Jun Chen1, Edward P Hackett1, Zoltan Kovacs1, Craig R Malloy1,2,1, Jae Mo Park1,1,3. 1. Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. 2. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. 3. Department of Electrical and Computer Engineering, The University of Texas at Dallas, Richardson, Texas, USA.
Abstract
PURPOSE: To evaluate the utility of hyperpolarized [1-13 C]-l-lactate to detect hepatic pyruvate carboxylase activity in vivo under fed and fasted conditions. METHODS: [1-13 C]-labeled sodium L-lactate was polarized using a dynamic nuclear polarizer. Polarization level and the T1 were measured in vitro in a 3 Telsa MR scanner. Two groups of healthy rats (fasted vs. fed) were prepared for in vivo studies. Each rat was anesthetized and intravenously injected with 60-mM hyperpolarized [1-13 C]-l-lactate, immediately followed by dynamic acquisition of 13 C (carbon-13) MR spectra from the liver at 3 Tesla. The dosage-dependence of the 13 C-products was also investigated by performing another injection of an equal volume of 30-mM hyperpolarized [1-13 C]-l-lactate. RESULTS: T1 and liquid polarization level of [1-13 C]-l-lactate were estimated as 67.8 s and 40.0%, respectively. [1-13 C]pyruvate and [1-13 C]alanine, [13 C]bicarbonate ( HCO 3 - ) and [1-13 C]aspartate were produced from hyperpolarized [1-13 C]-l-lactate in rat liver. Smaller HCO 3 - and larger aspartate were measured in the fed group compared to the fasted group. Pyruvate and alanine production were increased in proportion to the lactate concentration, whereas the amount of HCO 3 - and aspartate production was consistent between 30-mM and 60-mM lactate injections. CONCLUSION: This study demonstrates that a unique biomarker of pyruvate carboxylase flux, the appearance of [1-13 C]aspartate from [1-13 C]-l-lactate, is sensitive to nutritional state and may be monitored in vivo at 3 Tesla. Because [13 C] HCO 3 - is largely produced by pyruvate dehydrogenase flux, these results suggest that the ratio of [1-13 C]aspartate and [13 C] HCO 3 - (aspartate/ HCO 3 - ) reflects the saturable pyruvate carboxylase/pyruvate dehydrogenase enzyme activities.
PURPOSE: To evaluate the utility of hyperpolarized [1-13 C]-l-lactate to detect hepatic pyruvate carboxylase activity in vivo under fed and fasted conditions. METHODS: [1-13 C]-labeled sodium L-lactate was polarized using a dynamic nuclear polarizer. Polarization level and the T1 were measured in vitro in a 3 Telsa MR scanner. Two groups of healthy rats (fasted vs. fed) were prepared for in vivo studies. Each rat was anesthetized and intravenously injected with 60-mM hyperpolarized [1-13 C]-l-lactate, immediately followed by dynamic acquisition of 13 C (carbon-13) MR spectra from the liver at 3 Tesla. The dosage-dependence of the 13 C-products was also investigated by performing another injection of an equal volume of 30-mM hyperpolarized [1-13 C]-l-lactate. RESULTS: T1 and liquid polarization level of [1-13 C]-l-lactate were estimated as 67.8 s and 40.0%, respectively. [1-13 C]pyruvate and [1-13 C]alanine, [13 C]bicarbonate ( HCO 3 - ) and [1-13 C]aspartate were produced from hyperpolarized [1-13 C]-l-lactate in rat liver. Smaller HCO 3 - and larger aspartate were measured in the fed group compared to the fasted group. Pyruvate and alanine production were increased in proportion to the lactate concentration, whereas the amount of HCO 3 - and aspartate production was consistent between 30-mM and 60-mM lactate injections. CONCLUSION: This study demonstrates that a unique biomarker of pyruvate carboxylase flux, the appearance of [1-13 C]aspartate from [1-13 C]-l-lactate, is sensitive to nutritional state and may be monitored in vivo at 3 Tesla. Because [13 C] HCO 3 - is largely produced by pyruvate dehydrogenase flux, these results suggest that the ratio of [1-13 C]aspartate and [13 C] HCO 3 - (aspartate/ HCO 3 - ) reflects the saturable pyruvate carboxylase/pyruvate dehydrogenase enzyme activities.
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