BACKGROUND & AIMS
Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In non-alcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD.
METHODS
In a prospective clinical study, 37 NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis and lipid particle isolation then confirmed in a mouse model.
RESULTS
There was a specific increase of multiple plasma diacylglycerols (DAG) species at 4 hours postprandially in NAFLD subjects but not in controls. This was replicated in a NASH mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of VLDL in human samples and stable-isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids.
CONCLUSIONS
We identified a selective insulin-related increase in hepatic secretion of endogenously-derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. While it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.