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).

中文翻译：

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前瞻性观察研究和机制证据表明循环甘油三酯的脂肪分解会加重高甘油三酯血症性急性胰腺炎。


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 AP 病因更严重。这背后的原因尚不清楚。因此，我们研究了循环甘油三酯 （TGs） 中脂解生成非酯化脂肪酸 （NEFA） 是否会使临床结果恶化。方法 前瞻性分析 269 例 AP 患者的入院血清 TGs、NEFA 组成和浓度。这些与人口统计学、临床结局在 HTGAP （TGs >500mg/dL;美国心脏协会 2018 年指南）和其他 AP 病因。血清 NEFAs 与单独的血清甘油三酯脂肪酸 （TGFAs） 和 TGFA x 血清脂肪酶 （NEFA-TGFA x 脂肪酶） 的产物相关。对小鼠、大鼠进行研究以了解 HTG 脂肪分解在器官衰竭中的作用并解释 NEFA-TGFA 相关性。结果 与其他病因相比，HTG-AP 患者血清 NEFA 和 TGs 更高，AP 更严重 （19% vs. 7% p<0.03）。长链不饱和 NEFA 与相应 TGFAs 的相关性随着 TG 浓度高达 500 mg/dL 而增加，此后呈下降趋势。然而，NEFA-TGFA x 脂肪酶与 TGs >500mg/dL 的相关性变得更强。AP 和啮齿动物静脉输注脂肪酶导致循环 TGs 脂肪分解为 NEFA。这导致多系统器官衰竭，胰腺甘油三酯脂肪酶缺失或脂肪酶抑制可以防止这种情况。结论 HTG-AP 因循环 TGs 血管内脂肪分解产生的 NEFA 而变得严重。预防 TG 脂肪分解的策略可能有效改善 HTG-AP 的临床结局。试用注册 不适用。 资金该项目得到了 RO1DK092460、NIDDK R01DK119646、国防部 （VPS） 的 W81XWH-20-1-0400 PR191945以及 NIAAA （VPS） R01AA031257的支持。