title: S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Very-low-density lipoproteins (VLDLs) export lipids from the liver to peripheral tissues and are the precursors of low-density-lipoproteins. Low levels of hepatic S-adenosylmethionine (SAMe) decrease triglyceride (TG) secretion in VLDLs, contributing to hepatosteatosis in methionine adenosyltransferase 1A knockout mice but nothing is known about the effect of SAMe on the circulating VLDL metabolism. We wanted to investigate whether excess SAMe could disrupt VLDL plasma metabolism and unravel the mechanisms involved.
  
  
  METHODS
  Glycine N-methyltransferase (GNMT) knockout (KO) mice, GNMT and perilipin-2 (PLIN2) double KO (GNMT-PLIN2-KO) and their respective wild type (WT) controls were used. A high fat diet (HFD) or a methionine deficient diet (MDD) was administrated to exacerbate or recover VLDL metabolism, respectively. Finally, 33 patients with non-alcoholic fatty-liver disease (NAFLD); 11 with hypertriglyceridemia and 22 with normal lipidemia were used in this study.
  
  
  RESULTS
  We found that excess SAMe increases the turnover of hepatic TG stores for secretion in VLDL in GNMT-KO mice, a model of NAFLD with high SAMe levels. The disrupted VLDL assembly resulted in the secretion of enlarged, phosphatidylethanolamine-poor, TG- and apoE-enriched VLDL-particles; special features that lead to increased VLDL clearance and decreased serum TG levels. Re-establishing normal SAMe levels restored VLDL secretion, features and metabolism. In NAFLD patients, serum TG levels were lower when hepatic GNMT-protein expression was decreased.
  
  
  CONCLUSIONS
  Excess hepatic SAMe levels disrupt VLDL assembly and features and increase circulating VLDL clearance, which will cause increased VLDL-lipid supply to tissues and might contribute to the extrahepatic complications of NAFLD.
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Martínez-Uña
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mestre
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
authors.forename: Larraitz
authors.initials: L
authors.lastname: Fernández-Ares
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Fresnedo
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernandez-Ramos
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez-de Juan
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Martin-Guerrero
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: García-Orad
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Zigmund
authors.initials: Z
authors.lastname: Luka
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.affiliation: Liver Research Unit, University Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: García-Monzón
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Institute, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
authors.forename: Igor
authors.initials: I
authors.lastname: Aurrekoetxea
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Buqué
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain. Electronic address: patricia.aspichueta@ehu.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D050938:Glycine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000070780:Perilipin-2; D012436:S-Adenosylmethionine / Q000172:deficiency / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D014280:Triglycerides; D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase; C494511:Gnmt protein, mouse
keywords: Glycine N-methyltransferase; Non-alcoholic fatty-liver disease; S-Adenosylmethionine; Very-low density-lipoproteins