Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms

Figure 1. In normal liver, miR-122, -192, and -155 act as suppressors of lipid biosynthesis, while miR-27a/b suppresses gluconeogenesis. In the context of excess fatty acids and carbohydrates, as occurs during the development of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), each of those miRNAs are found in reduced abundance within the liver, presumably due to excess export. The loss of the inhibitory actions allows for a metabolic shift in favor of lipid and glucose production and away from lipid oxidation. The increase in miR-34a, acting through the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) axis, also contributes to a reduction in lipid oxidation. miR-155 and -192 play additional roles in activating M1 macrophages, contributing to the inflammatory and insulin-resistant milieu in adipose tissue and the liver. Green arrows reflect stimulatory actions and blunted red arrow represent inhibitory actions. β-OX, beta oxidation; FFA, free fatty acids; High-carb, high carbohydrate; Inflam, inflammation; IR, insulin resistance; miR, microRNA; miRNA, microRNA; TCA, tricarboxylic acid; TG, triglycerides; VLDL, very-low density lipoproteins.

Figure 2. Maternal malnutrition imparts long-lasting detrimental effects on offspring liver. Placental transfer of excess circulating free fatty acids (FFA) and carbohydrates from obese mother induces mitochondrial dysfunction and endoplasmic reticulum (ER) stress. The resulting mitochondrial dysfunction predisposes the offspring liver to reduced lipid peroxidation by decreasing SIRT3 and PGC1α expression, oxidative stress, inflammation, insulin resistance (IR), and increased gluconeogenesis leading to the development of NAFLD. In utero exposure to an obesogenic environment also induces early microbial dysbiosis, leading to the reprogramming of offspring liver towards an inflammatory phenotype by epigenetic modifications. β-OX, beta oxidation; ETC, electron transport chain; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Figure 3. Bone-marrow-derived and liver resident macrophages in offspring from obese mothers have trained memories towards inflammatory phenotypes and secrete inflammatory and fibrogenic factors to induce hepatic stellate cell activation. Activated stellate cells undergo rapid proliferation to further worsen inflammation, ultimately leading to fibrosis, organ failure, and death. HCC, hepatocellular carcinoma.