Basic-liver, pancreas, and biliary tractCystathionine β Synthase Deficiency Promotes Oxidative Stress, Fibrosis, and Steatosis in Mice Liver
Section snippets
Animals and Experimental Protocols
Heterozygous CBS-deficient (CBS +/−) mice were generously donated by Dr. N. Maeda (Department of Pathology, University of North Carolina, Chapel Hill, NC) and maintained in a controlled environment with access to unlimited food and water. All animals received human care according to the criteria outlined in the guide for the Care and Use of Laboratory Animals. CBS +/− mice were bred to obtain homozygous CBS-deficient (CBS −/−) mice. This produced CBS −/− and wild-type (CBS +/+) mice from the
Total Plasma and Hepatic Homocysteine Levels in CBS-Deficient Mice
Plasma tHcy concentration was 50-fold higher in CBS −/− mice, which is considered as a murine model of severe hyperhomocysteinemia,6 than that in CBS +/+ mice (205 ± 86 vs. 3.9 ± 0.9 μmol/L, respectively; P < .0001 by Student t test [n = 4 for each]). The mean hepatic concentration of tHcy in CBS −/− mice was approximately 20-fold higher than that in CBS +/+ mice (tHcy concentrations were 6.44 ± 3.86 vs. 0.34 ± 0.14 nmol/mg of cellular protein, respectively; P < .001 by Student t test [n = 5
Discussion
Despite clinical evidence for the toxicity of excess Hcy, the specific cytopathologic mechanisms of hepatocellular injury because of hyperhomocysteinemia have not been fully explored. The present study provides evidence that hyperhomocysteinemia because of CBS deficiency in mice was associated with increased hepatic oxidative stress. Enhanced lipid peroxidation seems to be a key feature in the liver injury observed in CBS-deficient mice. The process of lipid peroxidation generates numerous
References (57)
- et al.
Altered gene expression in liver from a murine model of hyperhomocysteinemia
J Biol Chem
(2003) - et al.
Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α 1 (I) gene expression in human liver fat-storing cells
Biochem Biophys Res Commun
(1993) - et al.
Nonalcoholic steatohepatitisa proposal for grading and staging the histological lesions
Am J Gastroenterol
(1999) Protein damage and degradation by oxygen radicalsI. General aspects
J Biol Chem
(1987)- et al.
Dilinoleoylphosphatidylcholine prevents transforming growth factor-β1-mediated collagen accumulation in cultured rat hepatic stellate cells
J Lab Clin Med
(2002) - et al.
Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms
J Biol Chem
(1997) - et al.
Hyperhomocysteinemia following oral methionine load is associated with increased lipid peroxidation
Thromb Res
(1997) - et al.
Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers
J Nutr
(2001) - et al.
L-Homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells
Free Radic Biol Med
(2004) - et al.
Methionine metabolism in mammalsAdaptation to methionine excess
J Biol Chem
(1986)
In the cystathionine β-synthase knockout mouse, elevations in total plasma homocysteine increase tissue S-adenosylhomocysteine, but responses of S-adenosylmethionine and DNA methylation are tissue specific
J Nutr
Abnormal lipid metabolism in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
J Biol Chem
Structure and functions of human oxysterol 7-hydroxylase cDNAs and gene CYP7B1
J Lipid Res
Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation
Gastroenterology
Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytesa new role for homocysteine in liver fibrosis
Biochim Biophys Acta
Nonalcoholic steatohepatitis
Gastroenterology
Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species
Hepatology
Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response
Atherosclerosis
TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocysteinemia
J Biol Chem
Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice
Hepatology
Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibitionimplications for reversibility of liver fibrosis
J Biol Chem
Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis
J Hepatol
Increased plasma homocysteine in liver cirrhosis
Hepatol Res
Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma
J Hepatol
Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemiaeffect of S-adenosylmethionine treatment
Hepatology
Disorders of transsulfuration
Homocysteine metabolism
Annu Rev Nutr
Homocysteine and atherothrombosis
N Engl J Med
Cited by (156)
Developmental and Inherited Liver Disease
2023, MacSween's Pathology of the Liver, Eighth EditionMethionine cycle in nonalcoholic fatty liver disease and its potential applications
2022, Biochemical PharmacologyImplications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential
2021, Journal of Advanced Research
Supported by the European Union Grant (QLRT-2001-00816), a grant “vin et santé” and the Fondation de France, a fellowship from the Fondation pour la Recherche Médicale (FRM) and the GEHT-ISTH 2001 (to K.R.), and a fellowship from the Société Française d’Hypertension Artérielle (SFHTA; to J.N.).
- 1
K.R. and J.N. contributed equally to this paper.
- 2
E.B.’s current address is EA 2526, Laboratoire de Biochimie et Génétique Moléculaire; Faculté des Sciences et Technologies, Université de la Réunion, 15, Avenue René Cassin, BP 7151; 97715 Saint Denis Messag Cedex 09, La réunion, France.