Dysregulation of phosphatidylethanolamine metabolism associated with upregulation of PNPLA6 in high-fat diet/streptozotocin mice.

Background: Dysregulation of lipid metabolism plays a key role in diabetes mellitus (DM). Phosphatidylethanolamine (PE) and its metabolites, lysophosphatidylethanolamine (LPE) and glycerophosphorylethanolamine (GPE), are involved in cell signaling and mitochondrial homeostasis. Disruption of PE metabolism is associated with insulin sensitivity and mitochondrial dysfunction. However, the mechanism underlying alterations in PE metabolites, especially LPE, in DM remains unclear. Methods: Six-week-old male C57BL/6N mice were divided into three groups: control (regular diet, Results: In the plasma of HFD/STZ mice, the levels of combined LPEs were increased in parallel with PE levels, whereas most LPE species were significantly decreased in the kidneys. Interestingly, GPE levels were markedly increased in the plasma, kidneys, and liver of HFD/STZ mice. The LPE/GPE ratio in the plasma and kidney was negatively correlated with key indicators of DM, such as inflammation, glucose intolerance, and renal dysfunction. Furthermore, PNPLA6, a lysophospholipase that cleaves acyl chains from PE and LPE, was upregulated in the kidney of HFD/STZ mice. Conclusion: Upregulation of PNPLA6 was associated with the reduced LPE/GPE ratio, which may contribute to the progression of DM. This study provides new insights into DM pathology and therapeutic targets.