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 4

Comparison of the effects of pharmacologic or genetic inhibition of ATGL or PNLIP on adipocyte-induced acinar injury.

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Comparison of the effects of pharmacologic or genetic inhibition of ATGL...
(A) Schematic showing the setup of the pancreatic acini/adipocyte coculture experiment using a Transwell system with a 3-μm mesh separating the acini from the adipocytes. (B–E) Effect of the generic lipase inhibitor orlistat (50 μM) and the ATGL-specific inhibitor Atglistatin (50 μM) on the pancreatic lipase activity in the medium (B), glycerol generation in the medium (C), and propidium iodide (PI) uptake (D) and trypan blue staining (E) of pancreatic acini at the end of 6 hours of coculture. (F) Activity of pancreatic lipase and amylase in the media from acini of WT or PNLIP-KO mice. Effect of coculturing acini from WT and PNLIP-KO mice with WT adipocytes on glycerol generation (G), propidium iodide uptake (H), and trypan blue staining (I) of acini at the end of 6 hours of coculture. Effect of culturing WT acini alone, with WT adipocytes or ATGL-KO adipocytes (with and without 50 μM orlistat [orli]) on the measurable pancreatic lipase activity in the medium (J), glycerol concentration in the medium (K), propidium iodide uptake (L), and trypan blue staining (M) by the acini. Original magnification, ×10 (E, I, and M). Each experiment was performed 3–7 times separately. Each symbol represents a different experiment. *P < 0.05 by ANOVA, indicating a significant change compared with other conditions in the group. †P < 0.05 by Student’s t test, indicating a significant and selective reduction with orlistat (but not Atglistatin or deletion of ATGL as may be relevant to the experimental design). Error bars represent SEM.