Abstract
The role of ketones in metabolic health has progressed over the past two decades, moving from what was perceived as a simple byproduct of fatty acid oxidation to a central player in a multiplicity of disease states. Previous work with hyperpolarized (HP) 13C has shown that ketone production can be detected when using precursors that labeled acetyl-CoA at the C1 position, often in tissues that are not normally recognized as ketogenic. Here, we assay metabolism of HP [2-13C]pyruvate in the perfused mouse liver, a classic metabolic testbed where nutritional conditions can be precisely controlled. Livers perfused with long-chain fatty acids or the medium-chain fatty acid octanoate showed no evidence of ketogenesis in the 13C spectrum. In contrast, addition of dichloroacetate, a potent inhibitor of pyruvate dehydrogenase kinase, resulted in significant production of both acetoacetate and 3-hydroxybutyrate from the pyruvate precursor. This result indicates that ketones are readily produced from carbohydrates, but only in the case where pyruvate dehydrogenase activity is upregulated.
Highlights
Ketones are known to compensate for scarcity of carbohydrates—either from dietary conditions or from a lack of stored glycogen (Werk et al, 1955; Balasse, 1979; McGarry and Foster, 1980)
While physiological free fatty acids are known to increase ketogenic rates in perfused organ systems in a dose-dependent manner similar to the mediumchain fatty acid octanoate, FFA typically induces less ketogenesis than octanoate (Krebs et al, 1969). Using these groups to modulate hepatic ketogenesis we show that an increase in pyruvate dehydrogenase (PDH) flux results in a concomitant increase in hepatic ketone production
Β-oxidation has been assumed to provide the vast majority of acetyl-CoA used for ketone production (Puchalska and Crawford, 2017)
Summary
Ketones are known to compensate for scarcity of carbohydrates—either from dietary conditions or from a lack of stored glycogen (Werk et al, 1955; Balasse, 1979; McGarry and Foster, 1980). Fletcher et al (2019) demonstrated that a decrease in ketogenesis correlated with increasing hepatic steatosis They further showed that hyperglycemia associated with NAFLD depends not on acetyl-CoA production but rather on its disposal as ketone bodies. While physiological free fatty acids are known to increase ketogenic rates in perfused organ systems in a dose-dependent manner similar to the mediumchain fatty acid octanoate, FFA typically induces less ketogenesis than octanoate (Krebs et al, 1969). Using these groups to modulate hepatic ketogenesis we show that an increase in PDH flux results in a concomitant increase in hepatic ketone production
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
