The emerging roles of PHOSPHO1 and its regulated phospholipid homeostasis in metabolic disorders

Abstract

Emerging evidence suggests that phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1), a specific phosphoethanolamine and phosphocholine phosphatase, is involved in energy metabolism. In this review, we describe the structure and regulation of PHOSPHO1, as well as current knowledge about the role of PHOSPHO1 and its related phospholipid metabolites in regulating energy metabolism. We also examine mechanistic evidence of PHOSPHO1- and phospholipid-mediated regulation of mitochondrial and lipid droplets functions in the context of metabolic homeostasis, which could be potentially targeted for treating metabolic disorders.

Keywords: PHOSPHO1; lipid droplets; metabolic disorders; mitochondrial function; phospholipid homeostasis.

FIGURE 1

Cross-species amino acid sequence comparisons of PHOSPHO1 orthologs at the four conserved motifs. Alignment was obtained and adapted from homoloGene, T-Coffee and Jalview results (Notredame et al., 2000; Troshin et al., 2011).

FIGURE 2

Molecule docking result of AlphaFold predicted 3D structure of mouse PHOSPHO1 protein with phosphocholine by CB-Dock (Liu et al., 2020). The pink color represents α-helices, and the yellow color represents β-sheets.

FIGURE 3

Common variant gene-level associations for PHOSPHO1 as the closest gene with metabolic disorders indicators.

FIGURE 4

Diagram of phospholipids metabolism pathways. PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; CDP-E, CDP-ethanolamine; E, Ethanolamine; DMG, Dimethylglycine; Methyl-THF, 5-methyltetrahydrofolate; THF, Tetrahydrofolate; SAM, Adenosylmethionine; SAH, Adenosylhomocysteine; LPC, Lyso-phosphatidylcholine; PEMT, Phosphatidylethanolamine n-methyltransferase; E/CK, Ethanolamine/choline kinase; E/CCT, Phosphoethanolamine/phosphocholine cytidylyltransferase; EPT, Ethanolamine phosphotransferase; CEPT, Choline/ethanolamine phosphotransferase.

FIGURE 5

Knockdown of phospholipids-regulating genes in THP-1 macrophages alters lipid droplets morphology induced by oleic acid. Five features of lipid droplets were selected and scaled to generate z-scores (Mejhert et al., 2020) and the heatmap.