Pathophysiology of NASH: Perspectives for a Targeted Treatment
Pathophysiology of NASH: Perspectives for a Targeted Treatment
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DOI：
10.2174/13816128113199990344
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发表时间：
2013-09-01
影响因子：
3.1
通讯作者：
Lotersztajn, Sophie
中科院分区：
文献类型：
--
作者：
Marra, Fabio;Lotersztajn, Sophie
非酒精性脂肪性肝炎（NASH）是一种较严重的非酒精性脂肪性肝病。在NASH中，脂肪肝、肝炎症、肝细胞损伤和纤维形成相关，这种情况最终可能导致肝硬化。目前NASH的治疗依赖于减轻体重和增加体力活动，但尚未批准药物治疗。新出现的数据表明，NASH的进展是由起源于肝脏、脂肪组织、肠道和胃肠道的平行事件引起的。因此，通过增加游离脂肪酸的流动和脂肪细胞因子的释放，以及肠道微生物组的改变，脂肪组织的功能障碍产生促炎信号，这是NASH进展的基础。其他“肝外影响”包括饮食因素和胃肠道激素。在肝脏内，肝细胞凋亡、内质网应激和氧化应激是导致肝细胞损伤的关键因素。此外，脂毒性介质和危险信号激活Kupffer细胞，Kupffer细胞通过释放炎症介质启动并延续炎症反应，促进炎症细胞募集和纤维化的发展。炎症和纤维化介质包括趋化因子、大麻素系统、炎性体和模式识别受体的激活。在这里，我们回顾了导致NASH出现和进展的主要机制，重点关注肝外信号和局部炎症机制，以确定最有希望治疗这种疾病的分子靶点。
Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and this condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underlie NASH progression. Additional 'extrahepatic hits' include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors.Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition.