Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Robert, Karine; Chassé, Jean François; Santiard-Baron, Dominique; Vayssettes, Catherine; Chabli, A.; Aupetit, J.; Maeda, Nobuyo; Kamoun, P.; London, Jacqueline; Janel, Nathalie

doi:10.1074/jbc.m213036200

Cited by 60 publications

(54 citation statements)

References 54 publications

(55 reference statements)

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“…In addition, the induction of HO-1 by homocysteine in cultured cells is also consistent with the increase in HO-1 expression observed in a murine model of hyperhomocysteine- mia (37). In contrast, ER stress fails to stimulate HO-1 expression in cultured hepatoma cells (38).…”

Section: Discussionsupporting

confidence: 68%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

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Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time-and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.

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Section: Discussionsupporting

confidence: 68%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

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“…CBS -/-mice showed severe growth retardation and most of them died within two weeks after birth. Plasma homocysteine levels in CBS -/-mice were higher in this study compared with previous studies, 401.66 ± 38.67 M vs. 205 ± 86 M, respectively (Robert et al, 2003a). This difference in homocysteine levels may be caused by a standard laboratory diet given in this study, instead of a special diet, in order to avoid the effect of diet therapy.…”

Section: Discussioncontrasting

confidence: 48%

“…The administration of pyridoxine putatively stimulates residual CBS activity. For the pyridoxine non-responsive group, a methionine-restricted, cysteine-supplemented dietary therapy (Robert et al, 2003a) should be employed even though its effectiveness is restricted. Pyridoxine, folic acid and vitamin B12 have continued to be administered in pyridoxine non-responders because they are cofactors of methionine metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…This difference in homocysteine levels may be caused by a standard laboratory diet given in this study, instead of a special diet, in order to avoid the effect of diet therapy. CBS -/-mice are usually fed a standard A04 rodent chow, which is rich in choline chloride that is necessary for their survival (Robert et al, 2003a). Betaine-homocysteine methyltransferase in liver and kidney cells can transfer a methyl group to methionine from betaine, the oxidized form of choline, providing a secondary pathway for homocysteine remethylation (Finkelstein, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria

Park

Kruger³

et al. 2006

Exp Mol Med

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Homocystinuria is a metabolic disorder caused by a deficiency of cystathionine β-synthase (CBS). The major clinical symptoms of this disease are mental retardation, lens dislocation, vascular disease with life-threatening thromboembolisms, and skeletal deformities. The major treatments for CBS deficiency include pharmacologic doses of pyridoxine or dietary restriction of methionine. There is currently no effective long-term treatment to lower the elevated plasma levels of homocysteine. However, gene therapy could be an effective novel approach for the treatment of homocystinuria. A recombinant adenoassociated virus vector carrying human CBS cDNA (rAAV-hCBS) was constructed and administered to CBS -/-mice by intramuscular (IM) and intraperitoneal (IP) injections. Serum homocysteine concentrations significantly decreased in treated mice compared with age-matched controls two weeks after treatment. The treated CBS -/-mice had life spans 3-7 days longer compared with untreated CBS -/-mice. In CBS -/-mice treated with rAAV-hCBS via IP injection, the vector was detected in all organs examined including liver, spleen, and kidney, and CBS gene expression was observed by immunohistochemical staining in the liver. These results indicate the efficacy of gene delivery and demonstrate the possibility of gene therapy mediated by AAV gene transfer in this mouse model of homocystinuria.

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“…Further studies with the CBS deficient mice revealed the importance of intracellular redox balance for nitric oxide bioactivity and endothelial function, and the importance of ER stress in abnormal hepatic accumulation of lipid [92,93] . Expression of several genes analyzed by DNA microarray was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice [94] . These genes encode ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver.…”

Section: Approaches For Study Of Hhcymentioning

confidence: 99%

Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Cheng

Kaplowitz

2004

WJG

179

104

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Deficiencies in vitamins or other factors (B6, B12, folic acid, betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (HHcy). HHcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. HHcy unleashes mediators of inflammation such as NFκB, IL-1β, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of HHcy. ER stress may also be involved in other liver diseases such as α 1 -antitrypsin (α 1 -AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans, and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease. Ji C, Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury.

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Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Cited by 60 publications

References 54 publications

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria

Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

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