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

ABSTRACT: 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.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.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.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.

SUBMITTER: Martinez-Una M

PROVIDER: S-EPMC4336596 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Martínez-Uña Maite M Varela-Rey Marta M Mestre Daniela D Fernández-Ares Larraitz L Fresnedo Olatz O Fernandez-Ramos David D Gutiérrez-de Juan Virginia V Martin-Guerrero Idoia I García-Orad Africa A Luka Zigmund Z Wagner Conrad C Lu Shelly C SC García-Monzón Carmelo C Finnell Richard H RH Aurrekoetxea Igor I Buqué Xabier X Martínez-Chantar M Luz ML Mato José M JM Aspichueta Patricia P

Journal of hepatology 20141018 3

<h4>Background & aims</h4>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 ...[more]

PMID: 25457203

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Project description:Background:Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Methods:From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles. Results:Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen. Conclusions:The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles.

Project description:BackgroundInsulin resistance (IR), one of the key components of the metabolic syndrome, is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the relationship between surrogate markers of IR and the severity of NAFLD among overweight or obese children.MethodologyA total of 56 consecutive children aged 6 to 18 years old were recruited from the pediatric obesity and type 2 diabetes mellitus (T2DM) clinic in University Malaya Medical Centre (UMMC) from 2016 to 2019. Data on anthropometric measurements, clinical components of metabolic syndrome and fasting serum insulin were collected. Triglyceride to high-density lipoprotein cholesterol ratio (TG: HDL-C), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Single Point Insulin Sensitivity Estimator (SPISE) were calculated. Transient elastography was performed with hepatic steatosis and liver fibrosis assessed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively.ResultsA total of 44 children (78.6%) had liver steatosis and 35.7% had presence of significant liver fibrosis (stage F≥2). Majority (89.3%) are obese and 24 children (42.9%) were diagnosed with metabolic syndrome. Higher number of children with T2DM and significant liver fibrosis were associated with higher tertiles of TG: HDL-C ratio (p<0.05). Top tertile of TG: HDL-C ratio was an independent predictor of liver fibrosis (OR=8.14, 95%CI: 1.24-53.36, p=0.029). ROC analysis showed that the area under the curve (AUC) of HOMA-IR (0.77) and TG: HDL-C ratio (0.71) were greater than that of metabolic syndrome (0.70), T2DM (0.62) and SPISE (0.22). The optimal cut-off values of HOMA-IR and TG: HDL-C ratio for detecting liver fibrosis among children with NAFLD are 5.20 and 1.58, respectively.ConclusionChildren with NAFLD and higher TG: HDL-C ratio are more likely to have liver fibrosis. TG: HDL-C ratio is a promising tool to risk stratify those with NAFLD who are at risk of developing advanced liver disease.

Dataset Information

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

Publications

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

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