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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 Article has an altmetric score of 117

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

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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 1

Comparison of biochemical parameters, histology of acute pancreatitis and diverticulitis in humans.

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Comparison of biochemical parameters, histology of acute pancreatitis an...
Cross-sectional CT scan images on the first day of acute diverticulitis (A) or acute pancreatitis (B–D) with fat stranding of visceral adipose tissue (yellow outline) around the colon (C), or the pancreas (P). Images in B–D show progression of visceral fat involvement (yellow line) on the different days after onset of pancreatitis mentioned at the bottom. (E) A representative example of a serial section of human tissue stained for myeloperoxidase during acute diverticulitis showing the colon on the right and lower edges of section. (E–K) Acute diverticulitis (E–H) and acute pancreatitis (I–K) stained with H&E (F and I), calcium stained with von Kossa (G and J), and IHC for PNLIP (H and K) are also shown. Higher-magnification views of the insets are shown below. Note von Kossa– and PNLIP-positive areas overlap (arrows) in areas of fat necrosis (FN), but not normal fat (green outline). Also note positive von Kossa staining in necrosed pancreas (Panc), which has loss of cell outlines (above the dotted red line). This localizes the saponified NEFAs in the necrosed pancreas. Scale bars: 500 μm (E–H) and 200 μm (I–K). (L) Thin layer chromatography comparing the relative amount of NEFAs and TG in samples from patients with acute pancreatitis or diverticulitis. Amylase (M), lipase (N), and trypsin (O) activities measured in these samples. Error bars represent SEM. (P) Western blot images comparing detectable ATGL and perilipin 1 (Peri-1), and adiponectin (Adipo) bands in these samples.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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