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Galactose protects against cell damage in mouse models of acute pancreatitis
Shuang Peng, … , Ole H. Petersen, Oleg V. Gerasimenko
Shuang Peng, … , Ole H. Petersen, Oleg V. Gerasimenko
Published June 12, 2018
Citation Information: J Clin Invest. 2018;128(9):3769-3778. https://doi.org/10.1172/JCI94714.
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Concise Communication Gastroenterology Oncology Article has an altmetric score of 4

Galactose protects against cell damage in mouse models of acute pancreatitis

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Abstract

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.

Authors

Shuang Peng, Julia V. Gerasimenko, Tetyana M. Tsugorka, Oleksiy Gryshchenko, Sujith Samarasinghe, Ole H. Petersen, Oleg V. Gerasimenko

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Figure 5

Pyruvate and galactose increase intracellular ATP levels and protect cells against ATP depletion induced by 2-DG.

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Pyruvate and galactose increase intracellular ATP levels and protect cel...
(A) Glucose removal induces substantial ATP depletion, whereas pyruvate or galactose boosts ATP production. Average traces show normalized changes of MgGreen fluorescence in PACs in the presence (blue trace, n = 8) or absence (orange trace, n = 7) of 10 mM glucose or in the presence of pyruvate (1 mM; green trace, n = 10) or galactose (1 mM; purple trace, n = 8). (B) Comparison of AUC for experiments shown in A. **P < 0.01; ***P < 0.001, 1-way ANOVA. (C) Pyruvate markedly reduces ATP depletion induced by 10 mM 2-DG. Averaged trace (shown with error bars) represents the result of application of 2-DG in the absence (red trace, n = 9) or presence of 1 mM pyruvate (after 5 minutes of preincubation, green trace, n = 7). (D) Comparison of necrotic cell death levels induced by 2 hours of incubation of PACs with 10 mM 2-DG or asparaginase with control (nontreated cells) (PI-stained cells, P = 0.36, 1-way ANOVA, 3 series of experiments with n > 100 cells in each sample). (E) Average traces show normalized changes of Fluo-4 fluorescence in PACs induced by 10 mM 2-DG alone (red trace, n = 10) or after 5 minutes preincubation of cells and continuous presence of 1 mM pyruvate (green trace, n = 8) for 25 minutes. (F) Quantitative analysis of experiments of the type shown in E by comparing AUC for 25 minutes of the recording after application of 10 mM 2-DG. ***P < 0.001, 2-tailed Student’s t test.

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