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

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions.

Keywords: clinical biomarkers; developmental programming; microRNAs; microbial dysbiosis; pediatric NAFLD; trained immunity.

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.