title: Real-time detection of hepatic gluconeogenic and glycogenolytic states using hyperpolarized [2-13C]dihydroxyacetone.
abstract: Glycogenolysis and gluconeogenesis are sensitive to nutritional state, and the net direction of flux is controlled by multiple enzymatic steps. This delicate balance in the liver is disrupted by a variety of pathological states including cancer and diabetes mellitus. Hyperpolarized carbon-13 magnetic resonance is a new metabolic imaging technique that can probe intermediary metabolism nondestructively. There are currently no methods to rapidly distinguish livers in a gluconeogenic from glycogenolytic state. Here we use the gluconeogenic precursor dihydroxyacetone (DHA) to deliver hyperpolarized carbon-13 to the perfused mouse liver. DHA enters gluconeogenesis at the level of the trioses. Perfusion conditions were designed to establish either a gluconeogenic or a glycogenolytic state. Unexpectedly, we found that [2-(13)C]DHA was metabolized within a few seconds to the common intermediates and end products of both glycolysis and gluconeogenesis under both conditions, including [2,5-(13)C]glucose, [2-(13)C]glycerol 3-phosphate, [2-(13)C]phosphoenolpyruvate (PEP), [2-(13)C]pyruvate, [2-(13)C]alanine, and [2-(13)C]lactate. [2-(13)C]Phosphoenolpyruvate, a key branch point in gluconeogenesis and glycolysis, was monitored in functioning tissue for the first time. Observation of [2-(13)C]PEP was not anticipated as the free energy difference between PEP and pyruvate is large. Pyruvate kinase is the only regulatory step of the common glycolytic-gluconeogenic pathway that appears to exert significant control over the kinetics of any metabolites of DHA. A ratio of glycolytic to gluconeogenic products distinguished the gluconeogenic from glycogenolytic state in these functioning livers.
authors.affiliation: From the Advanced Imaging Research Center.
authors.forename: Karlos X
authors.initials: KX
authors.lastname: Moreno
authors.affiliation: From the Advanced Imaging Research Center.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.affiliation: Children's Medical Center Research Institute, and.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: From the Advanced Imaging Research Center, Departments of Pharmacology and.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.affiliation: From the Advanced Imaging Research Center, Radiology, University of Texas - Southwestern Medical Center, Dallas, Texas 75390 and the Veterans Affairs North Texas Healthcare System, Lancaster, Texas 75216.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Malloy
authors.affiliation: From the Advanced Imaging Research Center, Radiology, University of Texas - Southwestern Medical Center, Dallas, Texas 75390 and matthew.merritt@utsouthwestern.edu.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002247:Carbon Isotopes; D004098:Dihydroxyacetone; D005260:Female; D005943:Gluconeogenesis; D050261:Glycogenolysis; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: D002247:Carbon Isotopes; D004098:Dihydroxyacetone
keywords: Diabetes; Dihydroxyacetone; Gluconeogenesis; Glucose Metabolism; Glycogenolytic; Glycolysis; Hyperpolarization; Nuclear Magnetic Resonance (NMR)