Female ethanolamine phosphate phospholyase knockout mice resisted high-fat diet-induced obesity with attenuated hepatic cholesterol deposition

Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phospho-ethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) synthesis. Whole-body knockout Etnppl mice were fed a high-fat diet (HFD) containing 45% kcal fat for 10 weeks. Etnppl -/- female mice were resistant to HFD-induced obesity and had decreased liver weight compared with Etnppl +/+ mice. Furthermore, Etnppl -/- female mice had improved glucose sensitivity and increased energy expenditure compared to Etnppl +/+ mice. Plasma triglycerides (TG) levels were elevated in Etnppl -/- female mice, although the rate of very low-density lipoprotein (VLDL) secretion was not increased. The hepatic expression of PCSK9 was elevated, indicating a possible decrease in VLDL uptake. Interestingly, both plasma and hepatic cholesterol levels were reduced in Etnppl -/- relative to Etnppl +/+ mice. No difference in hepatic phosphatidylcholine, PE or TG was detected between groups. Histopathological examination of hepatic tissues revealed decreased lipid deposition in Etnppl -/- mice that may be explained by the lower hepatic cholesterol level. Additionally, RNA sequencing analysis showed upregulation in genes related to cholesterol metabolism in Etnppl -/- female mice. In male mice, a slight decrease in weight gain was observed in Etnppl -/- mice compared to Etnppl +/+ mice. No change in plasma and hepatic lipid levels was detected in Etnppl -/- male mice. To conclude, ETNPPL impacts whole-body energy expenditure, weight gain, cholesterol metabolism, and hepatic lipoprotein metabolism without altering hepatic phospholipid levels.