Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine

Abstract

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the 'key switch' between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH.

Keywords: NASH; SAMe; biomarkers; hepatocellular carcinoma; treatment.

Figure 1

Mechanisms involved in IHS and NASH development. Insulin resistance and obesity, increase caloric intake, increase de novo lipogenesis, increased free fatty acid (FFA) flux from adipose tissue to the liver, and impaired VLDL secretion lead to fat accumulation in the liver and HIS (A). Multiples hits are involved in the development of NASH including mitochondrial impairment, role of microbiota, iron accumulation, genetic factors, and release of reactive oxygen species (B). Abbreviations: IR, insulin resistance, DNL, de novo lipogenesis; TCA, citric acid cycle; B-OX, beta-oxidation; FFA, free fatty acids; TG, triglyceride; VLDL, very low density lipoprotein; ROS, reactive oxygen species; IHS, isolated hepatic steatosis; NASH, non-alcoholic steatohepatitis. (A color version of this figure is available in the online journal.)

Figure 2

Effect of SAMe level on hepatic lipid metabolism and NASH development. In IHS, SAMe levels and PC–PE ratio are normal. NASH can occur when hepatic SAMe level is chronically elevated (i.e. GNMT knockdout mice) or low (i.e. MAT1A knockout mice). High SAMe level increases PC–PE ratio, activating VLDL and HDL export and increase DG production. High PC–PE ratio causes ER stress and high SAMe level activates natural killer cells in the liver. This may be a mechanism of how high SAMe level converts steatosis to NASH. Conversely, low SAMe level results in low PC–PE ratio, leading to impaired VLDL export and TG accumulation. Low PC–PE ratio increases membrane permeability and low SAMe level sensitizes the liver to LPS-induced expression and release of pro-inflammatory cytokines. These may cooperate to convert steatosis to NASH. Abbreviations: SAMe, S-adenosylmethionine; SAH, S-adenosylhomocysteine; PE, phosphatidylethanolamine; PC, phosphatidylcholine; TCA, citric acid cycle; B-OX, beta-oxidation; FFA, free fatty acids; TG, triglyceride; VLDL, very low-density lipoprotein; IHS, isolated hepatic steatosis; ROS, reactive oxygen species; ER, endoplasmic reticulum; NASH, nonalcoholic steatohepatitis. (A color version of this figure is available in the online journal.)