Insulin resistance is a major contributor to nonalcoholic fatty liver disease (NAFLD) . NAFLD is a progressive disease that leads to impaired hepatic function and liver cirrhosis. Increased ketogenesis has been correlated with a protective phenotype in mice and humans. During our study we identified differences in acetyl-CoA partitioning between the oxidative tricarboxylic acid cycle (TCA) , and ketogenesis. 8 week old C57Bl6 mice were fed a high fat or low fat (60% or 10% fat by calories respectively) diet for 16 weeks before performing liver perfusion in 12-14 hours fasted mice with 1 mM [D15]-octanoate fatty acid tracer. The effluent perfusate was collected and GC-MS analysis was performed to identify the distribution of deuterium label. Enrichments were greater in ketones (˜70%) than the TCA cycle (˜20%) with the unexpected determination that terminal acetyl-CoA units derived from fatty acids were preferentially used for ketogenesis as compared to internal acetyl-CoA units (Figure 1) . These changes were confirmed with fractional enrichment analysis and metabolic modeling of the ketogenic pathway and TCA cycle. This finding elucidates differential handling of acetyl-CoA that could be exploited for therapeutic benefit to NAFLD.


M.Mcleod: None. M.Ragavan: None. A.Rushin: None. M.Merritt: None. A.G.Giacalone: None.

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