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 8

Comparison of acinar cell signaling and early events during pancreatitis in PNLIP-KO (gray) versus WT mice (black).

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Comparison of acinar cell signaling and early events during pancreatitis...
(A) Cytosolic calcium increase in response to 100 nM caerulein (arrow) as measured in Fura-2 AM–loaded acini (mean ± SEM of 4 different experiments). (B and C) Comparison of physiologic amylase release into the medium (B) and pathologic conversion of trypsinogen to active trypsin (C) in response to physiologic (1 × 10–10 M) and supraphysiologic (pathologic, 1 × 10–7 M) doses of caerulein. Each symbol represents a separate experiment. (D and E) Circulating (plasma, Pl.) amylase (D) and pancreatic edema expressed as the ratio of the water weight to pancreas wet weight (%) (E). (F) Pancreatic histology showing necrosis (arrows). Scale bars: 50 μm. (G) Circulating pancreatic lipase levels measured at the end of 10 hours of caerulein-induced acute pancreatitis versus controls. Note similar parameters in the 2 groups, except lipase. (H–J) Circulating amylase (H), pancreatic edema in control mice and at the time of necropsy after IL-12– and IL-18–induced acute pancreatitis (I), and circulating pancreatic lipase (J) levels measured 24 hours after the first IL-12/IL-18 injection. Note similar parameters in the 2 groups, except lipase. Box plots depict mean (dashed line), median (solid line), 25th and 75th percentiles (2 boxes), 10th and 90th percentiles (whiskers), and outliers (dots). *P < 0.05 by Student’s t test versus controls or basal levels. Each group had 8–10 mice.