Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network

Hee-Sung Chae,Hyun-Jeong Ko,Dong-Yeop Kim,Sun Shim Choi,Byoung Hoon You,Hankyu Lee,Young Hee Choi,Young-Won Chin,Hyuk Wan Ko

doi:10.1038/s41598-018-24935-6

Abstract

Whole-transcriptome analysis and western blotting of sauchinone-treated HepG2 cells demonstrated that sauchinone regulated genes relevant to cholesterol metabolism and synthesis. In particular, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of low density lipoprotein receptor (LDLR) was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-cholesterol (LDL-C) uptake was increased. As a transcriptional regulator of PCSK9 expression, sterol regulatory elements binding protein-2 (SREBP-2) was proposed by transcriptome analysis and western blotting. Oral administration of sauchinone increased hepatic LDLR through PCSK9 inhibition in obese mice and showed the reduced serum LDL-C levels and downstream targets of SREBP-2. Thus, it is evident that sauchinone reduces hepatic steatosis by downregulating the expression of hepatic PCSK9 via SREBP-2.

Highlights

Cholesterol homeostasis is regulated by a family of transcription factors called sterol regulatory elements binding proteins (SREBPs)[1]
sterol regulatory elements binding protein-2 (SREBP-2) is involved in regulating cholesterol synthesis and metabolism genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), hydroxy -3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP), and squalene epoxidase (SQLE)[4,5,6]
To assess the effects of sauchinone on HepG2 cells, the RNA-seq approach was used for the mRNAs collected from HepG2 cells treated with various doses of sauchinone

Summary

Introduction

Cholesterol homeostasis is regulated by a family of transcription factors called sterol regulatory elements binding proteins (SREBPs)[1]. SREBP-2 is involved in regulating cholesterol synthesis and metabolism genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), hydroxy -3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP), and squalene epoxidase (SQLE)[4,5,6]. PCSK9 promotes degradation of these cell surface LDL receptors in selected cell types[13] Statins such as simvastatin are clinically used by reducing the quantity of LDL-C14,15. Treatment with antibody-based drug candidates in the absence or presence of statins targets PCSK9 activity to accomplish LDL-C control[20]. Sauchinone inhibits hepatic steatosis mediated by the SREBP isoform, SREBP-1c, and activates AMP-activated protein kinase (AMPK)[31]. The responsible genes, such as the gene encoding PCSK9, have not been determined

Methods

Results

Conclusion