title: Alginate oligosaccharide enhances LDL uptake via regulation of LDLR and PCSK9 expression.
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.
authors: College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea.
authors: Ji Hye
authors: JH
authors: Yang
authors: Food Industry Development Team, Jeonnam Bioindustry Foundation, Food Research Inst, Naju, Jeonnam, South Korea.
authors: Mi Ae
authors: MA
authors: Bang
authors: College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea.
authors: Chang Ho
authors: CH
authors: Jang
authors: Research Institute of Bioscience and Biotechnology, Bioresource Inc., Suncheon-si, South Korea.
authors: Gyung Hyun
authors: GH
authors: Jo
authors: Research Institute of Bioscience and Biotechnology, Bioresource Inc., Suncheon-si, South Korea.
authors: Seoung Ki
authors: SK
authors: Jung
authors: College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea. Electronic address: shki@chosun.ac.kr.
authors: Sung Hwan
authors: SH
authors: Ki
mesh_terms: D000464:Alginates / Q000494:pharmacology*; D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008813:Mice, Inbred ICR; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000464:Alginates; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Akt; Alginate oligosaccharide; LDL; LDL receptor; PCSK9; SREBP-2