Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.
Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.
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DOI：
10.1016/j.jhep.2010.01.003
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发表时间：
2010-04
影响因子：
25.7
通讯作者：
Gores GJ
中科院分区：
文献类型：
--
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
饱和游离脂肪酸诱导肝细胞脂凋亡。这种脂毒性涉及内质网应激反应、JNK的激活以及Bcl - 2蛋白表达和功能的改变。单不饱和游离脂肪酸棕榈油酸是一种源于脂肪的脂肪因子，其通过尚不明确的机制抑制游离脂肪酸介导的脂毒性。在此我们研究了细胞保护的相关机制。
我们采用分离的人和小鼠原代肝细胞以及Huh - 7和Hep 3B细胞系进行这些研究。细胞在有或无棕榈酸（16:0）、硬脂酸（18:0）和/或棕榈油酸（16:1，n - 7）的情况下进行孵育。
在原代细胞和细胞系中，棕榈油酸显著减少了棕榈酸或硬脂酸引起的脂凋亡。棕榈油酸加剧了Huh - 7细胞中棕榈酸诱导的脂肪变性，这排除了将抑制脂肪变性作为减少凋亡的一种机制。棕榈油酸抑制了棕榈酸诱导的内质网应激反应，这表现为CHOP表达降低、eIF2 -α磷酸化减少、XBP - 1剪接减少以及JNK激活受抑。棕榈酸增加了仅含BH3结构域的蛋白PUMA和Bim的表达，而棕榈油酸减弱了这种增加。与它对PUMA和Bim诱导的抑制作用一致，棕榈油酸阻止了下游死亡介质Bax的激活。
这些数据表明棕榈油酸通过阻断内质网应激相关的仅含BH3结构域的蛋白Bim和PUMA的增加来抑制脂凋亡。
Saturated free fatty acids induce hepatocyte lipoapoptosis. This lipotoxicity involves an endoplasmic reticulum stress response, activation of JNK, and altered expression and function of Bcl-2 proteins. The mono-unsaturated free fatty acid, palmitoleate is an adipose-derived lipokine, which suppresses free fatty acid-mediated lipotoxicity by unclear mechanisms. Herein we examined the mechanisms responsible for cytoprotection. We employed isolated human and mouse primary hepatocytes, and the Huh-7 and Hep 3B cell lines for these studies. Cells were incubated in presence and absence of palmitate (16:0), stearate (18:0), and or palmitoleate (16:1, n-7). Palmitoleate significantly reduced lipoapoptosis by palmitate or stearate in both primary cells and cell lines. Palmitoleate accentuated palmitate-induced steatosis in Huh-7 cells excluding inhibition of steatosis as a mechanism for reduced apoptosis. Palmitoleate inhibited palmitate induction of the endoplasmic reticulum stress response as demonstrated by reductions in CHOP expression, eIF2-α phosphorylation, XBP-1 splicing, and JNK activation. Palmitate increased expression of the BH3-only proteins PUMA and Bim, which was attenuated by palmitoleate. Consistent with its inhibition of PUMA and Bim induction, palmitoleate prevented activation of the downstream death mediator Bax. These data suggest palmitoleate inhibits lipoapoptosis by blocking endoplasmic reticulum stress-associated increases of the BH3-only proteins Bim and PUMA.
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影响因子：
64.5
作者：
Cao H;Gerhold K;Mayers JR;Wiest MM;Watkins SM;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
4.8
作者：
Miyazaki, M;Kim, YC;Ntambi, JM
通讯作者：
Ntambi, JM
影响因子：
64.5
作者：
Puthalakath, Hamsa;O'Reilly, Lorraine A.;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
4.8
作者：
Cazanave, Sophie C.;Mott, Justin L.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
3.1
作者：
Nehra, V;Angulo, P;Lindor, KD
通讯作者：
Lindor, KD