Hepatic Lpcat3 Accelerates Nonalcoholic Fatty Liver Disease by slut1e1-related promoting fatty acid oxidation and reducing fatty acid synthesis [MCD RNA-seq]. Hepatic Lpcat3 Accelerates Nonalcoholic Fatty Liver Disease by slut1e1-related promoting fatty acid oxidation and reducing fatty acid synthesis [MCD RNA-seq]

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease associated with metabolic disorders such as obesity, diabetes, and high cholesterol. It results in inflammation and fibrosis of liver tissue, eventually leading to cirrhosis and liver cancer. While LPCAT3 has been linked to the formation of fat cells, its role in the development of NASH is not yet fully understood. The purpose of this study was to gain insights into the mechanisms that accelerate NASH induced by LPCAT3. We utilized a genetic engineering rodent model and transcriptomics sequencing approach to explore the role and regulatory mechanism of LPCAT3 in the development of NAFLD. Approach & Results: We studied the impact of Lpcat3 deficiency on NASH progression using three distinct Lpcat3 liver-specific knockout mouse (LKO) models and conducted RNA sequencing, lipidomics, and metabolomics studies on liver samples. Human samples were obtained and analyzed for LPCAT3 expression in patients with NASH to determine its correlation with disease severity. The HepG2 and Huh-7 cell lines were utilized for in vitro analyses. We discovered that LPCAT3 expression was elevated in human NASH livers, and its expression correlated with NAFLD activity score and fibrosis stage. Lpcat3 deficiency in the mouse liver slows the development of diet-induced NASH. Lpcat3 deficiency mechanistically reduces lipid production by inhibiting lipid metabolic pathwaysDeletion of Lpcat3 significantly improved lipid accumulation in NASH mice, possibly due to the involvement of sult1e1 in lipogenesis and oxidation regulation. Moreover, the hepatic overexpression of Lpcat3 significantly intensified lipid buildup in steatotic cells, indicating that LPCAT3 plays a crucial role in the progression of NASH. Conclusions: The findings indicate that LPCAT3 regulates the participation of sult1e1 in both adipogenesis and oxidation, leading to enhanced NASH outcomes. Overall design: To elucidate the role and underlying mechanisms of LPCAT3 in non-alcoholic fatty liver disease (NAFLD), we employed a methionine-choline deficient (MCD) diet to induce the pathology in C57BL/6 mice.

非酒精性脂肪性肝炎（NASH）是一类常见的慢性肝脏疾病，与肥胖、糖尿病、高胆固醇血症等代谢紊乱密切相关。该病可引发肝组织炎症与纤维化，最终进展为肝硬化与肝细胞癌。尽管溶血磷脂酰胆碱酰基转移酶3（LPCAT3）已被证实与脂肪细胞形成相关，但其在NASH发生发展中的作用尚未完全阐明。本研究旨在深入解析LPCAT3介导的NASH加速进展的分子机制。我们采用基因工程啮齿类动物模型与转录组测序技术，探究LPCAT3在非酒精性脂肪性肝病（NAFLD）发生发展中的作用及其调控机制。
研究方法与结果：我们通过三种不同的Lpcat3肝脏特异性敲除（LKO）小鼠模型，探究Lpcat3缺失对NASH进程的影响，并对肝脏样本开展RNA测序、脂质组学与代谢组学分析。我们收集NASH患者的人体样本，检测其LPCAT3的表达水平，以明确该基因表达与疾病严重程度的相关性。此外，我们利用HepG2与Huh-7细胞系进行体外实验分析。
研究结果显示，NASH患者肝脏组织中LPCAT3的表达水平显著升高，且其表达与非酒精性脂肪性肝病活动度评分（NAFLD Activity Score, NAS）及纤维化分期呈正相关。小鼠肝脏中Lpcat3缺失可延缓膳食诱导的NASH进展。机制上，Lpcat3缺失通过抑制脂质代谢通路减少脂质生成。Lpcat3的缺失可显著改善NASH模型小鼠的脂质蓄积，这可能与磺基转移酶1E1（sult1e1）参与脂质生成与氧化调控有关。此外，肝脏过表达LPCAT3可显著加重脂肪变性细胞的脂质蓄积，表明LPCAT3在NASH进展中发挥关键调控作用。
结论：本研究结果表明，LPCAT3通过调控sult1e1参与脂肪生成与氧化过程，进而加剧NASH的疾病进展。
总体研究设计：为阐明LPCAT3在非酒精性脂肪性肝病（NAFLD）中的作用及其潜在分子机制，我们采用蛋氨酸-胆碱缺乏（MCD）饲料诱导C57BL/6小鼠构建NAFLD病理模型。