4.7 Article

Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine

Journal

SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41598-022-05140-y

Keywords

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Funding

  1. CBS scholarship
  2. Ontario Trilium award
  3. Canadian Institutes of Health Research [CIHR-450137, ECD-144626]

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This study explores the liver defects in the development of NASH in mice with heterozygous deletion of Pcyt2 and examines the therapeutic potential of phosphoethanolamine. The results reveal that Pcyt2 deficiency is a novel mechanism of NASH development and supplementation with phosphoethanolamine can reverse the pathological changes of NASH.
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.

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