title: High homocysteine induces betaine depletion.
abstract: Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.
authors.affiliation: Biochemistry Hormonology Laboratory, Robert-Debré Hospital, APHP, 48 Bd Serurier, Paris 75019, France Paris Sud University, Pharmacy Faculty, 5 rue Jean Baptiste Clément, Chatenay-Malabry 92019, France apolline.imbard@rdb.aphp.fr.
authors.forename: Apolline
authors.initials: A
authors.lastname: Imbard
authors.affiliation: Biochemistry Hormonology Laboratory, Robert-Debré Hospital, APHP, 48 Bd Serurier, Paris 75019, France Paris Sud University, Pharmacy Faculty, 5 rue Jean Baptiste Clément, Chatenay-Malabry 92019, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon 1649-003, Portugal.
authors.forename: Ruben
authors.initials: R
authors.lastname: Esse
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, U.S.A.
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, 48 Bd Serurier, Paris 75019, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.affiliation: Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Bruges 8000, Belgium.
authors.forename: An S
authors.initials: AS
authors.lastname: de Vriese
authors.affiliation: *Reference Center for Inherited Metabolic Diseases, Robert-Debré Hospital, APHP, Paris 75019, France.
authors.forename: Helene Ogier
authors.initials: HO
authors.lastname: de Baulny
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, U.S.A.
authors.forename: Warren
authors.initials: W
authors.lastname: Kruger
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, 48 Bd Serurier, Paris 75019, France *Reference Center for Inherited Metabolic Diseases, Robert-Debré Hospital, APHP, Paris 75019, France †Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Paris 75013, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: ‡Laboratory for Clinical Biochemistry and Metabolism, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine University Hospital, Freiburg D-79106, Germany.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000818:Animals; D001622:Betaine / Q000097:blood*; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D006712:Homocystinuria / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; C490439:Slc6a12 protein, mouse; D006710:Homocysteine; C072207:betaine plasma membrane transport proteins; D001622:Betaine; C494548:BHMT protein, human; D050940:Betaine-Homocysteine S-Methyltransferase; C494549:Bhmt protein, mouse; C494550:Bhmt protein, rat
keywords: S-adenosyl-methionine; betaine; cystathionine-β-synthase deficiency; hyperhomocysteinaemia