# Can Walnut Serve as a Magic Bullet for the Management of Non-Alcoholic Fatty Liver Disease?
## 3 Results and Discussion
### Mechanisms by Which Walnut Contributes to the Management of NAFLD
#### 3.2.1 Effects of Walnut on Metabolism
Polate, vitamin B-12, vitamin B-6, and vitamin B-2 are coenzymes of one-carbon metabolism and methionine, choline, serine, glycine, threonine and glucose are the methyl donors for this metabolism [65]. The liver is the major site of one-carbon metabolism and produces most of the S-adenosylmethionine, which is the unique methyl donor for many biological methylation reactions and is involved in VLDL secretion [66]. VLDL is a triglyceride-rich lipoprotein, and impaired excretion of VLDL from the liver may result in excessive fat accumulation in the liver [67]. Previous animal studies suggested that methyl-deficient diets (deficient in folate, vitamin B-12, methionine, and choline, all of which are one-carbon nutrients) can induce fatty liver changes and increase hepatic cell turnover, ultimately leading to the development of hepatic tumors in the animal model. A plausible mechanism is that the deficiency of one-carbon nutrients may lead to reduced VLDL secretion and fat accumulation in the liver [66]. Moreover, methyl deficiency induces low S-adenosylmethionine pools, thereby resulting in DNA hypomethyllation. This, in turn, leads to changes in the expression of genes that may play key roles in the regulation of growth and cell cycles, ultimately resulting in the development of hepatic tumor. As methyl-deficient diet can induce fatty liver, folate, vitamin B-12, methionine, and choline were called lipotropes, which mean compounds that prevent excess fat deposition. Methionine adenosyltransferase catalyzes the synthesis of S-adenosylmethionine from methionine in the liver. In a _methionine adenosyltransferase_ deficient mouse model, the low hepatic S-adenosylmethionine level resulted in reduced phosphatidylcholine and polyunsaturated fatty acids levels as well as impaired synthesis and release of VLDL-triglyceride, leading to the accumulation of triglyceride, diacylglycerol, and fatty acids. Accumulation of oxidized fatty acids in the liver, subsequent oxidative stress, and abnormal hepatic lipid status trigger the spontaneous development of steatosis and the progression to NASH and fibrosis [68], suggesting that S-adenosylmethionine deficiency may be a critical driver of NAFLD. S-adenosylmethionine supplementation in this mouse model corrected many of the biochemical abnormalities and resulted in a return to near normal liver histology and triglyceride levels. S-adenosylmethionine supplementation in rats fed a lipogenic methionine- and choline-deficient diet also improved liver histology. Fortunately, except for vitamin B-12, walnut is rich in all sorts of one-carbon nutrients, including folate, vitamin B-6, methionine, serine, glycine, threonine, glucose, choline, and betaine, all of which involve one-carbon metabolism, derangement of which can induce fatty liver. Accumulating evidence suggests that certain bioactive components from plant foods might exhibit beneficial effects on health through the modification of epigenetic phenomena that affect gene expression without altering DNA base pairs. The effects of dietary polyphenols appear to be manifested either through the direct inhibition of DNA methyltransferases or indirectly through metabolic effects associated with energy metabolism. Nutrients and dietary bioactive food components can alter gene expression through alterations in DNA methylation, histone modification, and microRNA; therefore, an \"epigenetic diet\" [69] has been proposed, which leads to beneficial health outcomes through the modification of the epigenome. Walnut contains a plenty of one-carbon nutrients, polyphenols, and other bioactive food components and could therefore be used as a component of epigenetic diet that affects NAFLD through epigenetic mechanism. Further studies are warranted to clarify the epigenetic effects of walnut on NAFLD.