title: Regulatory mechanism of mineral-balanced deep sea water on hypocholesterolemic effects in HepG2 hepatic cells.
abstract: Several previous studies have shown the benefits of deep sea water (DSW) in lipid metabolism. However, the effects of DSW on cellular cholesterol accumulation and synthesis induced by high glucose or free fatty acid plus high glucose [4.5g/L] (FFA/glucose) have not been fully elucidated to date. Herein, we showed the effects of mineral-balanced DSW [magnesium (Mg):calcium (Ca)=3:1] (MB-DSW) on cholesterol metabolism induced by high glucose or FFA/glucose in HepG2 hepatic cells. Moreover, the effects of high ratio Mg DSW [Mg:Ca=40:1] (Mg40) were also investigated. MB-DSW and Mg40 prevented the increase of cellular total cholesterol content in high glucose- or FFA/glucose-treated HepG2 hepatic cells. Furthermore, the inhibition by MB-DSW was closely related to the down-regulation of 3-hydroxy-3-methylglutatryl-CoA reductase (HMGCR) expression and an increase in the AMP-activated protein kinase (AMPK) phosphorylation, leading to decreased cholesterol synthesis in both high glucose- and FFA/glucose-treated conditions. However, this effect was not seen in case of Mg40. In addition, both MB-DSW and Mg40 induced the low-density lipoprotein receptor (LDLR) and diminished the proprotein convertase subtilisin/kexin type 9 (PCSK9) transcriptions in high glucose-treated HepG2 hepatic cells. This result demonstrates that the hypocholesterolemic effects of MB-DSW and Mg40 are mediated with LDL-c clearance through increases of LDLR and its transcription factors, such as peroxisome proliferator-activated receptor-α (PPAR-α), sterol regulatory element-binding protein (SREBP)-1a, and SREBP-2, mRNA synthesis and suppression of PCSK9 transcription. Moreover, apolipoprotein (Apo) A1 transcription was enhanced by MB-DSW and Mg40 without decreasing the expression of Apo B in high glucose-treated HepG2 hepatic cells. However, ApoA1 protein expression was not changed. Taken together, the present investigation suggests that DSW may prevent the high glucose- or FFA/glucose-induced increase of cellular cholesterol levels by inducing LDLR and ApoA1 transcriptions and inhibiting PCSK9 mRNA expression in HepG2 hepatic cells. Additionally, the ratio of Mg in DSW is an important factor that determines whether HMGCR expression and/or AMPK phosphorylation participate in the hypocholesterolemic effects of DSW.
authors.affiliation: Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Republic of Korea.
authors.forename: Kyu-Shik
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Republic of Korea.
authors.forename: Yun-Suk
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Seawater Utilization Plant Research Institute of Ships & Oean Engineering (KRISO) Goseong, Republic of Korea.
authors.forename: Deok-Soo
authors.initials: DS
authors.lastname: Moon
authors.affiliation: Seawater Utilization Plant Research Institute of Ships & Oean Engineering (KRISO) Goseong, Republic of Korea.
authors.forename: Hyeon Ju
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Republic of Korea. Electronic address: namks@dongguk.ac.kr.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Nam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008900:Mineral Waters / Q000008:administration & dosage*; D008903:Minerals / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D012623:Seawater; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D008077:Lipoproteins, LDL; D008900:Mineral Waters; D008903:Minerals; D012333:RNA, Messenger; D011973:Receptors, LDL; D014157:Transcription Factors; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D055372:AMP-Activated Protein Kinases; D000071449:Proprotein Convertase 9; D005947:Glucose
keywords: AMPK; HMG-CoA reductase; Hypercholesterolemia; Lipid metabolism; Mineral-balanced deep sea water