Marí Montserrat, Caballero Francisco, Colell Anna, Morales Albert, Caballeria Juan, Fernandez Anna, Enrich Carlos, Fernandez-Checa José C, García-Ruiz Carmen
Liver Unit, Institut de Malalties Digestives, Hospital Clínic i Provincial, Instituto Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Cell Metab. 2006 Sep;4(3):185-98. doi: 10.1016/j.cmet.2006.07.006.
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.
从脂肪变性进展为脂肪性肝炎（SH）的病因尚不清楚。利用肝脏脂肪变性的营养和遗传模型，我们发现，游离胆固醇（FC）负荷而非游离脂肪酸或甘油三酯，会使肝脏对肿瘤坏死因子（TNF）和Fas诱导的SH敏感。内质网（ER）和质膜中的FC分布不会引起内质网应激或改变TNF信号传导。相反，线粒体FC负荷是肝细胞对TNF敏感的原因，这是由于线粒体谷胱甘肽（mGSH）耗竭所致。原代肝细胞中的选择性mGSH耗竭重现了FC负荷肝细胞中对TNF和Fas的易感性；mGSH的补充使FC负荷的肝脏免受TNF介导的SH。此外，缺乏晚期内体胆固醇转运蛋白NPC1的小鼠或肥胖的ob/ob小鼠的肝细胞表现出线粒体FC积累、mGSH耗竭以及对TNF的易感性。因此，我们提出线粒体FC负荷在引发SH中起关键作用，它通过mGSH耗竭使肝细胞对TNF和Fas敏感。
