The pathogenesis of non-alcoholic fatty liver disease, particularly the mechanisms whereby a minority of patients develop a more severe phenotype characterised by hepatocellular damage, inflammation, and fibrosis is still incompletely understood. Herein, we discuss two pivotal aspects of the pathogenesis of NASH. We first analyse the initial mechanisms responsible for hepatocellular damage and inflammation, which derive from the toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in hepatocytes is not the major determinant of lipotoxicity, and that specific lipid classes act as damaging agents on liver cells. In particular, the role of free fatty acids such as palmitic acid, cholesterol, lysophosphatidylcholine and ceramides has recently emerged. These lipotoxic agents affect the cell behaviour via multiple mechanisms, including activation of signalling cascades and death receptors, endoplasmic reticulum stress, modification of mitochondrial function, and oxidative stress. In the second part of this review, the cellular and molecular players involved in the cross-talk between the gut and the liver are considered. These include modifications to the microbiota, which provide signals through the intestine and bacterial products, as well as hormones produced in the bowel that affect metabolism at different levels including the liver. Finally, the activation of nuclear receptors by bile acids is analysed.

中文翻译：

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NASH 发病机制中的脂毒性和肠肝轴

非酒精性脂肪性肝病的发病机制，特别是少数患者发展为以肝细胞损伤、炎症和纤维化为特征的更严重表型的机制尚不完全清楚。在此，我们讨论 NASH 发病机制的两个关键方面。我们首先分析了导致肝细胞损伤和炎症的初始机制，这些机制源自过量脂质的毒性作用。越来越多的数据表明，储存在肝细胞中的甘油三酯总量不是脂毒性的主要决定因素，特定的脂质类别对肝细胞起着破坏作用。特别是最近出现了游离脂肪酸如棕榈酸、胆固醇、溶血磷脂酰胆碱和神经酰胺的作用。这些脂毒剂通过多种机制影响细胞行为，包括信号级联和死亡受体的激活、内质网应激、线粒体功能的改变和氧化应激。在本综述的第二部分，考虑了参与肠道和肝脏之间串扰的细胞和分子参与者。这些包括对微生物群的修改，通过肠道和细菌产物提供信号，以及在肠道中产生的影响不同水平代谢的激素，包括肝脏。最后，分析了胆汁酸对核受体的激活。在本综述的第二部分，考虑了参与肠道和肝脏之间串扰的细胞和分子参与者。这些包括对微生物群的修改，通过肠道和细菌产物提供信号，以及在肠道中产生的影响不同水平代谢的激素，包括肝脏。最后，分析了胆汁酸对核受体的激活。在本综述的第二部分，考虑了参与肠道和肝脏之间串扰的细胞和分子参与者。这些包括对微生物群的修改，通过肠道和细菌产物提供信号，以及在肠道中产生的影响不同水平代谢的激素，包括肝脏。最后，分析了胆汁酸对核受体的激活。