Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics

Abstract

As a result of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represents a global medical concern in childhood with a closely related increased cardiometabolic risk. Knowledge on NAFLD pathophysiology has been largely expanded over the last decades. Besides the well-known key NAFLD genes (including the I148M variant of the PNPLA3 gene, the E167K allele of the TM6SF2, the GCKR gene, the MBOAT7-TMC4 rs641738 variant, and the rs72613567:TA variant in the HSD17B13 gene), an intriguing pathogenic role has also been demonstrated for the gut microbiota. More interestingly, evidence has added new factors involved in the "multiple hits" theory. In particular, omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment. In fact, different branches of omics including metabolomics, lipidomics (in particular sphingolipids and ceramides), transcriptomics (including micro RNAs), epigenomics (such as DNA methylation), proteomics, and glycomics represent the most attractive pathogenic elements in NAFLD development, by providing insightful perspectives in this field. In this perspective, we aimed to provide a comprehensive overview of NAFLD pathophysiology in children, from the oldest pathogenic elements (including genetics) to the newest intriguing perspectives (such as omics branches).

Keywords: Fatty; Genetics; Lipidomics; Liver; Pediatric.

Figure 1

The role of the gut-liver axis in non-alcoholic fatty liver disease. A: In healthy patients, the liver through the transport of bile salts and antimicrobial molecules to the intestinal lumen contributes to the maintenance of gut eubiosis. Conversely, the gut regulates bile acids (BAs) composition. BAs using farnesoid X receptor in the enterocytes and G protein-coupled bile acid receptor 1 are involved in the regulation of glucose and lipid metabolism, anti-inflammatory immune responses and host energy expenditure; B: In subjects with non-alcoholic fatty liver disease, altered gut microbial composition (dysbiosis), small intestinal bacterial overgrowth, and increased intestinal permeability (resulting from different factors including high-fat Western diet, genetic, inflammation) promote the influx of microbial-associated molecular patterns or pathogen-associated molecular patterns into the portal system reaching the liver. These molecular patterns are able to induce inflammatory responses mediated by the activation of pattern recognition receptors, like toll-like receptor, in Kupffer cells and hepatic stellate cells, leading to liver inflammation and fibrosis.

Figure 2

Main changes in hepatic lipid composition in non-alcoholic fatty liver disease. In non-alcoholic fatty liver disease subjects, hepatic concentrations of triacylglycerols, saturated fatty acids, free cholesterol, sphingolipids, glycerophospholipids and eicosanoids are increased, whereas ω-3 polyunsaturated fatty acids (PUFAs) and specialized proresolving mediators of PUFAs are decreased. Monounsaturated fatty acids, lysophosphatidylcholine and ceramide are also increased in the liver of these subjects.