Wang Y, Sternfeld L, Yang F, Rodriguez J A, Ross C, Hayden M R, Carriere F, Liu G, Hofer W, Schulz I
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Beijing, China.
Gut. 2009 Mar;58(3):422-30. doi: 10.1136/gut.2007.146258. Epub 2008 Oct 20.
Recurrent pancreatitis is a common complication of severe hypertriglyceridaemia in patients with various gene mutations in lipoprotein lipase (LPL) or apolipoprotein CII. However, the exact pathogenetic mechanism has not yet been defined.
Susceptibility to pancreatitis in LPL-deficient mice was compared with that of wild-type mice after intraperitoneal injections of caerulein by determination of amylase release and pancreatic pathological scores. The effect of chylomicrons and fatty acids on enzyme release, Ca(2+) signalling and cell injury in isolated pancreatic acinar cells from wild-type and LPL-deficient mice was investigated.
Caerulein induced higher levels of serum amylase and more severe inflammation in the pancreas of LPL-deficient mice than in wild-type mice. Addition of free fatty acids or chylomicrons to isolated pancreatic acinar cells led to the release of amylase and caused cell injury at higher concentrations. The effect of chylomicrons was partially blocked by orlistat, an inhibitor of pancreatic lipase. These results suggest that increased concentrations of free fatty acids from chylomicron hydrolysis by pancreatic lipase can induce acinar cell injury. Surprisingly, pancreatic lipase, whether in its active or inactive state could act like an agonist by inducing amylase secretion without cell injury. It caused an increase in cGMP levels and conversion of cell-damaging sustained elevations of [Ca(2+)] to normal Ca(2+) oscillations.
LPL-deficient mice with severe hypertriglyceridaemia display enhanced susceptibility to acute pancreatitis. High levels of chylomicrons and free fatty acids result in pancreatic cell injury. Pancreatic lipase has a dual effect: generating free fatty acids from chylomicrons and preventing Ca(2+) overload in pancreatic acinar cells.
复发性胰腺炎是脂蛋白脂肪酶（LPL）或载脂蛋白CII存在各种基因突变的患者中严重高甘油三酯血症的常见并发症。然而，确切的发病机制尚未明确。
通过测定淀粉酶释放量和胰腺病理评分，比较腹腔注射雨蛙素后LPL缺陷小鼠与野生型小鼠对胰腺炎的易感性。研究乳糜微粒和脂肪酸对野生型和LPL缺陷小鼠分离的胰腺腺泡细胞中酶释放、Ca(2+)信号传导和细胞损伤的影响。
与野生型小鼠相比，雨蛙素在LPL缺陷小鼠胰腺中诱导更高水平的血清淀粉酶和更严重的炎症。向分离的胰腺腺泡细胞中添加游离脂肪酸或乳糜微粒会导致淀粉酶释放，并在较高浓度下引起细胞损伤。乳糜微粒的作用被胰脂肪酶抑制剂奥利司他部分阻断。这些结果表明，胰脂肪酶水解乳糜微粒产生的游离脂肪酸浓度增加可诱导腺泡细胞损伤。令人惊讶的是，胰脂肪酶无论处于活性还是非活性状态，都可通过诱导淀粉酶分泌而不引起细胞损伤，起到类似激动剂的作用。它导致cGMP水平升高，并将细胞损伤性的[Ca(2+)]持续升高转化为正常的Ca(2+)振荡。
患有严重高甘油三酯血症的LPL缺陷小鼠对急性胰腺炎的易感性增强。高水平的乳糜微粒和游离脂肪酸会导致胰腺细胞损伤。胰脂肪酶具有双重作用：从乳糜微粒中产生游离脂肪酸，并防止胰腺腺泡细胞中的Ca(2+)过载。
