JNK; LDL receptor; cholesterol; SREBP-2

(Published: 20 May 2016)

Citation: Food & Nutrition Research 2016, 60: 31120 - http://dx.doi.org/10.3402/fnr.v60.31120

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Published
2016-05-20
How to Cite
1.
Kartawijaya M, Han H, Kim Y, Lee S-M. Genistein upregulates LDLR levels via JNK-mediated activation of SREBP-2. fnr [Internet]. 2016May20 [cited 2019Jun.20];600. Available from: https://foodandnutritionresearch.net/index.php/fnr/article/view/1016
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Original Articles