title: Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver.
abstract: OBJECTIVE
  Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia, which confers diverse clinical manifestations, notably liver disease. To investigate this aspect of hyperhomocysteinemia, we performed a thorough investigation of liver pathology in CBS-deficient mice, a murine model of severe hyperhomocysteinemia.
  
  
  METHODS
  The degree of liver injury and inflammation was assessed by histologic examination, by measurements of products of lipid peroxidation, and by formation of carbonyl groups on protein as a measure for the occurrence of protein oxidation. Analysis of profibrogenic, proinflammatory factors and cell apoptosis was performed by Western blots, real-time quantitative reverse-transcription polymerase chain reaction, caspase-3 activity, DNA laddering, and TUNEL assay.
  
  
  RESULTS
  Histologic evaluation of liver specimens of 8- to 32-week-old CBS-deficient mice showed that CBS-deficient mice develop inflammation, fibrosis, and hepatic steatosis, concomitant with an enhanced expression of tissue inhibitor of metalloproteinase-1, alpha-smooth muscle actin, pro(alpha)1 collagen type I, transforming growth factor-beta1, and proinflammatory cytokines. Moreover, even if the proapoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated, caspase-3 was not activated, DNA laddering was not detected, and number of positive TUNEL cells was not increased in liver of CBS-deficient mice compared with wild-type mice.
  
  
  CONCLUSIONS
  The results show that hyperhomocysteinemia in liver of CBS-deficient mice promotes oxidative stress, which may cause mitochondrial damage in association with activation of hepatic stellate cells, leading to liver injury. The absence of caspase-3 activation, DNA fragmentation, and TUNEL-positive cells shows that protective signals may counteract apoptotic signals in liver of CBS-deficient mice.
authors.affiliation: EA 3508, Université Paris 7-Denis Diderot, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Robert
authors.forename: Johnny
authors.initials: J
authors.lastname: Nehmé
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourdon
authors.forename: Gérard
authors.initials: G
authors.lastname: Pivert
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Delabar
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006710:Homocysteine / Q000097:blood; D006712:Homocystinuria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020138:Hyperhomocysteinemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D024042:Collagen Type I; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006710:Homocysteine; D003541:Cystathionine beta-Synthase