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Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide (about 25% of the general population) and 3-5% of patients develop non-alcoholic steatohepatitis (NASH), characterized by hepatocytes damage, inflammation and fibrosis, which increase the risk of developing liver failure, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD, particularly the mechanisms whereby a minority of patients develop a more severe phenotype, is still incompletely understood. In this review we examine the available literature on initial mechanisms of hepatocellular damage and inflammation, deriving from toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in the liver cells is not the main determinant of lipotoxicity and that specific lipid classes act as damaging agents. These lipotoxic species affect the cell behavior via multiple mechanisms, including activation of death receptors, endoplasmic reticulum stress, modification of mitochondrial function and oxidative stress. The gut microbiota, which provides signals through the intestine to the liver, is also reported to play a key role in lipotoxicity. Finally, we summarize the most recent lipidomic strategies utilized to explore the liver lipidome and its modifications in the course of NALFD. These include measures of lipid profiles in blood plasma and erythrocyte membranes that can surrogate to some extent lipid investigation in the liver., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Two recent randomized controlled trials demonstrated improved radiographic, histological and hepatometabolic cues of non-alcoholic steatohepatitis (NASH) in pediatric patients treated with the ω-3 fatty acid docosahexaenoic acid (DHA) in combination with vitamin D (VD) or with choline (CHO) and vitamin E (VE), the DHA-VD and DHA-CHO-VE trials, respectively). In the present study we verified the nutritional compliance to these DHA-based multivitamin treatments; lipidomics biomarkers of the reported outcome on NASH indicators were also investigated. Samples were obtained from 30 biopsy-proven pediatric NASH patients of the DHA-CHO-VE trial randomized in multivitamin treatment group and placebo group (n = 15 each), and from 12 patients of the treatment group of the DHA-VD trial. All patients underwent 6-month therapy plus 6 months of follow-up. Plasma samples and clinical data were obtained at baseline and at the end of the study (12 months). Selected biomarkers included the free form of DHA and other ω-3 fatty acid arachidonic acid (AA), indices of the vitamin E status, and some hepatic metabolites of these lipids. Radiographic and histological improvements of treated patients were associated with increased concentrations of DHA, α-linolenic acid and α-tocopherol (i.e. VE), and with decreased AA that was also investigated in complex lipids by untargetd lipidomics. As a result a significantly lowered AA/DHA ratio was observed to represent the main indicator of the response to the DHA-based therapy. Furthermore, baseline levels of AA/DHA showed strong association with NAS and US improvement. A stable correction of DHA AA metabolism interaction is associated with the curative effect of this therapy and may represent a key nutritional endpoint in the clinical management of pediatric NASH.

Lipid peroxidation is one of the earliest pathogenic events of non-alcoholic fatty liver disease (NAFLD). In this context, an increased oxidation of the lipoperoxyl radical scavenger α-tocopherol (α-TOH) should occur already in the subclinical phases of the disease to compensate for the increase oxidation of the lipid excess of liver and possibly of other tissues. However, this assumption remains unsupported by direct analytical evidence. In this study, GC-MS/MS and LC-MS/MS procedures have been developed and applied for the first time to measure the vitamin E oxidation metabolite α-tocopheryl quinone (α-TQ) in plasma of fatty liver (FL) subjects that were compared in a pilot cross-sectional study with healthy controls. The protein adducts of 4-hydroxynonenal (4-HNE) and the free form of polyunsaturated free fatty acids (PUFA) were measured as surrogate indicators of lipid peroxidation. α-TQ formation was also investigated in human liver cells after supplementation with α-TOH and/or fatty acids (to induce steatosis). Compared with controls, FL subjects showed increased (absolute and α-TOH-corrected) levels of plasma α-TQ and 4-HNE, and decreased concentrations of PUFA. α-TQ levels positively correlated with indices of liver damage and metabolic dysfunction, such as alanine aminotransferase, bilirubin and triglycerides, and negatively correlated with HDL cholesterol. Fatty acid supplementation in human hepatocytes stimulated the generation of cellular oxidants and α-TOH uptake leading to increased α-TQ formation and secretion in the extracellular medium - both were markedly stimulated by α-TOH supplementation. In conclusion, plasma α-TQ represents an early biomarker of the lipoperoxyl radical-induced oxidation of vitamin E and lipotoxicity of the fatty liver., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of α-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed α-tocopherol ω-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of α-tocopherol and decreased formation of the corresponding long-chain metabolites α-13-hydroxy and α-13-carboxy chromanols. A decreased expression was also observed for PPAR-γ and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and α-tocopherol and was also observed for PPAR-γ and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and ω-hydroxylation of α-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of α-tocopherol are impaired in experimental NAFLD., (Copyright © 2017. Published by Elsevier Inc.)