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

Medicia Kartawijaya; Hye Won Han; Yunhye Kim; Seung-Min Lee

doi:10.3402/fnr.v60.31120

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

DOI: https://doi.org/10.3402/fnr.v60.31120

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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