Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis.
Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis.
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DOI：
10.1136/gutjnl-2012-304058
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发表时间：
2014-08
期刊：
影响因子：
24.5
通讯作者：
Criddle DN
中科院分区：
文献类型：
--
作者：
Huang W;Booth DM;Cane MC;Chvanov M;Javed MA;Elliott VL;Armstrong JA;Dingsdale H;Cash N;Li Y;Greenhalf W;Mukherjee R;Kaphalia BS;Jaffar M;Petersen OH;Tepikin AV;Sutton R;Criddle DN
乙醇的非氧化代谢（NOME）通过羧酸酯脂肪酶（CEL）和其他与线粒体损伤和急性胰腺炎（AP）有关的酶作用产生脂肪酸乙酯（FAEE）。本研究调查了氧化和非氧化途径在线粒体功能障碍、胰腺损伤和酒精性AP发展中的相对重要性，以及NOME的有害影响是否可以预防。在存在或不存在4-甲基吡唑（4-MP）抑制氧化代谢的情况下，检测了乙醇和/或棕榈油酸（POA）对分离的胰腺腺泡细胞的细胞内钙（[Ca 2 +]C）、NAD（P）H、线粒体膜电位以及凋亡和坏死细胞死亡途径的激活。开发了一种新的酒精性AP的体内模型，该模型通过腹腔内给予乙醇和POA来诱导，以评估操纵酒精代谢的影响。在体外，4-MP抑制OME将低浓度乙醇/POA联合诱导的[Ca 2 +]C升高转化为持续升高，同时伴有线粒体去极化、NAD（P）H下降和细胞坏死。3-苄基-6-氯-2-吡喃酮（3-BCP），一种CEL抑制剂，可以阻止所有的影响。3-BCP还能显著抑制小鼠胰腺FAEE的升高，改善乙醇和POA诱导的急性胰腺损伤和炎症反应。当氧化代谢受到抑制时，本身不产生有害作用的低乙醇和脂肪酸的组合变得有毒。在体外和体内的损害显着抑制了CEL的封锁，表明通过抑制FAEE的产生治疗酒精性AP的特定疗法的发展潜力。
Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. Intracellular calcium ([Ca2+]C), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. Inhibition of OME with 4-MP converted predominantly transient [Ca2+]C rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation.
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影响因子：
29.4
作者：
Booth, David M.;Murphy, John A.;Criddle, David N.
通讯作者：
Criddle, David N.
影响因子：
56.9
作者：
LAPOSATA, EA;LANGE, LG
通讯作者：
LANGE, LG
DOI：
10.1111/j.1530-0277.2006.00138.x
发表时间：
2006-07-01
影响因子：
3.2
作者：
Best, Catherine A.;Sarkola, Taisto;Laposata, Michael
通讯作者：
Laposata, Michael
DOI：
10.1073/pnas.1016534108
发表时间：
2011-04-05
影响因子：
11.1
作者：
Gerasimenko, Julia V.;Lur, Gyorgy;Gerasimenko, Oleg V.
通讯作者：
Gerasimenko, Oleg V.
影响因子：
2.9
作者：
Lerch, MM;Albrecht, E;Krüger, B
通讯作者：
Krüger, B