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.
Highlights
Acute pancreatitis (AP) is an inflammatory disease that originates in the exocrine pancreas, where inactive pancreatic proenzymes become prematurely activated inside the pancreatic acinar cells (PACs), digesting the pancreas and its surroundings [1, 2]
Since the majority of cellular ATP is produced by glucose metabolism, we compared the effect of a glucose-free medium on necrosis to that induced by asparaginase, palmitoleic acid ethyl ester (POAEE), palmitoleic acid (POA), or bile acids (BAs) (Figure 1B)
It is well established that the initial stages of AP are characterized by intracellular Ca2+ overload, causing inadequate function of the mitochondria, leading to reduction of ATP production, premature intracellular activation of digestive enzymes, and cell death, mainly by necrosis [1, 2]
Summary
Acute pancreatitis (AP) is an inflammatory disease that originates in the exocrine pancreas, where inactive pancreatic proenzymes become prematurely activated inside the pancreatic acinar cells (PACs), digesting the pancreas and its surroundings [1, 2]. Stimulation of PACs with alcohol metabolites or bile acids (BAs) leads to aberrant calcium signaling due to excessive release from intracellular stores, followed by activation of massive Ca2+ entry through store-operated Ca2+ release–activated Ca2+ (CRAC) channels, causing intracellular Ca2+ overload [2, 4, 5]. Another cause of AP is the l-asparaginase treatment of acute lymphoblastic leukemia (ALL) [6, 7]. We propose a simple and promising way to rescue intracellular ATP levels in AP and AAP patients
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