Large triglyceride-rich lipoproteins in hypertriglyceridemia are associated with the severity of acute pancreatitis in experimental mice
Large triglyceride-rich lipoproteins in hypertriglyceridemia are associated with the severity of acute pancreatitis in experimental mice
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高甘油三酯血症中富含大甘油三酯的脂蛋白与实验小鼠急性胰腺炎的严重程度相关
DOI：
10.1038/s41419-019-1969-3
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发表时间：
2019-09-30
影响因子：
9
通讯作者：
Lu, Nonghua
中科院分区：
文献类型：
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作者：
Zhang, Yue;He, Wenhua;Lu, Nonghua
高脂血症的严重程度与急性胰腺炎的预后有关，但仍不清楚为什么一部分重度高脂血症患者不会发展为重度急性胰腺炎。为了研究高脂血症亚型是否影响急性胰腺炎的进展，我们分析了两种遗传修饰的高脂血症小鼠模型，即糖基磷脂酰肌醇高密度脂蛋白结合蛋白1敲除（Gpihbp 1 −/−）和载脂蛋白C3转基因（ApoC 3-tg）小鼠。腹腔注射雨蛙肽10次诱发急性胰腺炎。通过生化检测和病理分析评估急性胰腺炎的严重程度。采用超离心法收集血浆富含胆固醇脂蛋白（TRL），包括乳糜微粒和极低密度脂蛋白（VLDL），以评价其对原代胰腺腺泡细胞（PAC）的细胞毒性作用。我们发现Gpihbp 1 −/− TRLs的颗粒尺寸大于ApoC 3-tg TRLs。当血浆甘油三酯水平大于2000 mg/dL时，在Gpihbp 1 −/−小鼠中诱导了严重的胰腺损伤，整个小叶中出现大面积胰腺坏死。然而，具有相同甘油三酯水平的ApoC 3-tg小鼠即使在施用泊洛沙姆407以进一步增加甘油三酯水平时也没有发展大面积的胰腺坏死。同时，在急性胰腺炎模型中，Gpihbp 1 −/−小鼠胰腺中的游离脂肪酸（FFA）高于ApoC 3-tg小鼠。来自Gpihbp 1 −/−小鼠的TRL释放更多的FFA，并且比来自ApoC 3-tg小鼠的TRL对PAC的毒性更大。来自患者的乳糜微粒对PAC的影响与来自Gpihbp 1 −/−小鼠的TRL相同。与甘油三酯水平高于2000 mg/dL的小鼠相比，甘油三酯水平低于2000 mg/dL的Gpihbp 1 −/−小鼠的胰腺损伤较轻，胰腺坏死的发生率较低，与甘油三酯水平高于2000 mg/dL但给予非诺贝特的Gpihbp 1 −/−小鼠相似。这些结果表明，具有大TRL颗粒的高甘油三酯血症亚型可以影响急性胰腺炎的进展，并且乳糜微粒通过释放更多的FFA而显示出比VLDL更大的细胞毒性。
Hypertriglyceridemia severity is linked to acute pancreatitis prognosis, but it remains unknown why a portion of severe hypertriglyceridemia patients do not develop severe acute pancreatitis. To investigate whether hypertriglyceridemia subtypes affect acute pancreatitis progression, we analyzed two genetically modified hypertriglyceridemia mouse models—namely, glycosylphosphatidylinositol high-density lipoprotein binding protein 1 knockout (Gpihbp1−/−) and apolipoprotein C3 transgenic (ApoC3-tg) mice. Acute pancreatitis was induced by 10 intraperitoneal caerulein injections. Biochemical assays and pathological analysis were performed for the severity evaluation of acute pancreatitis. Plasma triglyceride-rich lipoproteins (TRLs), including chylomicrons and very low-density lipoprotein (VLDL), were collected via ultracentrifugation to evaluate their cytotoxic effects on primary pancreatic acinar cells (PACs). We found that the particle sizes of Gpihbp1−/− TRLs were larger than ApoC3-tg TRLs. Severe pancreatic injury with large areas of pancreatic necrosis in the entire lobule was induced in Gpihbp1−/− mice when plasma triglyceride levels were greater than 2000 mg/dL. However, ApoC3-tg mice with the same triglyceride levels did not develop large areas of pancreatic necrosis, even upon the administration of poloxamer 407 to further increase triglyceride levels. Meanwhile, in the acute pancreatitis model, free fatty acids (FFAs) in the pancreas of Gpihbp1−/− mice were greater than in ApoC3-tg mice. TRLs from Gpihbp1−/− mice released more FFAs and were more toxic to PACs than those from ApoC3-tg mice. Chylomicrons from patients showed the same effects on PACs as TRLs from Gpihbp1−/− mice. Gpihbp1−/− mice with triglyceride levels below 2000 mg/dL had milder pancreatic injury and less incidence of pancreatic necrosis than those with triglyceride levels above 2000 mg/dL, similar to Gpihbp1−/−mice with triglyceride levels above 2000 mg/dL but with fenofibrate administration. These findings demonstrated that hypertriglyceridemia subtypes with large TRL particles could affect acute pancreatitis progression and that chylomicrons showed more cytotoxicity than VLDL by releasing more FFAs.