Phosphoethanolamine improves non-alcoholic steatohepatitis, and enhances muscle insulin signaling, in Pcyt2 heterozygous mice.

Abstract

Phosphatidylethanolamine (PE) is primarily synthesized by the Kennedy pathway, where a series of enzymatic reactions incorporate ethanolamine and diacylglycerol (DAG). This pathway is dependent on CTP-ethanolamine cytidylyltransferase (ET/Pcyt2), which is the rate limiting enzyme. Pcyt2 heterozygous mice (Pcyt2(+/-)) accumulate DAG and triacylglycerol due to the lack of utilization in the Kennedy pathway, leading to the development of obesity, insulin resistance, hyperlipidemia, and steatohepatitis. Here, we demonstrate that supplementation with phosphoethanolamine (PEA), the substrate of Pcyt2, has the ability to improve steatohepatitis caused by the lack of DAG utilization. PEA also enhanced insulin signaling to promote protein synthesis in skeletal muscle. Genes involved in phospholipid biosynthesis and lipid metabolism were also stimulated by PEA to maintain phospholipid content and promote lipolysis. The effects of PCYT2 knockdown on human fibroblast cells were examined to provide insight as to how reductions in PCYT2 could result in lipid-related disorders in a human model.