Hepatic Lpcat3 Accelerates Nonalcoholic Fatty Liver Disease by slut1e1-related promoting fatty acid oxidation and reducing fatty acid synthesis [HFHS 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 investigate the role and mechanistic pathways of LPCAT3 in the context of non-alcoholic fatty liver disease (NAFLD), we induced the disease in C57BL/6 mice through the administration of a high-fat, high-fructose(HFHS) diet.