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J Nutr Biochem. 2015 Nov;26(11):1393-400. doi: 10.1016/j.jnutbio.2015.07.009. Epub 2015 Jul 30.

Alginate oligosaccharide enhances LDL uptake via regulation of LDLR and PCSK9 expression.

Author information

1
College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea.
2
Food Industry Development Team, Jeonnam Bioindustry Foundation, Food Research Inst, Naju, Jeonnam, South Korea.
3
Research Institute of Bioscience and Biotechnology, Bioresource Inc., Suncheon-si, South Korea.
4
College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea. Electronic address: shki@chosun.ac.kr.

Abstract

The hepatic low-density lipoprotein (LDL) receptor (LDLR) plays a crucial role in lipoprotein metabolism by lowering the plasma LDL-cholesterol concentration, which reduces the risk for cardiovascular diseases. Although alginate oligosaccharide (AOS), prepared from degradation, has several pharmacological effects, it is not known whether AOS affects lipoprotein metabolism. This study was conducted to investigate whether AOS up-regulated LDLR expression and LDL uptake in vitro and in vivo, and the underlying molecular mechanism. We found that AOS increased LDLR expression and intracellular uptake of LDL by hepatocytes in a dose- and time-dependent manner. It is well established that sterol-responsive element binding protein-2 (SREBP-2) is an essential transcription factor for LDLR gene expression. AOS enhanced SREBP-2 nuclear translocation and mRNA levels. The specific role of SREBP-2 activation in AOS-induced LDLR expression was verified using an LDLR promoter construct with a sterol response element deletion. The activation of SREBP-2 by AOS is mediated by phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3β pathways. Furthermore, we found that expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a crucial modulator of LDLR, was down-regulated by AOS; this related to the inhibition of hepatocyte nuclear factor-1α. Treatment of mice with AOS for 2 weeks stimulated LDLR expression and reduced PCSK9 expression, resulting in decreased plasma LDL-cholesterol levels. We conclude that AOS lowered plasma LDL-cholesterol levels through regulation LDLR expression. This effect was dependent on SREBP-2 and PCSK9.

KEYWORDS:

Akt; Alginate oligosaccharide; LDL; LDL receptor; PCSK9; SREBP-2

PMID:
26320675
DOI:
10.1016/j.jnutbio.2015.07.009
[Indexed for MEDLINE]

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