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

JOURNAL OF HEPATOLOGY

卷:62

Article

Martinez-Una, Maite^1,2  Varela-Rey, Marta³  Mestre, Daniela^1,2  Fernandez-Ares, Larraitz^1,2  Fresnedo, Olatz¹  Fernandez-Ramos, David³  Gutierrez-de Juan, Virginia³  Martin-Guerrero, Idoia⁴  Garcia-Orad, Africa⁴  Luka, Zigmund⁵  Wagner, Conrad⁵  Lu, Shelly C.⁶  Garcia-Monzon, Carmelo^7,8  Finnell, Richard H.⁹  Aurrekoetxea, Igor^1,2  Buque, Xabier^1,2  Martinez-Chantar, M. Luz^3,10  Mato, Jose M.³  Aspichueta, Patricia^1,2 

[1] Univ Basque Country UPV EHU, Dept Physiol, Leioa 48940, Spain

[2] Biocruces Res Inst, Bizkaia, Spain

[3] CIC bioGUNE, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Barcelona, Spain

[4] Univ Basque Country UPV EHU, Dept Genet Phys Anthropol & Anim Physiol, Leioa 48940, Spain

[5] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA

[6] Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, Div Gastroenterol & Liver Dis, Los Angeles, CA 90033 USA

[7] Univ Hosp Santa Cristina, Liver Res Unit, Inst Invest Sanitaria Princesa, Madrid, Spain

[8] Ctr Invest Biomed Red Enfermedades Hepat & Digest, Barcelona, Spain

[9] Univ Texas Austin, Dell Pediat Inst, Dept Nutr Sci, Austin, TX 78712 USA

[10] Univ Basque Country UPV EHU, Dept Biochem & Mol Biol, Leioa 48940, Spain

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

DOI  :  10.1016/j.jhep.2014.10.019

来源: Elsevier

【 摘 要 】

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, phosphatidyleth-anolamine-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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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