title: LXR agonist increases apoE secretion from HepG2 spheroid, together with an increased production of VLDL and apoE-rich large HDL.
abstract: BACKGROUND
  The physiological regulation of hepatic apoE gene has not been clarified, although the expression of apoE in adipocytes and macrophages has been known to be regulated by LXR.
  
  
  RESULTS
  We investigated the effect of TO901317, a LXR agonist, on hepatic apoE production utilizing HepG2 cells cultured in spheroid form, known to be more differentiated than HepG2 cells in monolayer culture. Spheroid HepG2 cells were prepared in alginate-beads. The secretions of albumin, apoE and apoA-I from spheroid HepG2 cells were significantly increased compared to those from monolayer HepG2 cells, and these increases were accompanied by increased mRNA levels of apoE and apoA-I. Several nuclear receptors including LXRα also became abundant in nuclear fractions in spheroid HepG2 cells. Treatment with TO901317 significantly increased apoE protein secretion from spheroid HepG2 cells, which was also associated with the increased expression of apoE mRNA. Separation of the media with FPLC revealed that the production of apoE-rich large HDL particles were enhanced even at low concentration of TO901317, and at higher concentration of TO901317, production of VLDL particles increased as well.
  
  
  CONCLUSIONS
  LXR activation enhanced the expression of hepatic apoE, together with the alteration of lipoprotein particles produced from the differentiated hepatocyte-derived cells. HepG2 spheroids might serve as a good model of well-differentiated human hepatocytes for future investigations of hepatic lipid metabolism.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurano
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Iso-O
authors.forename: Masumi
authors.initials: M
authors.lastname: Hara
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Ishizaka
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
mesh_terms: D000464:Alginates / Q000737:chemistry; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D020723:Glucuronic Acid / Q000737:chemistry; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000378:metabolism*; D000071518:Liver X Receptors; D008863:Microspheres; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D009994:Osmolar Concentration; D010316:Particle Size; D012333:RNA, Messenger / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000464:Alginates; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006845:Hydrocarbons, Fluorinated; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D013449:Sulfonamides; C505693:APOA1 protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides