title: Resveratrol exerts a biphasic effect on apolipoprotein M.
abstract: OBJECTIVE
  Resveratrol exerts a range of beneficial actions in several areas of pathophysiology, including vascular biology. Here, we have investigated the effects of resveratrol on apolipoprotein M (apoM), a carrier and modulator of sphingosine 1-phosphate (S1P), a vasoactive lipid mediator.
  
  
  METHODS
  We used a hepatoma cell line (HepG2), human primary hepatocytes and C57BL/6 mice. We measured apoM, S1P and related enzymes, LDL receptors and sirtuin1 activity, using Western blotting, RT-PCR and enzyme assays. We also used si-RNA to knock-down sirtuin1 in HepG2 cells.
  
  
  RESULTS
  In cultures of HepG2 cells, resveratrol (1-10 μM) increased intracellular apoM and S1P. High concentrations of resveratrol (100 μM) decreased extracellular (in the culture medium) apoM, whereas moderate concentrations of resveratrol (1-10 μM) increased extracellular apoM. High concentrations of resveratrol also increased LDL receptor expression, while all concentrations of resveratrol activated the histone deacetylase sirtuin1. In cultures of human primary hepatocytes, resveratrol, at all concentrations, increased both intra- and extracellular apoM. When wild-type mice were fed a resveratrol-containing chow (0.3% w/w) for 2 weeks, both the plasma and hepatic apoM and S1P levels were increased. However, the resveratrol diet did not affect hepatic LDL receptor levels in this in vivo study.
  
  
  CONCLUSIONS
  Resveratrol increased intra- and extracellular levels of apoM, along with intracellular S1P levels, while a high concentration of resveratrol reduced extracellular apoM. The present findings suggest that resveratrol has novel effects on the metabolic kinetics of S1P, a multi-functional bioactive phospholipid.
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurano
authors.affiliation: Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nojiri
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000097:blood / Q000378:metabolism*; D000075243:Apolipoproteins M; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D054834:Lipocalins / Q000097:blood / Q000378:metabolism*; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism; D051379:Mice; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000096:biosynthesis; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D054834:Lipocalins; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D013267:Stilbenes; C060506:sphingosine 1-phosphate; D056564:Sirtuin 1; D013110:Sphingosine; D000077185:Resveratrol