title: Triacylglycerol/phospholipid molecular species profiling of fatty livers and regenerated non-fatty livers in cystathionine beta-synthase-deficient mice, an animal model for homocysteinemia/homocystinuria.
abstract: Fatty liver is one of the typical manifestations in homocysteinemia/homocystinuria patients and their genetic animal model, mice lacking cystathionine β-synthase (Cbs(-/-)). The vast majority of Cbs(-/-) die within 4 weeks after birth via yet unknown mechanisms, whereas a small portion survive to adulthood, escaping fatty degeneration of the liver during lactation periods, through regeneration. To investigate the molecular basis of such fatty changes, we analyzed lipid components in fatty livers of 2-week-old Cbs(-/-) and regenerated non-fatty livers of 8-week-old Cbs(-/-) survivors using a chip-based nanoESI (electrospray ionization)-MS system, which allows quantitative detection of triacylglycerol/phospholipid molecular species. Hepatic levels of all major triacylglycerol species were much higher in Cbs(-/-) than in wild-type mice at 2 weeks, although not at 8 weeks. Levels of some phospholipid species were either up- or downregulated in 2-week-old Cbs(-/-); e.g. saturated (16:0 and 18:0) or mono-unsaturated (16:1 and 18:1) fatty acids-containing phosphatidylcholine/phosphatidylethanolamine species were upregulated, while poly-unsaturated fatty acids-containing phosphatidylcholine (18:2-18:2 and 18:2-20:5), phosphatidylethanolamine (18:1-20:4), and phosphatidylinositol (18:0-20:4) were downregulated. Capillary electrophoresis-MS analysis identified high-level accumulation of S-adenosylmethionine and S-adenosylhomocysteine in fatty livers of 2-week-old Cbs(-/-) but much less in non-fatty livers of 8-week-old Cbs(-/-). Although hepatic S-adenosylmethionine/S-adenosylhomocysteine ratios were comparable between 2-week-old Cbs(-/-) and wild-type, global protein arginine methylation was disturbed in fatty livers of Cbs(-/-). Our results suggest that cellular signaling mediated by altered phospholipid contents might be involved in pathogenesis of fatty liver in Cbs(-/-).
authors.affiliation: Department of Metabolome, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Akiko
authors.initials: A
authors.lastname: Kubo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Akahoshi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamada
authors.forename: Naoya
authors.initials: N
authors.lastname: Miura
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagahata
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood*; D006712:Homocystinuria / Q000378:metabolism*; D008115:Liver Regeneration; D051379:Mice; D010743:Phospholipids / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D014280:Triglycerides; D006710:Homocysteine