Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway
Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway
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DOI：
10.1002/hep.20283
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发表时间：
2004-07-01
期刊：
影响因子：
13.5
通讯作者：
Gores, GJ
中科院分区：
文献类型：
--
作者：
Feldstein, AE;Werneburg, NW;Gores, GJ
非酒精性脂肪性肝病（NAFLD）是一个严重的健康问题。尽管NAFLD是一种脂毒性形式，但其发病机制仍知之甚少。本研究的目的是检测游离脂肪酸（FFA）介导的肝脏脂毒性所涉及的细胞机制。用FFA处理肝细胞导致Bax转位至溶酶体以及溶酶体不稳定，溶酶体半胱氨酸蛋白酶组织蛋白酶B（ctsb）释放到细胞质中。这一过程也部分依赖于ctsb。溶酶体不稳定导致核因子κB依赖的肿瘤坏死因子α表达。在NAFLD患者中也观察到ctsb释放到细胞质中，且与疾病严重程度相关。在NAFLD的饮食小鼠模型中，ctsb的基因或药物失活可防止肝脂肪变性、肝损伤和胰岛素抵抗及其相关的“代谢紊乱综合征”的发生。总之，这些数据支持FFA介导的溶酶体不稳定的脂毒性模型。
Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to examine the cellular mechanisms involved in free fatty acid (FFA)-mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor kappaB-dependent tumor necrosis factor alpha expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated "dysmetabolic syndrome." In conclusion, these data support a lipotoxic model of FFA-mediated lysosomal destabilization.