Monitoring acute metabolic changes in the liver and kidneys induced by fructose and glucose using hyperpolarized [2‐¹³C]dihydroxyacetone

Abstract

Purpose To investigate acute changes in glucose metabolism in liver and kidneys in vivo after a bolus injection of either fructose or glucose, using hyperpolarized [2‐13C]dihydroxyacetone. Methods Spatially registered, dynamic, multi-slice MRS were acquired for the metabolic products of [2-13C]dihydroxyacetone in liver and kidneys. Metabolism was probed in 13 fasted rats at three time points: 0, 70 and 140 minutes. At 60 minutes, rats were injected intravenously with fructose (n=5) or glucose (n=4) at 0.8 g/kg to initiate acute response. Controls (n=4) did not receive a carbohydrate challenge. Results Ten minutes after fructose infusion, levels of [2-13C]phosphoenolpyruvate and [2-13C]glycerol-3-phosphate halved in liver: 51% (P=0.0010) and 47% (P=0.0001) of baseline, respectively. Seventy minutes later, levels returned to baseline. The glucose challenge did not alter the signals significantly, nor did repeated administration of the dihydroxyacetone imaging bolus. In kidneys, no statistically significant changes were detected after sugar infusion other than a 20% increase of the glycerol-3-phosphate signal between 10 and 80 minutes after fructose injection (P=0.0028). Conclusion Hyperpolarized [2-13C]dihydroxyacetone detects a real-time, transient metabolic response of the liver to an acute fructose challenge. Observed effects possibly include ATP depletion and changes in the unlabeled pool sizes of glycolytic intermediates.

Dihydroxyacetone induces G2/M arrest and apoptotic cell death in A375P melanoma cells

“…Absorption of the DHA into cells and its conversion into metabolically active DHAP, likely dictate the degree to which DHA can perturb metabolic pathways and induce oxidative stress. This is consistent with recent work injecting hyperpolarized [2‐ 13 C] DHA into mice, which showed rapid distribution of DHA to the liver and kidneys and metabolism of DHA to DHAP by liver and kidney cells, but showed different conversion rates of DHAP to glyceraldehyde 3‐phosphate depending on tissue type …”

“…Melanocytes and melanoma cells have the potential to be exposed to DHA throughout the epidermis and dermis, and the bioenergetics of the melanoma make it likely that exogenous DHA will be metabolized . While the transport mechanism by which DHA enters into cells still needs to be determined, it is clear that exogenous DHA can enter cells and alter metabolism in a tissue and cell specific manner . Thus, it is important to evaluate potential exposure effects, noting that there have been no studies examining the effect of DHA exposure on mucous membranes, which may occur during spray tanning …”

“…mice, which showed rapid distribution of DHA to the liver and kidneys and metabolism of DHA to DHAP by liver and kidney cells, but showed different conversion rates of DHAP to glyceraldehyde 3-phosphate depending on tissue type. 30 Melanocytes and melanoma cells have the potential to be exposed to DHA throughout the epidermis and dermis, and the bioenergetics of the melanoma make it likely that exogenous DHA will be metabolized. 25,31 While the transport mechanism by which DHA enters into cells still needs to be determined, it is clear that exogenous DHA can enter cells and alter metabolism in a tissue and cell specific manner.…”

Sensitivity enhancement for detection of hyperpolarized 13C MRI probes with 1H spin coupling introduced by enzymatic transformation in vivo

“…The first HP injection and scan applied 1 H decoupling, whereas the second injection and scan (approximately 90 min later, within the same scanning session) did not. A previous study applying similar methods showed that the extent of conversion of HP [2‐ 13 C]DHA to HP [2‐ 13 C]G3P in liver and kidney returns to a similar level within 80 min after the first injection . For in vivo experiments, effectiveness of decoupling was verified just before the HP experiment based on signal from a vial phantom containing 1‐mL [2‐ 13 C]glycerol (Cambridge Isotopes, Tewksbury, Massachusetts) placed adjacent to the rat.…”

“…In particular, certain HP probes of interest with long T 1 relaxation times and minimal 1 H couplings are enzymatically transformed in vivo to important metabolic products with major 1 H couplings. This can occur with dehydrogenase activity at the labeled carbon site, exemplified by the reduction via lactate dehydrogenase of HP [2-13 C]pyruvate to [2][3][4][5][6][7][8][9][10][11][12][13] C]lactate (9), which is observed as a well-resolved 13 C signal doublet at 3 T (J ¼ 146 Hz). Elimination of such large couplings, however, introduces high decoupling power requirements, which in turn require exceptionally good isolation between multinuclear RF channels, which is not typical for clinical MRI systems.…”