Probing perturbed hepatic metabolism in bile-duct-ligated rats with hyperpolarized 13C pyruvate and arginine

Cristina Ramona Cudalbu, Dmitri Firsov, Rolf Gruetter, Hikari Ananda Infinity Yoshihara
2018
Poster talk

Abstract

Detoxification of ammonia by the urea cycle and maintenance of glucose homeostasis by gluconeogenesis are two critical functions of the liver. The bile duct ligation (BDL) model of cirrhosis was used to test the ability of hyperpolarized [6-13C]arginine and [1-13C]pyruvate to detect changes in liver function. The conversion of hyperpolarized L-[6-13C]arginine to 13C-urea was observed in a sham-operated rat but not in BDL rats. Striking differences in pyruvate metabolism between the two groups were also noted, indicating that these probes can sense changes in hepatic mitochondrial and cytoplasmic metabolism associated with biliary cirrhosis.

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https://infoscience.epfl.ch/record/279675?ln=en

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Aspartic acid is involved in several central metabolic pathways, including gluconeogenesis, the urea cycle, de novo nucleotide synthesis, the malate-aspartate shuttle, and via transmination the TCA cycle. The conversion in vivo of hyperpolarized [1-13C]pyruvate to aspartate, via pyruvate carboxylation to oxaloacetate, has been reported in rat kidney [1] and in the mouse liver [2]. Additionally, the metabolism of hyperpolarized [1-13C]aspartate to oxaloacetate has been noted in cultured cells supplemented with 2-oxoglutarate [3]. Aspartate is also of interest with its conversion to succinate in ischemic tissue implicated in subsequent reperfusion injury [4]. Here we report initial experiments with hyperpolarized [1-13C]aspartate in the rat kidney. [1-13C]Aspartic acid was formulated with OX063 trityl radical as in [3] as the tris salt, with the addition of glycerol (14% v/v) to improve glassing. The formulation is highly viscous and dissolves poorly, limiting the usable dose. Experiments were performed in a 9.4T animal scanner and a 7T polarizer operating at 1K, with automated rapid transfer and infusion. Rats (n=2) were isoflurane anesthesized, a femoral vein catheterized, and a quadrature 13C surface coil placed over the kidney. Respiration-triggered (TR ~3s) pulse-acquire (BIR4-30o) scans were started at the time of infusion of [1-13C]aspartate (~16 μmol/kg in 1.2 ml). Three metabolites were detected, with chemical shifts of 183.51 ppm (1.5%), 182.31 ppm (0.5%) and 181.26 ppm (0.6%), corresponding to [1-13C]malate, [4-13C]malate and an unidentified species provisionally assigned as N-acetyl[1-13C]aspartate. [4- 13C]aspartate was at natural abundance, but [4-13C]malate results from conversion to fumarate or succinate and label scrambling, and the greater prominence of [1-13C]malate indicates oxaloacetate as an intermediate. These results show the potential of hyperpolarized [1- 13C]aspartate as an in vivo metabolic probe.

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[13C]bicarbonate labelled from hyperpolarized [1-13C]pyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state

Josefina Adriana Maria Bastiaansen, Emine Can, Arnaud Comment, Rolf Gruetter, Hikari Ananda Infinity Yoshihara

Hyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.

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