Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation

Area of Science:

• Cell Biology
• Metabolic Signaling
• Gastroenterology

Background:

• Pancreatitis is a significant cause of hospitalization with links to pancreatic cancer.
• The molecular mechanisms governing epithelial cell responses to pancreatic inflammation are not fully understood.
• Understanding these dynamics is crucial for managing pancreatitis and preventing cancer progression.

Purpose of the Study:

• To elucidate the molecular and cellular mechanisms underlying epithelial cell behavior during pancreatitis.
• To identify key signaling pathways involved in inflammation-induced pancreatic cell reprogramming.
• To explore potential therapeutic targets for pancreatitis management.

Main Methods:

• Investigated the role of Endoplasmic Reticulum-Associated Degradation (ERAD) in pancreatitis.
• Analyzed the impact of Niemann-Pick type C protein 1 (NPC1) on cholesterol metabolism in pancreatic acinar cells.
• Utilized genetic ablation of Acly and pharmacological inhibition of NPC1 in cerulein-induced pancreatitis models.
• Assessed the role of mechanistic Target of Rapamycin Complex 1 (mTORC1) in cholesterol-induced metaplasia.
• Performed ex vivo and in vivo experiments to study acinar-to-ductal metaplasia (ADM).

Main Results:

• Inflammation induces ERAD-mediated downregulation of NPC1, leading to lysosomal cholesterol sequestration in acinar cells.
• Genetic reduction of intra-pancreatic cholesterol via Acly ablation ameliorated pancreatitis.
• Pharmacological inhibition of NPC1 worsened pancreatitis.
• Lysosomal cholesterol accumulation activates mTORC1, promoting pancreatic acinar cell metaplasia.
• Cholesterol supplementation or NPC1 inhibition promoted ADM in an mTORC1-dependent manner.

Conclusions:

• Identified a novel metabolic-signaling axis involving cholesterol and mTORC1 in pancreatitis.
• Demonstrated that NPC1-mediated cholesterol regulation is critical for pancreatic epithelial cell fate during inflammation.
• Revealed a nutrient-sensing mechanism driving metaplasia in pancreatic acinar cells, relevant to pancreatitis and regeneration.