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

Abstract

Background Very-low density-lipoproteins (VLDL) export lipids from liver to peripheral tissues and are the precursors of low-density-lipoproteins. Low levels of hepatic S-adenosylmethionine (SAMe) decrease triglyceride (TG) secretion in VLDL contributing to hepatosteatosis in methionine adenosyltransferase 1A knockout mice but nothing is known about the effect of SAMe over circulating VLDL metabolism. Objective We wanted to investigate whether excess SAMe could disrupt VLDL plasma metabolism and unravel the mechanisms involved. Methods Glycine N-methyltransferase (GNMT) knockout (KO), GNMT-PLIN2-KO and their respective wild types (WT) 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 nonalcoholic fatty-liver disease (NAFLD); 11 with hypertriglyceridemia and 22 with normal lipidemia were used in this study. Results We found that excess SAMe increases 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 restore VLDL secretion, features and metabolism. In NAFLD patients, serum TG levels are lower when hepatic GNMT-protein expression is decreased. Conclusion 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. Electronic word count: 235

Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis

“…We have previously shown that feeding Gnmt -KO mice during 21 days with a methionine deficient diet (MDD) restored normal SAMe levels[17], recovered VLDL metabolism[36], decreased liver TG content, and ameliorated liver steatosis[17]. …”

Multi-omics analyses reveal metabolic alterations regulated by hepatitis B virus core protein in hepatocellular carcinoma cells

“…In our study, HBc not only regulated glycine metabolites expression but also directly affected the activity by binding with enzymes in the glycine metabolic pathway. Previous studies have found that these enzymes might be promising biomarker candidates for HCC31 and non-alcoholic fatty liver disease32. However, whether these enzymes play important roles in HBV-related HCC requires further study.…”

Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris

“…More specifically, glycine is utilized to catabolize excess S-adenosylmethionine by its remethylation into sarcosine via the enzyme glycine-N-methyltransferase (GNMT), 10 and excess hepatic S-adenosylmethionine concentrations have been linked to the regulation of apolipoprotein (apo) B mRNA expression and very low-density lipoprotein formation. [11][12][13] Disturbances in these reactions have been associated with lipid accumulation both in the liver and in macrophages, which further promotes oxidized low-density lipoprotein (LDL)-induced foam cell formation in the artery wall. 12 Therefore, glycine availability may affect lipid metabolism and thereby further modulate the risk of coronary artery disease (CAD).…”