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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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

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Figure 4

Effect of lipase activity on the relationship between individual NEFAs and TGFAs in patients with pancreatitis.

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Effect of lipase activity on the relationship between individual NEFAs a...
(A) Schematic comparing the Kennedy pathway (left side, green background) by which NEFAs are physiologically incorporated into the TGs for storage (adipose, liver) or transport (intestine) versus the pathological release of NEFAs from intravascular TG lipolysis by pancreatic lipases during HTG-AP (red background on the right side). (B) Correlation of serum lipase activity with individual TGFAs for all patients. Each column shows a unique FA. The upper value shows the correlation coefficient, and the lower number the P value. (C) All patient data were formatted as in B. Middle row (dark gray background) correlates individual serum NEFAs with serum lipase; top row (white background) correlates individual NEFAs and their TGFA concentrations; and bottom row (white background) correlates individual NEFAs and the product of serum lipase × TGFA concentrations. The light gray rows show P values comparing the strength of correlations (COCOR as described in Methods) between the middle row and corresponding top or bottom rows. Those with a P value of less than 0.05 are shown in red. (D) Bar graphs of correlations (R values) arranged by serum TG concentrations (x axis) for individual FAs. Each graph is for a FA (mentioned above) and shows correlations of its NEFAs with corresponding TGFAs (back bars) or NEFAs with the product of the corresponding TGFA concentration × serum lipase (red bars). Asterisks show the bar with significantly stronger correlations versus normal TGs, i.e., TGs below 150 mg/dL. All correlations are Spearman correlations, and P values are 2 tailed. The comparison of COCOR correlations between 2 Spearman coefficients were done as described in Methods, and P values are shown. Asterisks in D indicate a COCOR P value of less than 0.05 versus the normal (<150 mg/dL) TG group.