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Prospective observational study and mechanistic evidence showing lipolysis of circulating triglycerides worsens hypertriglyceridemic acute pancreatitis
Prasad Rajalingamgari, … , Christine L.H. Snozek, Vijay P. Singh
Prasad Rajalingamgari, … , Christine L.H. Snozek, Vijay P. Singh
Published November 7, 2024
Citation Information: J Clin Invest. 2025;135(1):e184785. https://doi.org/10.1172/JCI184785.
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Clinical Research and Public Health Gastroenterology Article has an altmetric score of 5

Prospective observational study and mechanistic evidence showing lipolysis of circulating triglycerides worsens hypertriglyceridemic acute pancreatitis

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Abstract

BACKGROUND While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than AP of other etiologies. The reasons underlying this are unclear. We thus examined whether lipolytic generation of nonesterified fatty acids (NEFAs) from circulating triglycerides (TGs) could worsen clinical outcomes.METHODS Admission serum TGs, NEFA composition, and concentrations were analyzed prospectively for 269 patients with AP. These parameters, demographics, and clinical outcomes were compared between HTG-AP (TGs >500 mg/dL; American Heart Association [AHA] 2018 guidelines) and AP of other etiologies. Serum NEFAs were correlated with serum TG fatty acids (TGFAs) alone and with the product of TGFA serum lipase (NEFAs – TGFAs × lipase). Studies in mice and rats were conducted to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations.RESULTS Patients with HTG-AP had higher serum NEFA and TG levels and more severe AP (19% vs. 7%; P < 0.03) than did individuals with AP of other etiologies. Correlations of long-chain unsaturated NEFAs with corresponding TGFAs increased with TG concentrations up to 500 mg/dL and declined thereafter. However, NEFA – TGFA × lipase correlations became stronger with TGs above 500 mg/dL. AP and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFAs. This led to multisystem organ failure, which was prevented by pancreatic TG lipase deletion or lipase inhibition.CONCLUSIONS HTG-AP is made severe by the NEFAs generated from intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes for patients with HTG-AP.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH) (RO1DK092460 and R01DK119646); Department of Defense (PR191945 under W81XWH-20-1-0400); National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH (R01AA031257).

Authors

Prasad Rajalingamgari, Biswajit Khatua, Megan J. Summers, Sergiy Kostenko, Yu-Hui H. Chang, Mohamed Elmallahy, Arti Anand, Anoop Narayana Pillai, Mahmoud Morsy, Shubham Trivedi, Bryce McFayden, Sarah Jahangir, Christine L.H. Snozek, Vijay P. Singh

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Figure 3

Effect on rats of intravenous infusion of TGs versus infusion of TGs with PPL, with or without the lipase inhibitor orlistat.

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Effect on rats of intravenous infusion of TGs versus infusion of  TGs wi...
Bar graphs (with SD and individual values) comparing the effects of infusion of PPL; TG (GTO); PPL plus TG; and PPL plus TG, plus the lipase inhibitor orlistat at baseline (Bas) and after infusion. Parameters are serum lipase (A), NEFAs (B), BUN (C), and ionized calcium (iCa) (D). (E) Representative images of H&E-stained images of pancreatic sections from rats infused with GTO alone or GTO plus PPL. Scale bars: 200 μm. (F–H) Plots of preterminal oxygen saturation (Ox sat) (F), LDH activity in BAL fluid from the lungs (G), and protein concentrations in the BAL (H). (I) Representative lung histologic images after H&E staining from each group mentioned at the top of the image. Scale bars: 100 μm. The rectangle inset is zoomed outside the ×20 image. In the PPL plus GTO group, arrows point to alveolar wall damage, and asterisks show fluid-filled alveoli. All data in graphs were compared by ordinary 1-way ANOVA with multiple comparisons.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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