title: Cystathionine protects against endoplasmic reticulum stress-induced lipid accumulation, tissue injury, and apoptotic cell death.
abstract: Cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine) is a non-proteinogenic thioether containing amino acid. In mammals, cystathionine is formed as an intermediate of the transsulfuration pathway by the condensation of serine and homocysteine (Hcy) in a reaction catalyzed by cystathionine β-synthase (CBS). Cystathionine is subsequently converted to cysteine plus ammonia and α-ketobutyrate by the action of cystathionine γ-lyase (CGL). Pathogenic mutations in CBS result in CBS-deficient homocystinuria (HCU) which, if untreated, results in mental retardation, thromboembolic complications and connective tissue disorders. Currently there is no known function for cystathionine other than serving as an intermediate in transsulfuration and to date, the possible contribution of the abolition of cystathionine synthesis to pathogenesis in HCU has not been investigated. Using both mouse and cell-culture models, we have found that cystathionine is capable of blocking the induction of hepatic steatosis and kidney injury, acute tubular necrosis, and apoptotic cell death by the endoplasmic reticulum stress inducing agent tunicamycin. Northern and Western blotting analysis indicate that the protective effects of cystathionine occur without any obvious alteration of the induction of the unfolded protein response. Our data constitute the first experimental evidence that the abolition of cystathionine synthesis may contribute to the pathology of HCU and that this compound has therapeutic potential for disease states where ER stress is implicated as a primary initiating pathogenic factor.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
authors.forename: Lori S
authors.initials: LS
authors.lastname: Greiner
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Evans
authors.forename: Sudesh K
authors.initials: SK
authors.lastname: Sood
authors.forename: Sarka
authors.initials: S
authors.lastname: Lhotak
authors.forename: Neil E
authors.initials: NE
authors.lastname: Markham
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.forename: Vivek
authors.initials: V
authors.lastname: Balasubramaniam
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D003540:Cystathionine / Q000737:chemistry*; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006712:Homocystinuria / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D009336:Necrosis / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D011489:Protein Denaturation; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D008055:Lipids; D014415:Tunicamycin; D003540:Cystathionine; D003541:Cystathionine beta-Synthase