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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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 7

Inflammation and severity in ob/ob PNLIP-KO (gray), ob/ob littermates (black), and ob/ob ATGL-KO (blue) mice with caerulein-induced acute pancreatitis (CER AP).

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Inflammation and severity in ob/ob PNLIP-KO (gray), ob/ob littermates (b...
(A) Peritoneal cavity of controls and during pancreatitis. Black rectangle shows the pancreas, and adjacent kidney (K), perinephric fat. Note pancreas (P) (magnified view of inset in lower panel) is edematous, lobulated in pancreatitis. Arrows highlight fat necrosis around the kidneys, which is lacking in PNLIP-KO mice. (B) Pancreatic lipase activity in the gonadal fat pads. (C) Western blot of visceral adipose for ATGL with GAPDH as a loading control (same gel, noncontiguous) and a contemporaneously run gel for PNLIP with a vinculin loading control (same gel, noncontiguous). Dotted lines depict splicing junctions. (D) Serum NEFAs in pancreatitis and controls (white bar). (E) mRNA levels of cytokines in the visceral adipose tissue from mice with pancreatitis showing differences in the levels versus control mice without pancreatitis. Serum (Sr.) IL-6 (F), TNF-α (G), MCP-1 (H), and BUN (I) in the various groups. *P < 0.05 versus controls without pancreatitis by ANOVA. Box plots depict mean (dashed line), median (solid line), 25th and 75th percentiles (2 boxes), 10th and 90th percentiles (whiskers), and outliers (dots). (J) Kidney TUNEL staining (brown nuclei, arrows highlight some) of the various groups. Note the increase in the ob/ob and ob/ob ATGL-KO mice with pancreatitis. Scale bars: 100 μm. Trends of the carotid pulse distension (K) to measure shock, rectal temperature (L) to measure organ failure (shown as mean ± SEM), and survival (M) in the various groups. The dashed lines are PNLIP-KO mice with pancreatitis. *P < 0.05 versus other groups by ANOVA. †P < 0.05, indicates a significant reduction in the ob/ob PNLIP-KO group with acute pancreatitis versus the ob/ob group by ANOVA. Each group had 8–10 mice.