Inhibiting hepatic LPCAT3 ameliorates alcoholic liver injury through regulating NAMPT and PTLP signaling
Background and Aims: Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key molecule regulating intracellular phospholoesters has abundantly expression level in metabolic tissues including liver, intestine and adipose. And it is considered to be directly related to the biosynthesis of inflammatory lipid mediators in humans. However, the mechanism of LPCAT3 in alcoholic liver disease (ALD) is unclear. Approach and Results: Liver-specific LPCAT3 liver knockout (LPCAT3-LKO) mice were established using CRISPR/Cas9, and then an ALD model followed by NIAAA modele was established. After LPCAT3-specific knockout of liver tissue, ALT, AST, TG, TC and liver TG, TC in ALD mice were reduced. Our group found that three downstream targets of LPCAT3, namely phospholipid transfer protein (PLTP) and nicotinamide phosphoribosyltransferase (NAMPT) and elongation of long-chain fatty acids family member 5 (ELOVL5) through RNA sequencing and the unbiased systematic investigative approach. In addition, our experimental data indicated that LPC and PC metabolism were altered in ALD mice by using targeted metabolomics. PCR and WB showed that PLTP and NAMPT protein expression levels were ascended in the LKO_x005F_x0002_EtOH group than Flox-EtOH group in the ALD model group. At the same time, in ethanol-induced cell models, LPCAT3 overexpression upregulated ALT and TG levels, aggravated hepatocytes, damage and lipid production, and reduced the expression of PLTP and NAMPT. Conclusions: The results provide novel views on the significance of LPCAT3 in regulating liver phospholipid synthesis in the pathogenesis of ALD. Reduction of LPCAT3 in liver tissue is able to mitigate alcohol-induced hepatocyte damage and lipid production by regulating PLTP and NAMPT. Overall design: To investigate the mechanistic role of LPCAT3 in alcoholic liver injury, we established an NIAAA mouse model.