Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes.

Ayasa Ochiai,Masamori Iwase,Jun Inoue,Shingo Miyata,Ryuichiro Sato,Makoto Shimizu

doi:10.1038/srep24940

Abstract

A high level of plasma low-density lipoprotein (LDL) cholesterol is considered a risk factor for atherosclerosis. Because the hepatic LDL receptor (LDLR) is essential for clearing plasma LDL cholesterol, activation of LDLR is a promising therapeutic target for patients with atherosclerotic disease. Here we demonstrated how the flavonoid kaempferol stimulated the gene expression and activity of LDLR in HepG2 cells. The kaempferol-mediated stimulation of LDLR gene expression was completely inhibited by knockdown of Sp1 gene expression. Treatment of HepG2 cells with kaempferol stimulated the recruitment of Sp1 to the promoter region of the LDLR gene, as well as the phosphorylation of Sp1 on Thr-453 and Thr-739. Moreover, these kaempferol-mediated processes were inhibited in the presence of U0126, an ERK pathway inhibitor. These results suggest that kaempferol may increase the activity of Sp1 through stimulation of Sp1 phosphorylation by ERK1/2 and subsequent induction of LDLR expression and activity.

Highlights

A high level of plasma low-density lipoprotein (LDL) cholesterol is considered a risk factor for atherosclerosis
Treatment with kaempferol for 24 h increased the LDL receptor (LDLR) proteins (Fig. 1c) and LDL uptake (Fig. 1d,e) in HepG2 cells. These results indicate that kaempferol stimulates LDLR gene expression and led to increased LDL uptake
Our results demonstrated that the flavonoid kaempferol stimulated Sp1 activity through accelerated phosphorylation on Thr-453 and Thr-739 by ERK1/2 and LDLR gene expression and activity

Summary

Introduction

A high level of plasma low-density lipoprotein (LDL) cholesterol is considered a risk factor for atherosclerosis. Kaempferol stimulated the activity of Sp1 through its phosphorylation on Thr-453 and Thr-739 by ERK1/2, which increased DNA binding of Sp1 to the promoter region of the LDLR gene. We have previously established a stable cell line that expressed the luciferase reporter gene under the control of the LDLR promoter region from − 595 to + 36. We used this stable cell line and found that kaempferol stimulated the promoter activity of the LDLR gene (Fig. 1a).

Results

Conclusion