Phosphate Improves Mitochondrial Function and Reduces Pancreatitis in Hypertriglyceridemia

Hypertriglyceridemia-associated pancreatitis (HTGP) accounts for 9% to 10% of acute pancreatitis; however, the exact cause and associated factors advancing HTGP are unclear. Clinical studies have revealed that hypophosphatemia is a common factor in many patients with pancreatitis. Phosphate depletion occurs in metabolic disorders and can lead to dyslipidemia. To determine if phosphate status is critical in HTGP, we used an APOC3 transgenic mouse model of hypertriglyceridemia. We found that hypertriglyceridemic mice exhibit mild pancreatic injury with elevated intra-acinar nonendoplasmic reticulum (non-ER) organelle calcium levels, decreased mitochondrial function, and increased levels of pancreatic tissue myeloperoxidase and proinflammatory cytokines (TNF-α, IL-6, and IL-1β) compared to mice with normal serum triglycerides. Phosphate supplementation normalized the non-ER stored calcium levels, restored mitochondrial function, and attenuated fatty acid-induced sustained intracellular calcium elevation in acini, protecting the pancreas from hypertriglyceridemia-induced injury by reducing inflammation. Furthermore, phosphate supplementation reduced the severity of caerulein-induced pancreatic injury in mice on a low-phosphate diet under hypertriglyceridemic conditions. This study highlights an important role for phosphate in protecting the pancreas during hypertriglyceridemia by reversing the dysregulated calcium homeostasis in non-ER organelles, restoring mitochondrial function in acini, and reducing the severity of hypertriglyceridemia-associated pancreatitis.