Department of Critical Care Medicine, Nanjing Jinling Hospital, Medical School of Southeast University, Nanjing, China; Medical School of Southeast University, Nanjing, China.
Department of Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Am J Pathol. 2024 Aug;194(8):1494-1510. doi: 10.1016/j.ajpath.2024.03.014. Epub 2024 May 3.
Dyslipolysis of adipocytes plays a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, the degree of adipocyte lipolysis related to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. Herein, the visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in cerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study indicated that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mouse AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis aggravated AP. Genetic blockage of ATGL specifically in adipocytes alleviated the damage to AP. The application of atglistatin effectively protected against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.
脂肪细胞的脂解作用在各种疾病中起着关键作用。脂肪甘油三酯脂肪酶（ATGL）是脂肪细胞自主脂解的限速酶。然而，与急性胰腺炎（AP）预后相关的脂肪细胞脂解程度以及 ATGL 介导的脂解在 AP 发病机制中的作用仍不清楚。在此，测量了 AP 患者和小鼠模型的急性阶段内脏脂肪组织消耗率。检测了胆酸钠诱导的 AP 模型中的脂解水平和 ATGL 表达。使用脂解刺激剂 CL316,243 和脂肪组织特异性 ATGL 敲除小鼠进一步研究脂解在 AP 中的作用。在 C57Bl/6N 和 ob/ob AP 模型中使用了 ATGL 特异性抑制剂 atglistatin。这项研究表明，急性阶段内脏脂肪组织消耗率的增加与 AP 患者的不良预后独立相关，这在小鼠 AP 模型中得到了验证。AP 小鼠的脂肪细胞脂解增加。脂解的刺激加重了 AP。脂肪细胞特异性 ATGL 的遗传阻断减轻了 AP 的损伤。atglistatin 的应用在瘦鼠和肥胖鼠中均能有效预防 AP。这些发现表明，ATGL 介导的脂肪细胞脂解会加重 AP，并强调了 ATGL 作为 AP 治疗靶点的治疗潜力。
