Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

Area of Science:

• Cellular biology
• Gastroenterology
• Molecular mechanisms of disease

Background:

• Endoplasmic reticulum (ER) proteostasis is vital for pancreatic acinar cell function.
• Unfolded protein response (UPR) pathways are implicated in pancreatitis pathogenesis.
• The role of ER-associated protein modifications in pancreatic outcomes is understudied.

Purpose of the Study:

• To investigate the role of the ER acetyl-CoA transporter AT-1 in pancreatic homeostasis.
• To determine the consequences of AT-1 dysfunction on pancreatic acinar cell physiology.

Main Methods:

• Utilized AT-1 hypomorphic and inducible acinar-specific AT-1 knockout mouse models.
• Performed histologic and biochemical analyses to assess AT-1 loss effects.
• Examined ER stress markers and pancreatitis development.

Main Results:

• AT-1 expression is downregulated in acute and chronic pancreatitis.
• Acinar-specific AT-1 deletion induces chronic ER stress (UPR activation).
• AT-1 loss leads to spontaneous chronic pancreatitis, acinar cell loss, and atrophy.

Conclusions:

• AT-1 plays a critical role in maintaining pancreatic acinar cell homeostasis.
• Perturbations in AT-1 function disrupt the unfolded protein response.
• AT-1 deficiency is a contributing factor to the development of pancreatic disease.