Format

Send to

Choose Destination
See comment in PubMed Commons below
J Hepatol. 2015 Mar;62(3):673-81. doi: 10.1016/j.jhep.2014.10.019. Epub 2014 Oct 18.

S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease.

Author information

  • 1Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain.
  • 2CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain.
  • 3Department of Physiology, University of the Basque Country UPV/EHU, Spain.
  • 4Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Spain.
  • 5Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 6Division 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.
  • 7Liver 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.
  • 8Department of Nutritional Sciences, Dell Pediatric Institute, The University of Texas at Austin, Austin, TX, USA.
  • 9CIC 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.
  • 10Department of Physiology, University of the Basque Country UPV/EHU, Spain; Biocruces Research Institute, Spain. Electronic address: patricia.aspichueta@ehu.es.

Abstract

BACKGROUND & AIMS:

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.

KEYWORDS:

Glycine N-methyltransferase; Non-alcoholic fatty-liver disease; S-Adenosylmethionine; Very-low density-lipoproteins

PMID:
25457203
PMCID:
PMC4336596
DOI:
10.1016/j.jhep.2014.10.019
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center