Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease.

Little is known about lipid changes that occur in the setting of metabolic-dysfunction-associated steatotic liver disease (MASLD) regression. We previously reported improvements in hepatic steatosis, de novo lipogenesis (DNL), and metabolomic profiles associated with oxidative stress, inflammation, and selected lipid metabolism in 40 adolescent boys (11-16 y) with hepatic steatosis ≥5% (98% meeting the definition of MASLD). Participants were randomized to a low-free-sugar diet (LFSD) (n = 20) or usual diet (n = 20) for 8 weeks. Here, we employed untargeted/targeted lipidomics to examine lipid adaptations associated with the LFSD and improvement of hepatic steatosis. Our LC-MS/MS analysis revealed decreased triglycerides (TGs), diacylglycerols (DGs), cholesteryl esters (ChE), lysophosphatidylcholine (LPC), and phosphatidylcholine (PC) species with the diet intervention (p < 0.05). Network analysis demonstrated significantly lower levels of palmitate-enriched TG species post-intervention, mirroring the previously shown reduction in DNL in response to the LFSD. Targeted oxylipins analysis revealed a decrease in the abundance of 8-isoprostane and 14,15-DiHET and an increase in 8,9-DiHET (p < 0.05). Overall, we observed reductions in TGs, DGs, ChE, PC, and LPC species among participants in the LFSD group. These same lipids have been associated with MASLD progression; therefore, our findings may indicate normalization of key biological processes, including lipid metabolism, insulin resistance, and lipotoxicity. Additionally, our targeted oxylipins assay revealed novel changes in eicosanoids, suggesting improvements in oxidative stress. Future studies are needed to elucidate the mechanisms of these findings and prospects of these lipids as biomarkers of MASLD regression.

Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer trial study protocol: a randomised clinical trial of fibre-rich legumes targeting the gut microbiome, metabolome and gut transit time of overweight and obese patients with a history of noncancerous adenomatous polyps.

INTRODUCTION: Recently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC). METHODS/DESIGN: This study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1-3 and one meal/day in months 4-6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1-2 pounds per week. ETHICS AND DISSEMINATION: The National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563). TRIAL REGISTRATION NUMBER: NCT04780477.

Validation of a screening panel for pediatric metabolic dysfunction-associated steatotic liver disease using metabolomics.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, is the most common liver disease in children. Liver biopsy remains the gold standard for diagnosis, although more efficient screening methods are needed. We previously developed a novel NAFLD screening panel in youth using machine learning applied to high-resolution metabolomics and clinical phenotype data. Our objective was to validate this panel in a separate cohort, which consisted of a combined cross-sectional sample of 161 children with stored frozen samples (75% male, 12.8±2.6 years of age, body mass index 31.0±7.0 kg/m2, 81% with MASLD, 58% Hispanic race/ethnicity). METHODS: Clinical data were collected from all children, and high-resolution metabolomics was performed using their fasting serum samples. MASLD was assessed by MRI-proton density fat fraction or liver biopsy and cardiometabolic factors. Our previously developed panel included waist circumference, triglycerides, whole-body insulin sensitivity index, 3 amino acids, 2 phospholipids, dihydrothymine, and 2 unknowns. To improve feasibility, a simplified version without the unknowns was utilized in the present study. Since the panel was modified, the data were split into training (67%) and test (33%) sets to assess the validity of the panel. RESULTS: Our present highest-performing modified model, with 4 clinical variables and 8 metabolomics features, achieved an AUROC of 0.92, 95% sensitivity, and 80% specificity for detecting MASLD in the test set. CONCLUSIONS: Therefore, this panel has promising potential for use as a screening tool for MASLD in youth.

The Impact and Burden of Dietary Sugars on the Liver.

NAFLD, or metabolic dysfunction-associated steatotic liver disease, has increased in prevalence hand in hand with the rise in obesity and increased free sugars in the food supply. The causes of NAFLD are genetic in origin combined with environmental drivers of the disease phenotype. Dietary intake of added sugars has been shown to have a major role in the phenotypic onset and progression of the disease. Simple sugars are key drivers of steatosis, likely through fueling de novo lipogenesis, the conversion of excess carbohydrates into fatty acids, but also appear to upregulate lipogenic metabolism and trigger hyperinsulinemia, another driver. NAFLD carries a clinical burden as it is associated with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Patient quality of life is also impacted, and there is an enormous economic burden due to healthcare use, which is likely to increase in the coming years. This review aims to discuss the role of dietary sugar in NAFLD pathogenesis, the health and economic burden, and the promising potential of sugar reduction to improve health outcomes for patients with this chronic liver disease.

Metabolome × Microbiome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys.

Dietary sugar reduction is one therapeutic strategy for improving nonalcoholic fatty liver disease (NAFLD), and the underlying mechanisms for this effect warrant further investigation. Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic fat reductions in youth with NAFLD. Data/samples were from a randomized controlled trial in adolescent boys (11-16 years, mean ± SD: 13.0 ± 1.9 years) with biopsy-proven NAFLD who were either provided a low free-sugar diet (LFSD) (n = 20) or consumed their usual diet (n = 20) for 8 weeks. Plasma metabolomics was performed on samples from all 40 participants by coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with mass spectrometry. In a sub-sample (n = 8 LFSD group and n = 10 usual diet group), 16S ribosomal RNA (rRNA) sequencing was performed on stool to examine changes in microbial composition/diversity. The diet treatment was associated with differential expression of 419 HILIC and 205 C18 metabolite features (p < 0.05), which were enriched in amino acid pathways, including methionine/cysteine and serine/glycine/alanine metabolism (p < 0.05), and lipid pathways, including omega-3 and linoleate metabolism (p < 0.05). Quantified metabolites that were differentially changed in the LFSD group, compared to usual diet group, and representative of these enriched metabolic pathways included increased serine (p = 0.001), glycine (p = 0.004), 2-aminobutyric acid (p = 0.012), and 3-hydroxybutyric acid (p = 0.005), and decreased linolenic acid (p = 0.006). Microbiome changes included an increase in richness at the phylum level and changes in a few genera within Firmicutes. In conclusion, the LFSD treatment, compared to usual diet, was associated with metabolome and microbiome changes that may reflect biological mechanisms linking dietary sugar restriction to a therapeutic decrease in hepatic fat. Studies are needed to validate our findings and test the utility of these "omics" changes as response biomarkers.