Finding the balance: The role of S -adenosylmethionine and phosphatidylcholine metabolism in development of nonalcoholic fatty liver disease
Authors: René L. Jacobs, Jelske N. van der Veen, Dennis E. Vance
Journal: Hepatology (2013)

In the 1950s, Catoni1 identified S-adenosylmethionine (SAMe or AdoMet) as an active methyl donor. SAMe methylates DNA, RNA, phospholipids, creatine, proteins, histones, among other targets, and is a precursor of polyamine and glutathione. The liver is responsible for 85% of all trans-methylation reactions2 and SAMe deficiency has been linked to liver diseases, including cancer and nonalcoholic fatty liver disease (NAFLD). SAMe supplementation may be an interesting therapeutic approach for several liver diseases, including cholestasis, alcoholic liver disease, hepatitis C, and NAFLD. Phosphatidylcholine (PC) synthesis is the likely link between decreased SAMe supply and NAFLD progression. Liver cells are unusual in that they synthesize 30% of hepatic PC by way of the sequential methylation of phosphatidylethanolamine (PE) catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT); the rest of PC is biosynthesized by way of the CDP-choline pathway.3 Animals with decreased hepatic SAMe content, either because of dietary methyl deficiency4, 5 or disruption of genes involved in hepatic SAMe synthesis,6, 7 have impaired PC synthesis (Fig. 1A). Hepatic PC is required for assembly/secretion of very low-density lipoproteins (VLDL). When PC synthesis is impaired, triacylglycerol (TG) accumulates in the liver. Impaired synthesis of SAMe or PC also increase hepatic TG by activating SREBP-1 and de novo lipogenesis.5 Hence, the supply of SAMe and PC is vital for maintaining hepatic lipid homeostasis. The glycine N-methyltransferase (GNMT) knockout mouse (Gnmt−/−) reveals an additional level of complexity to the relationship between hepatic SAMe and NAFLD.8 GNMT methylates glycine to form sarcosine (methyl-glycine). Sarcosine has no known metabolic function but is demethylated to regenerate glycine. This futile cycle enables the catabolism of excess hepatic SAMe without aberrant production of methylated products. Deletion of GNMT increased steady-state SAMe levels 40-fold and induced NAFLD in mice.8 Gnmt−/− mice developed NAFLD by 3 months and hepatocellular carcinoma by 8 months of age. While these studies highlight a clear link between excess SAMe and NAFLD, the mechanism underlying these findings was unclear. In this issue of Hepatology, Martínez-Uña et al.9 provide new insight into mechanisms by which both low and high SAMe levels promote hepatic lipid accumulation (Fig. 1B). Deletion of GNMT decreased hepatic PE and increased PC, diacylglycerol (DG), and TG. VLDL secretion was increased in Gnmt−/− mice and fatty acid synthesis and oxidation were unchanged; these findings did not explain the hepatic TG accumulation. Through a series of careful experiments, the authors showed that elevated hepatic SAMe in Gnmt−/− mice induces the conversion of PE to PC by way of PEMT.9 Consequently, in order to maintain a normal membrane PC/PE ratio, the liver stimulates PC secretion by way of VLDL and high-density lipoproteins and increases PC degradation by way of phospholipase D or C, leading to increased DG production (Fig. 1A). Thus, PC catabolism promotes hepatic TG accumulation. When Gnmt−/− mice were fed a methionine-deficient diet, hepatic SAMe and flux of PE to PC flux were normalized, and hepatic lipids were restored to control levels. Thus, the authors show that excess SAMe levels stimulate both PC synthesis and catabolism, thereby contributing to the development of hepatic steatosis. Since the Km of GNMT for SAMe is relatively high compared to other methyltransferases, the primary role of GNMT is postulated to be the elimination of excess hepatic SAMe. Thus, PEMT may be an "overflow pathway" for SAMe when GNMT is absent.11 However, increased flux of methyl groups through PEMT, unlike GNMT, enhances TG synthesis. The level of hepatic SAMe is altered by the transition from the fed to fasting state and by consumption of a high versus low protein diet.10 The following questions are raised: Does PEMT-dependent PC synthesis contribute to TG production during these conditions? Do relatively small increases in hepatic SAMe influence other methyltransferase reactions? The Mato group reported that Gnmt−/− mice have both aberrant DNA and histone hypermethylation, leading to activation of the Ras and JAK/STAT signaling pathways8; activation of these pathways contributes to the development of hepatocellular carcinoma in Gnmt−/− mice.9 Clearly, many methyltransferase reactions are stimulated by excess hepatic SAMe; however, more research is required to understand this relationship during normal physiological conditions. Wiggins and Gibbons11 reported that PC serves as a source of TG in rat hepatocytes. Several studies have shown that lipoprotein-derived PC is a quantitatively important direct precursor of hepatic TG.12, 13 For example, 50% of LDL-PC taken up by mouse hepatocytes is converted into TG by way of hydrolysis of PC to DG and esterification of DG by acyl-CoA:diacylglycerol acyltransferase.13 Moreover, ∼50% of hepatic PC is derived from circulating lipoproteins12 and 30% of HDL-derived PC in mouse liver was converted to TG.12 Hence, PC in circulating lipoproteins should be considered a significant source of TG for the etiology of NAFLD. PC made both by PE methylation and supplied by lipoproteins contributes to hepatic steatosis. Ling et al.14 provided evidence that a decreased hepatic PC/PE molar ratio is associated with NAFLD progression in mice. A reduced hepatic PC/PE ratio was also observed in some patients with nonalcoholic steatohepatitis (NASH).15 The amounts of hepatic PC and PE are regulated to maintain membrane integrity and control the movement of metabolites across membranes.15 A reduction in the PC/PE ratio increases membrane permeability, leading to leakage of cellular contents to the extracellular space, thereby activating resident Kupffer cells and promoting cytokine-mediated hepatocyte injury. Together, these changes contribute to cellular injury and the pathogenesis of NASH.15 Fu et al.16 reported that the hepatic PC/PE ratio was higher in obese (leptin-deficient) mice compared to lean mice. Short hairpin RNA (shRNA) silencing of PEMT normalized the PC/PE ratio in the obese mice and reduced ER stress.16 The Gnmt−/− mice have elevated PC/PE and develop steatohepatitis. TG accumulation and the PC/PE ratio are normalized when Gnmt−/− mice are fed a methionine-deficient diet.9 Taken together, it is clear that both abnormally high and low levels of SAMe and PC/PE ratio can be a determinant of NAFLD (Fig. 1C). It is also clear that maintaining a balance among these metabolites is important in preventing fatty liver disease. René L. Jacobs, Ph.D.1,2 Jelske N. van der Veen, Ph.D.2,3 Dennis E. Vance, Ph.D.2,3 1Department of Agricultural, Food and Nutritional Science University of Alberta, Edmonton Alberta, Canada 2Group on the Molecular and Cell Biology of Lipids University of Alberta Edmonton, Alberta, Canada 3Department of Biochemistry University of Alberta Edmonton, Alberta, Canada