Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation
Cristiane de Oliveira, … , Mark E. Lowe, Vijay P. Singh
Cristiane de Oliveira, … , Mark E. Lowe, Vijay P. Singh
Published January 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1931-1947. https://doi.org/10.1172/JCI132767.
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Research Article Gastroenterology Inflammation

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

Abstract

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis–associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.

Authors

Cristiane de Oliveira, Biswajit Khatua, Pawan Noel, Sergiy Kostenko, Arup Bag, Bijinu Balakrishnan, Krutika S. Patel, Andre A. Guerra, Melissa N. Martinez, Shubham Trivedi, Ann McCullough, Dora M. Lam-Himlin, Sarah Navina, Douglas O. Faigel, Norio Fukami, Rahul Pannala, Anna Evans Phillips, Georgios I. Papachristou, Erin E. Kershaw, Mark E. Lowe, Vijay P. Singh

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Figure 9

Diagrammatic representation of the difference in pathophysiology of acute diverticulitis and acute pancreatitis.

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Diagrammatic representation of the difference in pathophysiology of acut...
Shown here are the pathophysiology explaining the histological, biochemical, and clinical findings noted in diverticulitis (left) and pancreatitis (right). In the upper part of the left image is shown a perforated diverticulum in the colon with spillage of contents into the visceral adipose tissue. In the lower panel is the zoomed-in view showing the consequent intense local inflammation in the pericolonic visceral adipose tissue. However, the triglycerides (red E) within adipocytes are not degraded and the ATGL (green dots) remains intact. This is associated with a low prevalence of organ failure during diverticulitis. On the right is shown the involvement of visceral adipose tissue in pancreatitis, with the zoomed-in view at the bottom showing the leakage of pancreatic enzymes (dark blue), including PNLIP (light blue), into the visceral adipose tissue. The resulting adipocyte injury results in entry of PNLIP into the injured adipocytes, resulting in hydrolysis of adipocyte triglycerides into NEFAs (red wavy lines), and degradation of ATGL seen as loss of green dots. The entry of NEFAs into the systemic circulation causes elevated cytokines, organ failure including acute respiratory distress syndrome (ARDS), acute renal failure (ARF), and cardiovascular failure (CVF).