We investigated the metabolic effects of betaine (Bet) supplementation on CTP:phosphoethanolamine cytidylyltransferase/Pcyt2 heterozygous mice (HET). HET received either no treatment or were allowed access to 1% Bet supplemented water for 8 weeks. As we previously showed with choline (Cho), Bet improved hypertriglyceridemia, and hepatic steatosis in HET. The protection from obesity associated with reduced hepatic steatosis and increased lipid breakdown in adipocytes was attributed to increased energy requirements for metabolism and elimination of supplemented Bet and Cho. 1H-NMR-based profiling revealed metabolic changes caused by Bet and Cho supplementation. Cho increased the citric acid cycle intermediate succinic acid while reducing isoleucine, valine, threonine, and lysine. Bet increased α-ketoglutaric acid and did not stimulate catabolism of amino acids. Increased histidine and alanine are specific biomarkers for Bet treatment. Cho and Bet caused glycerol accumulation and reduced sarcosine, taurine, acetate, and β-hydroxybutyrate levels. These data provide new insights on how Cho and Bet supplementation can aid in treatment of obesity related disorders due to their positive effects on lipolysis, the citric acid cycle, and mitochondrial oxidative demethylation.
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 Pcyt2 substrate, phosphoethanolamine (PEtn), 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 PEtn 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 PEtn 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 metabolite PEtn offers therapeutic potential for NASH reversion.
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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