Journal of Lipid Research
Volume 53, Issue 9, September 2012, Pages 1811-1822
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Research Articles
Mechanism of hypertriglyceridemia in CTP:phosphoethanolamine cytidylyltransferase-deficient mice

https://doi.org/10.1194/jlr.M021881Get rights and content
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Phosphatidylethanolamine is an important inner-leaflet phospholipid, and CTP:phosphoethanolamine cytidylyltransferase-Pcyt2 acts as the main regulator of the de novo phosphatidylethanolamine synthesis from ethanolamine and diacylglycerol. Complete deletion of the mouse Pcyt2 gene is embryonic lethal, and the single-allele deficiency leads to development of the metabolic syndrome phenotype, including liver steatosis, hypertriglyceridemia, obesity, and insulin resistance. This study aimed to specifically elucidate the mechanisms of hypertriglyceridemia in Pcyt2 heterozygous mice (Pcyt2+/−). Evidence here shows that unlike 8 week-old mice, 32 week- and 42 week-old Pcyt2+/− mice experience increased VLDL secretion and liver microsomal triglyceride transfer protein activity. Older Pcyt2+/− mice also demonstrate increased levels of postprandial plasma TAGs, increased stimulation of genes responsible for intestinal lipid absorption, transport and chylomicron secretion, and dramatically elevated plasma Angptl4, apoB-100, and apoB-48 content. In addition, plasma HL and LPL activities and TAG clearance following a lipid challenge were significantly reduced in Pcyt2+/− mice relative to control littermates. Collectively, these results establish that the hypertriglyceridemia that accompanies Pcyt2 deficiency is the result of multiple metabolic adaptations, including elevated hepatic and intestinal lipoprotein secretion and stimulated expression and/or activity of genes involved in lipid absorption and transport and lipoprotein assembly, together with reduced plasma TAG clearance and utilization with peripheral tissues.

phospholipid
very low density lipoprotein secretion
chylomicron formation
triglyceride

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This work was supported by grants from the Canadian Institutes of Health Research-CIHR (MOP 86448) (M.B.) and NSERC Discovery (D.V.). We declare that CIHR had no involvement in the collection and data analysis, in the interpretation and writing of the manuscript, and in the decision to submit the manuscript for publication.