Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis
Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis
复制标题
DOI：
10.1016/j.cmet.2006.07.006
复制
发表时间：
2006-09-01
期刊：
影响因子：
29
通讯作者：
Garcia-Ruiz, Carmen
中科院分区：
文献类型：
--
作者：
Mari, Montserrat;Caballero, Francisco;Garcia-Ruiz, Carmen
从脂肪变性进展到脂肪性肝炎(SH)的病因仍不清楚。利用肝脏脂肪变性的营养和遗传模型，我们表明，游离胆固醇(FC)负荷，而不是游离脂肪酸或甘油三酯，对肿瘤坏死因子和Fas诱导的SH敏感。Fc在内质网和质膜中的分布不会引起内质网应激或改变肿瘤坏死因子信号。相反，线粒体Fc负荷解释了由于线粒体谷胱甘肽(MGSH)耗竭而导致的肝细胞对肿瘤坏死因子的敏感性。原代肝细胞mGSH选择性耗竭重现了Fc负载肝细胞对肿瘤坏死因子和Fas的易感性；它的再耗竭将Fc负载的肝脏从肿瘤坏死因子介导的SH中拯救出来。此外，缺乏NPC1的小鼠或肥胖的ob/ob小鼠的肝细胞表现出线粒体Fc积聚、mGSH耗竭和对肿瘤坏死因子的敏感性。因此，我们提出了线粒体Fc负荷在沉淀SH中的关键作用，即通过耗尽mGSH使肝细胞对肿瘤坏死因子和Fas敏感。
The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion.