Abstract
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 (Pcyt2+/−), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of the artificial Pcyt2 substrate, phosphonoethylamine (PEA), is examined. Pcyt2+/− were investigated at 2 and 6–8 months (mo) of age and in addition, 6-mo old Pcyt2+/− with developed NASH were supplemented with PEA for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes changes in liver metabolic regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older Pcyt2+/− experiences perturbed glucose and fatty acid metabolism. Older Pcyt2+/− liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased inflammation. Supplementation with PEA reverses Pcyt2+/− 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 artificial Pcyt2 substrate PEA offers therapeutic potential for NASH reversion.
Highlights
The mechanisms of nonalcoholic steatohepatitis (NASH) development in the context of age and genetics are not fully elucidated
To help elucidate the mechanism by which heterozygous ablation of Pcyt[2] affects glucose metabolism by age, we performed glucose (GTT) and pyruvate (PTT) and tolerance tests on 2-mo and 8-mo mice
In this study we focus on the mechanisms of age-related development of NASH in Pcyt2+/− mice
Summary
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 Pcyt[2] (Pcyt2+/−), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Pcyt2+/− were investigated at 2 and 6–8 months (mo) of age and in addition, 6-mo old Pcyt2+/− with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Pcyt[2] 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. According to dbSNP database PCYT2 is heavily mutated, with over 4400 single nucleotide polymorphisms identified and 60 allele mutations within the gene coding r egion[16] Together this suggests the candidacy of PCYT2 gene and importance of establishing the significance of reduced PCYT2 activity in metabolic diseases
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