Diet-induced liver fat reduction associated with fasting metabolite changes but not postprandial responses

BACKGROUND: Postprandial metabolic impairments play a key role in the pathophysiology of cardiometabolic diseases. While liver fat content has been linked to distinct fasting metabolite profiles, its relationship with postprandial metabolite profiles remains unexplored. In this study, we aimed to (1) examine to what extent liver fat content is associated with the postprandial metabolomic profile beyond fasting metabolites; and (2) investigate whether diet-induced changes in liver fat content are associated with changes in plasma metabolites identified in objective 1. METHODS: In a subpopulation (n = 1986) of an existing cohort study and a 12-week dietary intervention study (n = 80), liver fat content was measured by proton magnetic resonance spectroscopy and categorized as low (< 2.5%), middle (2.5-5.5%), or high (> 5.5%). In the cohort study, plasma metabolomic profiles were quantified by NMR spectroscopy at fasting (T) and 150 min after a mixed meal (T). We examined associations between liver fat content and plasma metabolites at T, T and postprandial response (ΔT-T) using multivariate linear regression. In the intervention study, plasma metabolomic profiles were quantified at fasting (T) and at multiple postprandial time points (120, 240, and 360 min) following a mixed meal, both before and after the intervention. We further examined associations between liver fat content and plasma metabolites at T, and postprandial response (incremental area under the curves [iAUCs]) and explored associations between diet-induced changes in liver fat content and changes in identified metabolites at fasting and postprandial responses (iAUCs). RESULTS: High liver fat group was characterized by higher fasting and postprandial levels of triglycerides, all VLDL and the small LDL/HDL subclasses, ApoB, fatty acids, glycoprotein acetyls, and BCAAs, and lower medium/larger HDL subclasses, and acetate compared to the low liver fat group. In the high vs. low liver fat group, postprandial responses of cholesterol content of S-LDL, IDL, and S-HDL, glutamine and histidine, omega-3% and DHA % were lower. Diet-induced reductions in liver fat were associated with reductions in 40 fasting plasma metabolites, including VLDL-TG, tyrosine, isoleucine, fatty acid ratios, and most of the VLDL subclasses. CONCLUSIONS: Postprandial metabolomic profiling revealed additional associations between liver fat content and plasma metabolites beyond fasting measures, particularly in lipoprotein cholesterol and fatty acid composition. Diet-induced reductions in liver fat were associated with favorable changes in fasting metabolites, but not postprandial metabolite responses. Future studies with harmonized postprandial assessment are needed to further elucidate the postprandial observations and the underlying mechanisms. TRIAL REGISTRATION: The trials in this study were registered at clinicaltrials.gov as NL21981.058.08/P08.109 and NCT02194504.