Detecting de novo Hepatic Ketogenesis Using Hyperpolarized [2-¹³C] Pyruvate

Area of Science:

• Biochemistry
• Metabolic pathways
• Physiology

Background:

• Ketones were historically viewed as mere fatty acid oxidation byproducts.
• Recent research suggests ketones play a significant role in various disease states.
• Hyperpolarized (HP) ¹³C techniques have detected ketone production from labeled acetyl-CoA precursors.

Purpose of the Study:

• To investigate ketone production from carbohydrate metabolism using HP [2-¹³C]pyruvate.
• To examine the influence of pyruvate dehydrogenase activity on ketogenesis in the perfused mouse liver.
• To determine if carbohydrates can serve as a direct precursor for ketone bodies.

Main Methods:

• Utilized a perfused mouse liver model for controlled metabolic experiments.
• Administered hyperpolarized [2-¹³C]pyruvate as a metabolic tracer.
• Analyzed ¹³C spectra to detect ketogenesis under varying conditions (fatty acids, octanoate, dichloroacetate).

Main Results:

• No ketogenesis was observed when livers were perfused with long-chain fatty acids or octanoate.
• Significant production of acetoacetate and 3-hydroxybutyrate occurred when dichloroacetate (a pyruvate dehydrogenase kinase inhibitor) was added.
• This indicates ketone body synthesis from carbohydrate sources is feasible under specific enzymatic conditions.

Conclusions:

• Ketone bodies can be readily produced from carbohydrate precursors like pyruvate.
• The key regulatory step for carbohydrate-driven ketogenesis is the activity of pyruvate dehydrogenase.
• This finding highlights a previously underappreciated pathway for ketone production in metabolic health and disease.