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.
View: Text | PDF
Clinical Research and Public Health Gastroenterology

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

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

×

Figure 2

Parameters of mice with HTG alone or HTG-AP, those given NEFAs, and in vitro studies using pancreatic acini.

Options: View larger image (or click on image) Download as PowerPoint
Parameters of mice with HTG alone or HTG-AP, those given NEFAs, and in v...
(A–H) Mice were given poloxamer-407 on day –1 to induce HTG (H) alone (blue). HTG-AP (HAP) was induced on day 0 (i.e., 1 day after poloxamer-407) in C57bl/6 WT mice (red) or pancreatic TG lipase–KO mice (PTL KO) (green dots). Dot plots with means are shown for serum lipase (A), serum TGs (B), and serum NEFAs (C) for the days indicated on the x axis. Serum creatinine at necropsy (D), along with carotid pulse distention (E) and rectal temperature (F) recorded before euthanasia are shown. (G) Comparison of the survival curves for the 2 groups with P values based on the log-rank (Mantel-Cox) test. (H and I) Images of H&E-stained pancreatic sections from WT mice (H) and PTL-KO mice (I) with HAP. Scale bars: 200 μm. (J and K) Dot plots showing pancreatic necrosis (J) and pancreatic edema (K) in WT and PTL-KO mice with HAP. (L–N) Dot plots with means comparing the effects of administering linoleic acid (red dots) or palmitic acid (blue dots) on serum BUN levels at necropsy (L), along with carotid pulse distention (M) and rectal temperature (Temp) (N) recorded before euthanasia. P values were determined by 2-way ANOVA was done (A–F), log-rank (Mantel-Cox) test (G), Mann-Whitney U test (J), 2-tailed Student’s t test was done (K), and ordinary 1-way ANOVA (L–N).