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 phosphoethanolamine (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 wk. 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 with Etnppl^+/+ mice. Plasma triglyceride (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 with 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.NEW & NOTEWORTHY Etnppl^-/- female mice resisted diet-induced obesity with enhanced energy expenditure and less adipose tissue. In addition, Etnppl^-/- female mice fed an HFD showed decreased liver cholesterol deposition. RNA sequencing revealed changes in genes related to cholesterol and lipid metabolism in Etnppl^-/- female mice. Etnppl^-/- female mice fed an HFD supplemented with cholesterol had no difference in plasma and hepatic cholesterol levels compared with Etnppl^+/+ mice.