The role of phosphate in alcohol-induced experimental pancreatitis.

Heavy alcohol consumption is a common cause of acute pancreatitis, however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia and hypophosphatemia has been observed in some patients with acute pancreatitis. Due to abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit ATP synthesis and, thereby, contribute to alcohol-induced pancreatitis.Mice were fed a low phosphate diet (LPD) prior to orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini.LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on a LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular ATP and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury.Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, low phosphate diet + ethanol provides a new model for studying alcohol-associated pancreatic injury.

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Authors: Ahmad Farooq, Courtney M Richman, Sandip M Swain, Rafiq A Shahid, Steven R Vigna, Rodger A Liddle