Rajalingamgari Prasad, Khatua Biswajit, Summers Megan J, Kostenko Sergiy, Chang Yu-Hui H, Elmallahy Mohamed, Anand Arti, Narayana Pillai Anoop, Morsy Mahmoud, Trivedi Shubham, McFayden Bryce, Jahangir Sarah, Snozek Christine Lh, Singh Vijay P
Department of Medicine.
Department of Clinical Trials and Biostatistics.
J Clin Invest. 2024 Nov 7;135(1):e184785. doi: 10.1172/JCI184785.
BACKGROUNDWhile 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.METHODSAdmission 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.RESULTSPatients 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.CONCLUSIONSHTG-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.FUNDINGNational 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).
背景
虽然大多数高甘油三酯血症是无症状的，但高甘油三酯血症相关性急性胰腺炎（HTG-AP）可能比其他病因引起的急性胰腺炎（AP）更严重。其潜在原因尚不清楚。因此，我们研究了循环甘油三酯（TGs）经脂解产生的非酯化脂肪酸（NEFAs）是否会使临床结局恶化。
方法
对269例急性胰腺炎患者的入院血清甘油三酯、非酯化脂肪酸组成和浓度进行前瞻性分析。比较了HTG-AP（甘油三酯>500mg/dL；美国心脏协会[AHA]2018年指南）和其他病因引起的急性胰腺炎患者的这些参数、人口统计学特征和临床结局。血清非酯化脂肪酸分别与血清甘油三酯脂肪酸（TGFAs）以及甘油三酯脂肪酸与血清脂肪酶的乘积（非酯化脂肪酸-TGFAs×脂肪酶）进行相关性分析。进行小鼠和大鼠研究以了解HTG脂解在器官衰竭中的作用，并解释非酯化脂肪酸与甘油三酯脂肪酸的相关性。
结果
与其他病因引起的急性胰腺炎患者相比，HTG-AP患者的血清非酯化脂肪酸和甘油三酯水平更高，急性胰腺炎更严重（19%对7%；P<0.03）。长链不饱和非酯化脂肪酸与相应甘油三酯脂肪酸的相关性在甘油三酯浓度高达500mg/dL时随浓度升高而增加，此后下降。然而，当甘油三酯高于500mg/dL时，非酯化脂肪酸-TGFAs×脂肪酶的相关性变得更强。啮齿动物的急性胰腺炎和静脉注射脂肪酶会导致循环甘油三酯脂解为非酯化脂肪酸。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预防这种情况。
结论
循环甘油三酯血管内脂解产生的非酯化脂肪酸使HTG-AP病情加重。预防甘油三酯脂解的策略可能对改善HTG-AP患者的临床结局有效。
资助
美国国立糖尿病、消化和肾脏疾病研究所（NIDDK，NIH）（RO1DK092460和R01DK119646）；国防部（根据W81XWH-20-1-0400的PR191945）；美国国立酒精滥用与酒精中毒研究所（NIAAA），NIH（R01AA031257）。
