非酒精性脂肪性肝炎（NASH），以炎症和纤维化为特征，正在成为肝细胞癌（HCC）的主要病因。肝脏脂质组学分析表明，NASH患者的多不饱和磷脂酰胆碱（PC）水平降低，但膜PC组成在NASH发病机制中的作用尚未得到研究。溶血磷脂酰胆碱酰转移酶3（LPCAT3）是一种磷脂重塑酶，可产生多不饱和磷脂，是肝脏膜PC含量的主要决定因素。我们分析了人体患者样本中LPCAT3的表达以及其表达与NASH严重程度之间的相关性。我们使用Lpcat3肝脏特异性敲除小鼠（LKO）研究了Lpcat3缺失对NASH进展的影响。我们在肝样品中进行了RNA测序、脂质组学和代谢组学。原代肝细胞和肝细胞系被用于体外分析。我们发现LPCAT3在人类NASH肝脏中被显著抑制，其表达与NAFLD活动评分和纤维化阶段呈负相关。小鼠肝脏中Lpcat3的缺失促进了自发性和饮食诱导的NASH / HCC。机制上，Lpcat3缺乏增加了由于线粒体失衡而产生的反应性氧化物的产生。Lpcat3的丧失增加了内线粒体膜磷脂饱和度，并提高了应激诱导的自噬作用，导致线粒体含量减少和断裂增加。此外，在肝脏中过度表达Lpcat3可减轻NASH的炎症和纤维化。这些结果表明，膜磷脂组成调节NASH进展，操纵LPCAT3表达可能是NASH的有效治疗方法。版权所有©2023美国肝病研究协会。

Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in NASH patients, but the roles of membrane PC composition in the pathogenesis of NASH has not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver specific knockout mice (LKO). RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We show that LPCAT3 is dramatically suppressed in human NASH livers, and its expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.Copyright © 2023 American Association for the Study of Liver Diseases.