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

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 LH Snozek; Vijay P. Singh

doi:10.1172/JCI184785

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

Prasad Rajalingamgari,¹ Biswajit Khatua,¹ Megan J. Summers,¹ Sergiy Kostenko,¹ Yu-Hui H Chang,² Mohamed Elmallahy,³ Arti Anand,³ Anoop Narayana Pillai,¹ Mahmoud Morsy,¹ Shubham Trivedi,¹ Bryce McFayden,¹ Sarah Jahangir,³ Christine LH Snozek,⁴ and Vijay P. Singh³

Published November 7, 2024 - More info

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Abstract

Background: While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than other AP etiologies. The reasons underlying this are unclear. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes. Methods: Admission serum TGs, NEFA compositions and concentrations were analyzed prospectively in 269 patients with AP. These and demographics, clinical outcomes were compared between HTGAP (TGs >500mg/dL; American Heart Association 2018 guidelines) and other AP etiologies. Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFA x lipase). Studies in mice, rats were done to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations. Results: HTG-AP patients had higher serum NEFAs and TGs and more severe AP (19% vs. 7% p<0.03) than other etiologies. Correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFA x lipase correlations got stronger with TGs >500mg/dL. AP, and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFA. This led to multi-system organ failure, which was prevented by pancreatic triglyceride lipase deletion, or lipase inhibition. Conclusions: HTG-AP is made severe by the NEFAs generated form intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP. Trial registration: Not applicable. Funding: This project was supported by Grant numbers RO1DK092460, R01DK119646 from the NIDDK, PR191945 under W81XWH-20-1-0400 from the DOD (VPS), and R01AA031257 from the NIAAA (VPS).

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

Prasad Rajalingamgari,¹ Biswajit Khatua,¹ Megan J. Summers,¹ Sergiy Kostenko,¹ Yu-Hui H Chang,² Mohamed Elmallahy,³ Arti Anand,³ Anoop Narayana Pillai,¹ Mahmoud Morsy,¹ Shubham Trivedi,¹ Bryce McFayden,¹ Sarah Jahangir,³ Christine LH Snozek,⁴ and Vijay P. Singh³

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

Prasad Rajalingamgari,1 Biswajit Khatua,1 Megan J. Summers,1 Sergiy Kostenko,1 Yu-Hui H Chang,2 Mohamed Elmallahy,3 Arti Anand,3 Anoop Narayana Pillai,1 Mahmoud Morsy,1 Shubham Trivedi,1 Bryce McFayden,1 Sarah Jahangir,3 Christine LH Snozek,4 and Vijay P. Singh3

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Prasad Rajalingamgari,¹ Biswajit Khatua,¹ Megan J. Summers,¹ Sergiy Kostenko,¹ Yu-Hui H Chang,² Mohamed Elmallahy,³ Arti Anand,³ Anoop Narayana Pillai,¹ Mahmoud Morsy,¹ Shubham Trivedi,¹ Bryce McFayden,¹ Sarah Jahangir,³ Christine LH Snozek,⁴ and Vijay P. Singh³