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Ethanolamine phosphate phospholyase knockout mice have reduced weight gain and altered lipid metabolism when fed a high-fat diet

ABSTRACT: 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 adiposity 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-/- female mice 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE283434 | GEO | 2025/07/11

REPOSITORIES: GEO

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Project description:The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. Owing to their central role in controlling hepatic lipid and lipoprotein metabolism their activity is tightly coordinated, and accordingly dysregulation of the SREBP pathway is associated with development of dyslipidemia and non-alcoholic fatty liver disease. Using a suite of genome-wide genetic screens we have recently identified SPRING (C12ORF49) as a novel post-transcriptional regulator of SREBP activation in vitro. Our previous work demonstrated that constitutive ablation of Spring in mice is embryonically lethal. Here we show that inducible global deletion of Spring is also untolerated, and therefore to interrogate the physiological role of SPRING in controlling hepatic lipid metabolism we developed liver-specific Spring knockout mice (LKO). Liver transcriptomics and proteomics analysis revealed severely attenuated SREBP signaling in livers and in hepatocytes of LKO mice, which was associated with marked effects on both plasma and hepatic lipid levels. In plasma, total cholesterol levels were dramatically reduced in both male and female LKO mice, apparent in both the LDL and HDL fractions, while triglyceride levels remained largely unaffected. In liver, loss of Spring diminished cholesterol and triglyceride biosynthesis resulting in decreased hepatic cholesterol and triglyceride content. This coincided with reduced secretion of VLDL into the circulation. Consistent with diminished hepatic de novo lipogenesis, LKO mice were protected from developing hepatosteatosis when challenged with a fructose-rich diet. Supporting the significance of our findings in mice, we identified common and rare SPRING genetic variants that are strongly associated with circulating HDL-c and ApoA1 levels in humans. Collectively, our study positions SPRING as a core component of hepatic SREBP signaling, and consequently of systemic lipid metabolism in mice and humans.

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Ethanolamine phosphate phospholyase knockout mice have reduced weight gain and altered lipid metabolism when fed a high-fat diet

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