Tracing oxidative metabolism: [¹¹C]acetate-PET with radiometabolite correction reveals early hepatic metabolic alterations in the diet-induced MAFLD model.

[¹¹C]Acetate-positron emission tomography (PET), widely applied in cardiology and oncology, offers unique potential as a noninvasive imaging method for assessing oxidative metabolism in metabolic disorders. In this study, we investigated its ability to detect early metabolic changes in the diet-induced model of metabolic dysfunction-associated fatty liver disease (MAFLD). Sprague Dawley rats were maintained on either a standard diet or a high-fat diet for 10 weeks before undergoing dynamic [11C]acetate-PET/computed tomography measurement. Four weeks later, radiometabolite analysis was performed in half of the animals, while the remainder underwent nonradioactive blood gas measurements. Uptake of [11C]acetate at 60 min after administration was quantified in the kidneys, myocardium, and liver (SUVmean and SUVmax), followed by analysis of time activity curves (employing AUC), alongside monoexponential clearance rates (kmono) and kinetic modeling using 1- and 2-tissue compartment models (Vt). MAFLD animals exhibited altered [¹¹C]acetate metabolism, with [11C]CO2 excretion patterns validated by non-radiative blood gas analyses. While healthy rats showed a radiometabolite peak at ∼30 min postinjection, MAFLD rats displayed an earlier maximum at 5 min and a secondary peak at 40 min, indicating a shift in longitudinal oxidative metabolism. Despite contradictions between SUVs and kmono, compartmental modeling demonstrated a clear separation of healthy from MAFLD groups, solely in hepatic volume of distribution (Vt). These results establish repurposing of [11C]acetate-PET, particularly when combined with metabolite correction, as a sensitive approach for phenotyping and identifying metabolic alterations in MAFLD and also hold translational promise for understanding and monitoring of other obesity-related liver dysfunctions.