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

Martínez-Uña M, Varela-Rey M, Mestre D, Fernández-Ares L, Fresnedo O, Fernandez-Ramos D, Gutiérrez-de Juan V, Martin-Guerrero I, García-Orad A, Luka Z, Wagner C, Lu SC, García-Monzón C, Finnell RH, Aurrekoetxea I, Buqué X, Martínez-Chantar ML, Mato JM, Aspichueta P
J Hepatol. 2015 62 (3): 673-81

PMID: 25457203 · PMCID: PMC4336596 · DOI:10.1016/j.jhep.2014.10.019

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.

Copyright © 2014 European Association for the Study of the Liver. All rights reserved.

MeSH Terms (22)

Adult Aged Aged, 80 and over Animals Diet, High-Fat Disease Models, Animal Female Glycine N-Methyltransferase Humans Lipoproteins, VLDL Liver Male Membrane Proteins Mice Mice, Knockout Middle Aged Models, Biological Non-alcoholic Fatty Liver Disease Perilipin-2 S-Adenosylmethionine Triglycerides Young Adult

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