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Nonalcoholic fatty liver disease (NAFLD), nowadays the most prevalent chronic liver disease in Western countries, is characterized by a variable phenotype ranging from steatosis to nonalcoholic steatohepatitis (NASH). Intracellular lipid accumulation is considered the hallmark of NAFLD and is associated with lipotoxicity and inflammation, as well as increased oxidative stress levels. In this study, a lipidomic approach was used to investigate the plasma lipidome of 12 NASH patients, 10 Nonalcoholic Fatty Liver (NAFL) patients, and 15 healthy controls, revealing significant alterations in lipid classes, such as glycerolipids and glycerophospholipids, as well as fatty acid compositions in the context of steatosis and steatohepatitis. A machine learning XGBoost algorithm identified a panel of 15 plasma biomarkers, including HOMA-IR, BMI, platelets count, LDL-c, ferritin, AST, FA 12:0, FA 18:3 ω3, FA 20:4 ω6/FA 20:5 ω3, CAR 4:0, LPC 20:4, LPC O-16:1, LPE 18:0, DG 18:1_18:2, and CE 20:4 for predicting steatohepatitis. This research offers insights into the connection between imbalanced lipid metabolism and the formation and progression of NAFL D, while also supporting previous research findings. Future studies on lipid metabolism could lead to new therapeutic approaches and enhanced risk assessment methods, as the shift from isolated steatosis to NASH is currently poorly understood.

Detailed investigation of the lipidome remodeling upon normal weight conditions, obesity, or weight loss, as well as the influence of physical activity, can help to understand the mechanisms underlying dyslipidemia in metabolic conditions correlated to the emergence and progression of non-alcoholic fatty liver disease (NAFLD). C57BL/6 male mice were fed a normal diet (ND) or a high-fat diet (HFD) for 20 weeks. Subgroups within the high-fat diet (HFD) group underwent different interventions: some engaged in exercise (HFDex), others were subjected to weight loss (WL) by changing from the HFD to ND, and some underwent a combination of weight loss and exercise (WLex) during the final 8 weeks of the 20-week feeding period. To support our understanding, not only tissue-specific lipid remodeling mechanisms but also the cross-talk between different tissues and their impact on the systemic regulation of lipid metabolism are essential. Exercise and weight loss-induced specific adaptations in the liver and visceral adipose tissue lipidomes of mice were explored by the UPLC-TOF-MS/MS untargeted lipidomics methodology. Lipidomic signatures of ND and HFD-fed mice undergoing weight loss were compared with animals with and without physical exercise. Several lipid classes were identified as contributing factors in the discrimination of the groups by multivariate analysis models, such as glycerolipids, glycerophospholipids, sphingolipids, and fatty acids, with respect to liver samples, whereas triglycerides were the only lipid class identified in visceral adipose tissue. Lipids found to be dysregulated in HFD animals are related to well-established pathways involved in the biosynthesis of PC, PE, and TG metabolism. These show a reversing trend back to basic levels of ND when animals change to a normal diet after 12 weeks, whereas the impact of exercise, though in some cases it slightly enhances the reversing trend, is not clear.

Patients with non-alcoholic steatohepatitis (NASH) show significantly faster progress in the stages of fibrosis compared to those with non-alcoholic fatty liver (NAFL) disease. The non-invasive diagnosis of NASH remains an unmet clinical need. Preliminary data have shown that sphingolipids, especially ceramides, fatty acids, and other lipid classes may be related to the presence of NASH and the histological activity of the disease. The aim of our study was to assess the association of certain plasma lipid classes, such as fatty acids, acylcarnitines, and ceramides, with the histopathological findings in patients with NASH. The study included three groups: patients with NASH (N = 12), NAFL (N = 10), and healthy [non non-alcoholic fatty liver disease (NAFLD)] controls (N = 15). Plasma samples were collected after 12 h of fasting, and targeted analyses for fatty acids, acylcarnitines, and ceramides were performed. Baseline clinical and demographic characteristics were collected. There was no significant difference in baseline characteristics across the three groups or between NAFL and NASH patients. Patients with NASH had increased levels of several fatty acids, including, among others, fatty acid (FA) 14:0, FA 15:0, FA 18:0, FA 18:3n3, as well as Cer(d18:1/16:0), compared to NAFL patients and healthy controls. No significant difference was found between NAFL patients and healthy controls. In conclusion, patients with NASH exhibited a distinctive plasma lipid profile that can differentiate them from NAFL patients and non-NAFLD populations. More data from larger cohorts are needed to validate these findings and examine possible implications for diagnostic and management strategies of the disease.