Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

Area of Science:

• Gastroenterology and Hepatology
• Metabolic and Bariatric Surgery
• Endocrinology

Background:

• Visceral adipose tissue (VAT) dysfunction is implicated in various diseases, with varying clinical outcomes from mild illness to organ failure.
• Adipose tissue involvement is common in abdominal diseases, but its specific role in disease progression and organ failure remains unclear.

Purpose of the Study:

• To compare visceral adipose tissue injury patterns in acute pancreatitis versus acute diverticulitis.
• To elucidate the role of visceral adipose tissue lipolysis in organ failure during acute pancreatitis.

Main Methods:

• Comparison of VAT injury patterns in mouse models of acute pancreatitis and acute diverticulitis.
• Investigation of pancreatic lipase activity and nonesterified fatty acid (NEFA) generation in VAT.
• Utilized pancreatic triglyceride lipase (PNLIP)-knockout and adipocyte triglyceride lipase (ATGL)-knockout mouse models.

Main Results:

• Acute pancreatitis-associated VAT exhibited lipolysis independent of ATGL, driven by pancreatic lipase.
• PNLIP influx into VAT during pancreatitis hydrolyzed triglycerides, generating excess NEFAs and causing organ failure.
• PNLIP-knockout mice showed reduced VAT lipolysis, milder inflammation, less organ failure, and improved survival during pancreatitis compared to ATGL knockouts.

Conclusions:

• During pancreatitis, PNLIP contributes to excessive VAT lipolysis and organ failure independently of ATGL.
• PNLIP-mediated lipolysis in VAT is a key mechanism worsening organ failure in acute pancreatitis, unlike in acute diverticulitis.
• Targeting PNLIP may offer a therapeutic strategy to mitigate organ failure in acute pancreatitis.