A hedgehog survival pathway in 'undead' lipotoxic hepatocytes.
A hedgehog survival pathway in 'undead' lipotoxic hepatocytes.
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DOI：
10.1016/j.jhep.2012.05.011
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发表时间：
2012-10
影响因子：
25.7
通讯作者：
Gores, Gregory J.
中科院分区：
文献类型：
--
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Werneburg, Nathan W.;Razumilava, Nataliya;Mertens, Joachim C.;Bronk, Steve F.;Gores, Gregory J.
非酒精性脂肪性肝炎（NASH）中坏死的肝细胞产生音刺猬（SHH）。该观察结果与细胞死亡程序已经启动但不能执行的细胞表型一致。我们的目的是确定气球肝细胞是否有可能禁用细胞死亡执行机制，如果是这样，可以在体外模拟其功能生物学。对人NASH标本进行免疫组织化学。使用具有靶向caspase 9的shRNA敲低的Huh-7细胞（shC 9细胞）或来自caspase 3−/−小鼠的原代肝细胞进行体外研究。NASH中坏死的肝细胞显示caspase 9的表达减少。这种表型使用shC 9细胞建模;这些细胞对棕榈酸酯（PA）或溶血磷脂酰胆碱（LPC）引起的脂凋亡具有抗性，尽管形成了脂滴。在通过PA或LPC的脂质加载期间，shC 9细胞激活JNK，JNK通过AP-1诱导SHH表达。在脂毒性应激期间，shC 9和caspase 3−/−细胞中进一步描绘了自分泌刺猬生存信号通路。NASH中坏死的肝细胞下调caspase 9，caspase 9是执行线粒体凋亡途径的关键caspase。经工程改造以减少胱天蛋白酶9表达的肝细胞对脂调亡具有抗性，部分原因是由于刺猬自分泌存活信号通路。
Ballooned hepatocytes in nonalcoholic steatohepatitis (NASH) generate sonic hedgehog (SHH). This observation is consistent with a cellular phenotype in which the cell death program has been initiated but cannot be executed. Our aim was to determine if ballooned hepatocytes have potentially disabled the cell death execution machinery, and if so, can their functional biology be modeled in vitro. Immunohistochemistry was performed on human NASH specimens. In vitro studies were performed using Huh-7 cells with shRNA targeted knockdown of caspase 9 (shC9 cells) or primary hepatocytes from caspase 3−/− mice. Ballooned hepatocytes in NASH display diminished expression of the caspase 9. This phenotype was modeled using shC9 cells; these cells were resistant to lipoapoptosis by palmitate (PA) or lysophosphatidylcholine (LPC) despite lipid droplet formation. During lipid loading by either PA or LPC, shC9 cells activate JNK which via AP-1 induces SHH expression. An autocrine hedgehog survival signaling pathway was further delineated in both shC9 and caspase 3−/− cells during lipotoxic stress. Ballooned hepatocytes in NASH downregulate caspase 9, a pivotal caspase executing the mitochondrial pathway of apoptosis. Hepatocytes engineered to reduce caspase 9 expression are resistant to lipoapoptosis, in part, due to a hedgehog autocrine survival signaling pathway.
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影响因子：
25.7
作者：
Lackner, Carolin;Gogg-Kamerer, Margit;Denk, Helmut
通讯作者：
Denk, Helmut
DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
11.8
作者：
Fan, Yun;Bergmann, Andreas
通讯作者：
Bergmann, Andreas
影响因子：
11.2
作者：
Regl, G;Kasper, M;Aberger, F
通讯作者：
Aberger, F
影响因子：
7.3
作者：
Mahindroo N;Punchihewa C;Fujii N
通讯作者：
Fujii N