ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload.
ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload.
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DOI：
10.1016/j.molmet.2014.05.004
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发表时间：
2014-08
影响因子：
8.1
通讯作者：
Young JD
中科院分区：
文献类型：
--
作者：
Egnatchik RA;Leamy AK;Jacobson DA;Shiota M;Young JD
棕榈酸超载会导致肝细胞功能障碍，其特征是细胞凋亡增强和柠檬酸循环 (CAC) 代谢改变；然而，这种现象发生的机制尚不完全清楚。我们假设棕榈酸酯剂量升高会破坏细胞内钙稳态，导致钙从内质网净流入线粒体，激活异常的氧化代谢。我们用棕榈酸盐和钙螯合剂处理原代肝细胞和 H4IIEC3 细胞，以确定细胞内钙流在脂毒性中的作用。然后，我们应用 13C 代谢流分析 (MFA) 来确定钙在促进棕榈酸酯刺激的线粒体改变中的影响。与钙特异性螯合剂 BAPTA 共同治疗可抑制细胞凋亡和耗氧标记物。此外，13C MFA 显示，与单独用棕榈酸酯处理的细胞相比，BAPTA 共同处理的细胞的 CAC 通量减少。我们的结果表明，棕榈酸诱导的脂肪细胞凋亡依赖于钙刺激的线粒体激活，从而诱导氧化应激。
Palmitate overload induces hepatic cell dysfunction characterized by enhanced apoptosis and altered citric acid cycle (CAC) metabolism; however, the mechanism of how this occurs is incompletely understood. We hypothesize that elevated doses of palmitate disrupt intracellular calcium homeostasis resulting in a net flux of calcium from the ER to mitochondria, activating aberrant oxidative metabolism. We treated primary hepatocytes and H4IIEC3 cells with palmitate and calcium chelators to identify the roles of intracellular calcium flux in lipotoxicity. We then applied 13C metabolic flux analysis (MFA) to determine the impact of calcium in promoting palmitate-stimulated mitochondrial alterations. Co-treatment with the calcium-specific chelator BAPTA resulted in a suppression of markers for apoptosis and oxygen consumption. Additionally, 13C MFA revealed that BAPTA co-treated cells had reduced CAC fluxes compared to cells treated with palmitate alone. Our results demonstrate that palmitate-induced lipoapoptosis is dependent on calcium-stimulated mitochondrial activation, which induces oxidative stress.
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DOI：
10.1056/nejmoa0907929
发表时间：
2010-05-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sanyal AJ;Chalasani N;Kowdley KV;McCullough A;Diehl AM;Bass NM;Neuschwander-Tetri BA;Lavine JE;Tonascia J;Unalp A;Van Natta M;Clark J;Brunt EM;Kleiner DE;Hoofnagle JH;Robuck PR;NASH CRN
通讯作者：
NASH CRN
影响因子：
4.8
作者：
Li, Zheng Zheng;Berk, Michael;Feldstein, Ariel E.
通讯作者：
Feldstein, Ariel E.
影响因子：
4
作者：
Gyorgy Hajnoczky;Gyrogy Csordas;Yi, Muqing
通讯作者：
Yi, Muqing
影响因子：
4.8
作者：
Li, YK;Ge, MT;Tabas, I
通讯作者：
Tabas, I
棕榈酸盐诱导的线粒体代谢的激活促进了H4IIEC3大鼠肝细胞的氧化应激和凋亡。
影响因子：
9.8
作者：
Egnatchik, Robert A.;Leamy, Alexandra K.;Noguchi, Yasushi;Shiota, Masakazu;Young, Jamey D.
通讯作者：
Young, Jamey D.