Dynamic Post-Prandial Metabolism in Patients With Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in the Western world and is a leading cause of liver-related morbidity and mortality. Excessive caloric intake and specific nutritional components have been implicated in its pathogenesis, but the complex metabolic pathways linking nutrient consumption with hepatic fat accumulation have not yet been fully elucidated. Analysis of pathophysiology and the search for biomarkers in NAFLD has largely focused on fasting samples; the dynamic response to a caloric load has not been interrogated, beyond glucose tolerance testing. Metabolomics is a novel high-throughput technique, allowing for simultaneous detection of hundreds to thousands of metabolites, and the evaluation of their interconnectivity and causal relationships. We propose a pilot study to investigate the metabolic response of patients with NAFLD to a standardized food challenge, by applying a metabolomics-based dynamic approach. In this study we will recruit up to 50 patients with NAFLD and compare them to 12 controls with metabolic syndrome without NAFLD, and 12 healthy controls. Following an overnight fast, subjects will be situated in a metabolic chamber for continuous measurement of metabolic rates and will be given a liquid mixed meal containing approximately 30% of daily caloric requirement over a period of 15 minutes. The energy expenditure (EE) and respiratory quotient (RQ), reflecting preference for carbohydrate or fat oxidation, will be measured at 1-minute resolution. Blood will be drawn at baseline, and at 30 min, 1, 2, 4 and 24 hours after ingestion. Plasma will be separated and stored in -80 (Infinite)C. Following completion of recruitment, stored samples will be analyzed at the NCI Laboratory of Metabolism by LC/MS and GC/MS, metabolites of interest identified, and individual metabolites quantitated and normalized to their pre-prandial level. Study results will hopefully identify novel metabolic markers of disease, and uncover altered signaling pathways unique to NAFLD that are activated primarily under fed state conditions.