title: Choline supplementation restores substrate balance and alleviates complications of Pcyt2 deficiency.
abstract: Choline plays a critical role in systemic lipid metabolism and hepatic function. Here we conducted a series of experiments to investigate the effect of choline supplementation on metabolically altered Pcyt2(+/-) mice. In Pcyt2(+/-) mice, the membrane phosphatidylethanolamine (PE) turnover is reduced and the formation of fatty acids (FA) and triglycerides (TAG) increased, resulting in hypertriglyceridemia, liver steatosis and obesity. One month of choline supplementation reduced the incorporation of FA into TAG and facilitated TAG degradation in Pcyt2(+/-) adipocytes, plasma and liver. Choline particularly stimulated adipocyte and liver TAG lipolysis by specific lipases (ATGL, LPL and HSL) and inhibited TAG formation by DGAT1 and DGAT2. Choline also activated the liver AMPK and mitochondrial FA oxidation gene PPARα and reduced the FA synthesis genes SREBP1, SCD1 and FAS. Liver (HPLC) and plasma (tandem mass spectroscopy and (1)H-NMR) metabolite profiling established that Pcyt2(+/-) mice have reduced membrane cholesterol/sphingomyelin ratio and the homocysteine/methionine cycle that were improved by choline supplementation. These data suggest that supplementary choline is beneficial for restoring FA and TAG homeostasis under conditions of obesity caused by impaired PE synthesis.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
authors.forename: Laila C
authors.initials: LC
authors.lastname: Schenkel
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
authors.forename: Sugashan
authors.initials: S
authors.lastname: Sivanesan
authors.affiliation: Aquatic and Crop Resource Development, National Research Council Canada, Halifax, NS, Canada B3H 3Z1.
authors.forename: Junzeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Clinical Chemistry, Laboratory of Metabolic Disorders, University Hospital Ghent, 9000 Ghent, Belgium.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Wuyts
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
authors.forename: Adrian
authors.initials: A
authors.lastname: Taylor
authors.affiliation: University of Guelph, Ontario Veterinary College, Dep. Clinical Studies, Guelph, Canada.
authors.forename: Adronie
authors.initials: A
authors.lastname: Verbrugghe
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1. Electronic address: mbakovic@uoguelph.ca.
authors.forename: Marica
authors.initials: M
authors.lastname: Bakovic
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000215:Acylation; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives; D002794:Choline / Q000494:pharmacology*; D019587:Dietary Supplements; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008817:Mice, Mutant Strains; D010713:Phosphatidylcholines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D012316:RNA Nucleotidyltransferases / Q000172:deficiency* / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D014280:Triglycerides; C116917:acylcarnitine; D055372:AMP-Activated Protein Kinases; D012316:RNA Nucleotidyltransferases; C020126:Ethanolamine-phosphate cytidylyltransferase; D002794:Choline; D002331:Carnitine
keywords: Choline; Ethanolamine; Kennedy pathway; Pcyt2; Phospholipids