Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation
Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation
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DOI：
10.1172/jci132767
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发表时间：
2020-04-01
影响因子：
15.9
通讯作者：
Singh, Vijay P.
中科院分区：
文献类型：
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作者：
de Oliveira, Cristiane;Khatua, Biswajit;Singh, Vijay P.
内脏脂肪组织在许多疾病中起着关键作用。虽然影像学研究经常显示脂肪参与腹部疾病，但其结果可能从轻度自限性疾病到全身炎症和器官衰竭不等。因此，我们比较了急性胰腺炎和急性憩室炎期间内脏脂肪损伤的模式，以确定其在器官衰竭中的作用。急性胰腺炎相关脂肪组织在缺乏脂肪细胞甘油三酯脂肪酶（ATGL）的情况下进行脂解。将胰脂肪酶注射到小鼠内脏脂肪组织中水解脂肪甘油三酯并产生过量的非酯化脂肪酸（NEFA），这在没有急性胰腺炎的情况下引起器官衰竭。胰腺甘油三酯脂肪酶（PNLIP）在胰腺炎时在脂肪组织中增加，并通过多种机制进入脂肪细胞，水解脂肪甘油三酯并产生过量的NEFA。在胰腺炎期间，与肥胖脂肪细胞特异性ATGL敲除小鼠不同，肥胖PNLIP敲除小鼠内脏脂肪组织脂解较低，炎症较轻，器官衰竭较轻，存活率提高。与ATGL基因敲除小鼠不同，PNLIP基因敲除小鼠受到脂肪细胞诱导的胰腺腺泡损伤的保护，而不影响NEFA信号传导或急性胰腺炎诱导。因此，在胰腺炎期间，与憩室炎不同，PNLIP泄漏到内脏脂肪组织中可独立于脂肪细胞自主性ATGL引起过度内脏脂肪组织脂解，从而加重器官衰竭。
Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.