The mechanisms of NASH development in the context of age and genetics are not fully elucidated. This study investigates the age-dependent liver defects during NASH development in mice with heterozygous deletion of Pcyt2 (ETKO), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of Pcyt2 substrate, phosphoethanolamine (PEtn), is examined. ETKO were investigated at 2, 6 and 8 months of age and in addition, 6-mo old ETKO with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes specific transcriptional and signaling adaptations in lipid/fatty acids and energy metabolism regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older ETKO liver experiences perturbed protein, glucose, and fatty acid metabolism. Older ETKO liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased insulin resistance and inflammation. Supplementation with PEtn reverses ETKO steatosis, inflammation, and other aspects of NASH, showing that was directly caused by Pcyt2 deficiency. Pcyt2 deficiency is a novel mechanism of metabolic dysregulation due to reduced membrane ethanolamine phospholipid synthesis, and the metabolite PEtn offers therapeutic potential for NASH reversion.

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