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The rise in paediatric non-alcoholic fatty liver disease (NAFLD) is particularly alarming. We recently reported that Hydroxytyrosol (HXT) and Vitamin E (VitE) may improve oxidative stress, insulin resistance, and steatosis in children with biopsy-proven NAFLD. Here, we investigated if HXT+VitE may reduce systemic inflammation in the above-mentioned patients. This study analysed the plasma levels of IL (interleukin)-6, IL-1β, IL-10, tumour necrosis factor (TNF)-α, 4‑hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′deoxyguanosine (8-OHdG) in children enrolled in the HXT+VitE trial (ClinicalTrials.gov, NCT02842567). Changes in markers of systemic inflammation were found in both placebo (Pla) and HXT+VitE. In particular, after four months, the levels of IL-1β and TNF-α were reduced in both groups, while IL-6 decreased, and IL-10 increased significantly only in the group treated with HXT+VitE. Children treated with HXT+VitE showed a significant decrease of 4-HNE and 8-OHdG that correlated with the improvement of triglyceride levels. Noticeably, only the 8-OHdG decrease correlated with steatosis amelioration and with the increase of IL-10 levels. The treatment with HXT and VitE reduced the NAFLD-related systemic inflammation in children, mainly by an increase of IL-10 circulating levels that occurred in response to DNA damage recovery, ultimately improving steatosis and hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Abstract Nonalcoholic fatty liver disease (NAFLD) is a multifaceted disorder that ranges from simple fatty liver to nonalcoholic steatohepatitis (NASH) with or without fibrosis, which may evolve toward cirrhosis and hepatocellular carcinoma. It is currently considered a "global" and "epidemic" disease, whose prevalence is progressively increasing even in pediatric age. The incidence of NAFLD is very high in overweight/obese children, and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, for NAFLD, there are few guidelines for diagnostic and follow-up methods, and scarce validated protocols for treatment. The initial indications consist of gradual weight loss and regular exercise, but in children, the difficulty of adhering to long-term behavioral changes makes this approach limited. The purpose of this narrative review is to examine the mechanism underlying the pathogenic mechanisms that lead to NAFLD in children, with a major focus on the role of nutrition. Because this is particularly relevant in light of the absence of pharmacological treatments suitable for children, we also overview clinical studies on the potential effects of nutritional supplementations, including vitamins, docosahexaenoic acid, and probiotics.in children. To this aim, updated search was conducted on PubMed and clinicaltrials.gov databases. Future research should consider additional clinical studies in pediatric NAFLD patients to validate the benefits of dietary supplements and to define the appropriate dosage and duration for intervention. Furthermore, experimental studies with -omics approaches could be helpful to deepen the related mechanisms and to search for a possible optimal supplement combination against NAFLD in children. [ABSTRACT FROM AUTHOR]

• The KLB rs17618244 variant increases the risk of ballooning and lobular inflammation in children with NAFLD. • KLB plasma levels are lower in carriers of the rs17618244 minor A allele. • KLB plasma levels are associated with lobular inflammation, ballooning and fibrosis. • KLB mutant induces intracellular lipid accumulation in HepG2 and Huh7. • KLB mutant causes upregulation of lipotoxic and proinflammatory genes. Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes. [ABSTRACT FROM AUTHOR]

Abstract: High-fat and high-carbohydrate diets may predispose to simple steatosis, alone or associated with necroinflammation and fibrosis (steatohepatitis). However, there are few reports about the real effect of these nutrients on hepatocyte redox homeostasis and consequent molecular derangement. Here, we investigated whether different diets would induce oxidative damage in primary rat hepatocytes and thereby affect the activity of phosphatase and tensin homolog (PTEN). We used Sprague–Dawley rats fed, for 14 weeks, a standard diet (SD), a high-fat/low-carbohydrate diet (HFD-LC), a normal-fat/high-fructose diet (NFD-HF), or a high-fat/high-fructose diet (HFD-HF). Metabolic and histological parameters were analyzed in blood and liver samples, while oxidative stress markers and related posttranscriptional modification of PTEN were analyzed in isolated hepatocytes. Our results indicate that different dietetic hypercaloric regimens caused liver damage and a significant increase of body and liver weight, as well as elevated plasma levels of alanine aminotransferase, triglycerides and insulin. Hepatocytes from NFD-HF and HFD-HF rats displayed a decrement of cell viability and proliferation rate. Hepatocytes from animals treated with hypercaloric regimens also exhibited oxidative stress greater than SD hepatocytes. Finally, NFD-HF and HFD-HF hepatocytes showed an increased PTEN phosphorylation and decreased PTEN activity, which seem strongly correlated to an increased glutathionylation of the protein. In conclusion, we demonstrate that fructose-enriched diets cause a tissue and hepatocyte damage that might exacerbate those observed in the presence of high-fat alone and might render, via redox homeostasis imbalance, the hepatocytes more prone to posttranslational modifications and activity alteration of PTEN. [Copyright &y& Elsevier]