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

IF 13.3 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-11-07 DOI:10.1172/JCI184785

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

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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).

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前瞻性观察研究和机理证据显示，循环中甘油三酯的脂肪分解会加重高甘油三酯急性胰腺炎。

背景：虽然大多数高甘油三酯血症无症状，但高甘油三酯血症相关急性胰腺炎（HTG-AP）可能比其他急性胰腺炎病因更严重。其原因尚不清楚。因此，我们研究了从循环甘油三酯（TGs）中生成非酯化脂肪酸（NEFA）的脂肪分解作用是否会恶化临床预后：方法：我们对 269 例 AP 患者的入院血清 TGs、NEFA 成分和浓度进行了前瞻性分析。这些数据与人口统计学、临床预后在 HTGAP（TG>500mg/dL；美国心脏协会 2018 年指南）和其他 AP 病因之间进行了比较。血清 NEFA 单独与血清甘油三酯脂肪酸（TGFA）相关，也与 TGFA x 血清脂肪酶的乘积（NEFA-TGFA x 脂肪酶）相关。对小鼠和大鼠进行了研究，以了解 HTG 脂肪分解在器官衰竭中的作用，并解释 NEFA-TGFA 的相关性：结果：HTG-AP 患者的血清 NEFA 和 TG 值更高，AP 更严重（19% 对 7% p500mg/dL）。在啮齿类动物中，AP 和静脉注射脂肪酶会导致循环中的 TG 脂肪分解为 NEFA。这导致了多系统器官衰竭，而胰腺甘油三酯脂肪酶缺失或脂肪酶抑制剂可防止这种衰竭：结论：循环中甘油三酯在血管内脂解产生的 NEFA 使 HTG-AP 变得严重。防止 TG 脂肪分解的策略可能有效改善 HTG-AP 的临床预后：不适用：本项目得到了美国国立卫生研究院（NIDDK）的 RO1DK092460 和 R01DK119646 号拨款、美国国防部（DOD）W81XWH-20-1-0400 号 PR191945 号拨款（VPS）以及美国国立卫生研究院（NIAAA）R01AA031257 号拨款（VPS）的支持。

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来源期刊

Journal of Clinical Investigation 医学-医学：研究与实验

CiteScore

24.50

自引率

1.30%

发文量

1034

审稿时长

2 months

期刊介绍： The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.