Probing hepatic metabolism of [2-13C]dihydroxyacetone in vivo with 1H-decoupled hyperpolarized 13C-MR

Irene Marco-Rius,Dragana Savic,Jack J. Miller,Damian Tyler,Kerstin N. Timm,Kevin M. Brindle,De-en Hu,Alan J. Wright,Arnaud Comment

doi:10.1007/s10334-020-00884-y

Abstract

ObjectivesTo enhance detection of the products of hyperpolarized [2-13C]dihydroxyacetone metabolism for assessment of three metabolic pathways in the liver in vivo. Hyperpolarized [2-13C]DHAc emerged as a promising substrate to follow gluconeogenesis, glycolysis and the glycerol pathways. However, the use of [2-13C]DHAc in vivo has not taken off because (i) the chemical shift range of [2-13C]DHAc and its metabolic products span over 144 ppm, and (ii) 1H decoupling is required to increase spectral resolution and sensitivity. While these issues are trivial for high-field vertical-bore NMR spectrometers, horizontal-bore small-animal MR scanners are seldom equipped for such experiments.MethodsReal-time hepatic metabolism of three fed mice was probed by 1H-decoupled 13C-MR following injection of hyperpolarized [2-13C]DHAc. The spectra of [2-13C]DHAc and its metabolic products were acquired in a 7 T small-animal MR scanner using three purpose-designed spectral-spatial radiofrequency pulses that excited a spatial bandwidth of 8 mm with varying spectral bandwidths and central frequencies (chemical shifts).ResultsThe metabolic products detected in vivo include glycerol 3-phosphate, glycerol, phosphoenolpyruvate, lactate, alanine, glyceraldehyde 3-phosphate and glucose 6-phosphate. The metabolite-to-substrate ratios were comparable to those reported previously in perfused liver.DiscussionThree metabolic pathways can be probed simultaneously in the mouse liver in vivo, in real time, using hyperpolarized DHAc.

Highlights

The human liver performs a broad range of tasks that affect the function of the whole body, from maintaining plasma glucose homeostasis to filtering toxic chemicals from food and drinks [1]
The resonances observed following pulse #3 (Fig. 3d) were assigned by reference to a previous study performed in perfused livers in a glycogenolytic state [10], where the same resonances were observed after the infusion of hyperpolarized [2-13C]DHAc
We have demonstrated that HP [2-13C]DHAc enables simultaneous detection of intermediates in GNG, glycolysis and glycerol synthesis in vivo with a spectral resolution and sensitivity similar to that reported in perfused mouse liver [10]

Summary

Introduction

The human liver performs a broad range of tasks that affect the function of the whole body, from maintaining plasma glucose homeostasis to filtering toxic chemicals from food and drinks [1]. Magnetic Resonance Materials in Physics, Biology and Medicine (2021) 34:49–56 damage to the liver may result in permanent loss of liver mass, with potentially fatal consequences. Magnetic resonance (MR) could play an important role in the identification of biomarkers to assess metabolic function of the liver in situ and non-invasively. The clinical value of 13C-MR has been limited by its intrinsically low sensitivity compared to 1H-MR due to (1) its low natural abundance, (2) lower nuclear polarization, a consequence of the four times lower gyromagnetic ratio of the carbon-13 nucleus, and, where molecularly relevant, (3) splitting of the 13C resonances due to spin–spin coupling with protons. The third limitation can be resolved with 1H decoupling during 13C signal reception

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