title: Cystathionine beta-synthase deficiency alters hepatic phospholipid and choline metabolism: Post-translational repression of phosphatidylethanolamine N-methyltransferase is a consequence rather than a cause of liver injury in homocystinuria.
abstract: Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC). Comparative metabolomic analysis of HO mouse liver revealed decreased levels of choline, and choline phosphate indicating disruption of the Kennedy pathway. Alterations in the relative levels of multiple species of PL included significant increases in PL degradation products consistent with enhanced membrane PL turnover. A significant decrease in PC containing 20:4n6 which primarily formed by the methylation of phosphatidylethanolamine to PC was consistent with decreased flux through PEMT. Hepatic expression of PEMT in both the cbs-/- and HO models is post-translationally repressed with decreased levels of PEMT protein and activity that inversely-correlates with the scale of liver injury. Failure to induce further repression of PEMT in HO mice by increased homocysteine, methionine and S-adenosylhomocysteine or depletion of glutathione combined with examination of multiple homocysteine-independent models of liver injury indicated that repression of PEMT in HCU is a consequence rather than a cause of liver injury. Collectively, our data show significant alteration of a broad range of hepatic PL and choline metabolism in HCU with the potential to contribute to multiple aspects of pathogenesis in this disease.
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G2E1, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2E1, Canada.
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G2E1, Canada; Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2E1, Canada.
authors.forename: John P
authors.initials: JP
authors.lastname: Kennelly
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: ken.maclean@UCdenver.edu.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
mesh_terms: D000818:Animals; D002794:Choline / Q000378:metabolism*; D004195:Disease Models, Animal; D006712:Homocystinuria / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000737:chemistry* / Q000293:injuries; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D010743:Phospholipids; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline
keywords: Choline; Cystathionine beta-synthase; Homocysteine; Homocystinuria; Phosphatidylethanolamine N-methyltransferase; Phospholipids