Mechanistic insights into how intrapancreatic fat deposition drives the development of acute pancreatitis

Figures

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  Figure 1. IPFD damages pancreatic acinar cells via free fatty acids. IPFD hydrolyzes free fatty acids, which are transported into pancreatic acinar cells via FATP and FABP on the cell surface. FFAs are subjected to mitochondrial β-oxidation, which results in the excessive generation of ROS and the subsequent activation of inflammatory signaling pathways as well as ferroptosis signaling pathways. Furthermore, high concentrations of FFAs can induce the activation of calcium channels, causing a sharp rise in intracellular Ca²⁺ levels, which triggers the opening of MPTP, disrupts mitochondrial homeostasis, impairs ATP biosynthesis, and ultimately induces calcium overload, thereby contributing to the formation of an inflammatory storm. Notably, calcium overload can also modulate the activity of downstream cell cycle regulatory proteins, thereby facilitating the necroptosis of pancreatic acinar cells. (FFAs, free fatty acids; FATP, fatty acid transporter proteins; FABP, fatty acid-binding proteins; ROS, reactive oxygen species; MPTP, mitochondrial permeability transition pores; ORAI1, calcium channel protein 1).

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  Figure 2. IPFD damages vascular endothelial cells and ductal cells via free fatty acids. FFAs bind to CD36 on the surface of vascular endothelial cells, inhibit the AMPK pathway, produce large amounts of ROS, and damage membrane lipids. Damaged blood vessels contract strongly, leading to insufficient pancreatic microcirculatory perfusion, and recruit immune cells and platelets to aggregate and form thrombi, resulting in pancreatic ischemic necrosis. FFAs impair the function of CFTR on the surface of ductal cells by affecting the absorption of fat-soluble vitamins, inducing the formation of protein clots in the duct and preventing the smooth excretion of pancreatic juice, ultimately causing pancreatic duct obstruction. (FFAs, free fatty acids; ROS, reactive oxygen species; CFTR, cystic fibrosis transmembrane conductance regulator protein).

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  Figure 3. IPFD-induced pancreatic enzyme abnormal activation and vicious cycle formation. IPFD obstructs the pancreatic duct, causing pancreatic tissue ischemia and hypoxia, which reduces ATP production, induces lysosome rupture, releases cathepsin B, and directly activates trypsin. Additionally, adipocytes in IPFD trigger inflammation and activate the MAPK signaling pathway, which results in calcium overload and further contributes to the abnormal activation of pancreatic digestive enzymes. During autodigestion of pancreatic tissue induced by activated pancreatic enzymes, IPFD is hydrolyzed to release FFAs. FFAs can directly damage pancreatic tissue through lipotoxicity and further activate pancreatic enzymes by damaging pancreatic ductal cells, forming a vicious cycle and ultimately leading to AP severity. (TAP, trypsinogen activation peptide; AMY, amylase; LPS, Lipase).