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Sex-specific dysregulation of cysteine oxidation and the methionine and folate cycles in female cystathionine gamma-lyase mice: a serendipitous model of the methylfolate trap.

Jiang H, Hurt KJ, Breen K, Stabler SP, Allen RH, Orlicky DJ, Maclean KN - Biol Open (2015)

Bottom Line: In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide.Cgl mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls.Female Cgl mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

No MeSH data available.


Related in: MedlinePlus

The hepatic phenotype of female Cgl  mice is consistent with a possible protective role for cystathionine against liver injury in Cgl  mice. (A) H&E (upper panels) and Plin2 immunohistochemical staining (lower panels) from representative liver sections from male and female Cgl  mice reveals mild levels of lipid accumulation and Plin2 expression (green signal) in female but not male Cgl  mice. Data shown is representative of 5 animals per group. PT, portal triad; CV, central vein. (B) Masson-trichrome staining of female Cbs and Cgl  mice with similar levels of plasma tHcy. No fibrosis was observed in any Cgl  (right panel) mouse sample. Photomicrographs shown are representative of staining from 20 views taken from 5 mutant mice and 5 wild type controls and were assessed by a pathologist without knowledge of genotype. Scale bars: 200 µm.
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BIO013433F7: The hepatic phenotype of female Cgl mice is consistent with a possible protective role for cystathionine against liver injury in Cgl mice. (A) H&E (upper panels) and Plin2 immunohistochemical staining (lower panels) from representative liver sections from male and female Cgl mice reveals mild levels of lipid accumulation and Plin2 expression (green signal) in female but not male Cgl mice. Data shown is representative of 5 animals per group. PT, portal triad; CV, central vein. (B) Masson-trichrome staining of female Cbs and Cgl mice with similar levels of plasma tHcy. No fibrosis was observed in any Cgl (right panel) mouse sample. Photomicrographs shown are representative of staining from 20 views taken from 5 mutant mice and 5 wild type controls and were assessed by a pathologist without knowledge of genotype. Scale bars: 200 µm.

Mentions: A previously described Cbs mouse model of HCU incurs severe liver injury with approximately 90% of mice dying of liver failure in the first two weeks of life (Watanabe et al., 1995). Mice that survive the early neonatal period typically present with severe liver injury including panlobular microsteatosis, fibrosis, macrophage infiltration and severely elevated levels of plasma ALT (Maclean et al., 2010a). Previous work in our laboratory has indicated that elevated cystathionine acts to protect the liver of the HO mouse model of HCU and that this compound can exert significant protective effects against endoplasmic reticulum stress induced liver and kidney damage in WT mice (Maclean et al., 2012a, 2010b). The presence of similar levels of tHcy in the female Cgl mice to those observed in Cbs and HO HCU mice prompted a histological and immunohistochemical examination of male and female Cgl mouse livers. In this analysis, male Cgl mice exhibited no evidence of hepatic dysfunction with no detectable steatosis, fibrosis or inflammation (Fig. 7). ALT values for all male Cgl mice investigated were within the normal range. H&E staining revealed that female Cgl mice exhibit very low levels of hepatic steatosis. This finding was confirmed by staining for the cytoplasmic lipid droplet protein Plin2 (Fig. 7A). Masson trichrome staining of female Cgl mice revealed no evidence of hepatic fibrosis (Fig. 7B) and plasma ALT levels were within the normal range. Collectively, our data indicates that female Cgl mice incur minimal liver damage compared to Cbs mice with similar levels of tHcy and are consistent with a possible hepatoprotective role for elevated cystathionine against liver injury that merits further investigation.Fig. 7.


Sex-specific dysregulation of cysteine oxidation and the methionine and folate cycles in female cystathionine gamma-lyase mice: a serendipitous model of the methylfolate trap.

Jiang H, Hurt KJ, Breen K, Stabler SP, Allen RH, Orlicky DJ, Maclean KN - Biol Open (2015)

The hepatic phenotype of female Cgl  mice is consistent with a possible protective role for cystathionine against liver injury in Cgl  mice. (A) H&E (upper panels) and Plin2 immunohistochemical staining (lower panels) from representative liver sections from male and female Cgl  mice reveals mild levels of lipid accumulation and Plin2 expression (green signal) in female but not male Cgl  mice. Data shown is representative of 5 animals per group. PT, portal triad; CV, central vein. (B) Masson-trichrome staining of female Cbs and Cgl  mice with similar levels of plasma tHcy. No fibrosis was observed in any Cgl  (right panel) mouse sample. Photomicrographs shown are representative of staining from 20 views taken from 5 mutant mice and 5 wild type controls and were assessed by a pathologist without knowledge of genotype. Scale bars: 200 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4582125&req=5

BIO013433F7: The hepatic phenotype of female Cgl mice is consistent with a possible protective role for cystathionine against liver injury in Cgl mice. (A) H&E (upper panels) and Plin2 immunohistochemical staining (lower panels) from representative liver sections from male and female Cgl mice reveals mild levels of lipid accumulation and Plin2 expression (green signal) in female but not male Cgl mice. Data shown is representative of 5 animals per group. PT, portal triad; CV, central vein. (B) Masson-trichrome staining of female Cbs and Cgl mice with similar levels of plasma tHcy. No fibrosis was observed in any Cgl (right panel) mouse sample. Photomicrographs shown are representative of staining from 20 views taken from 5 mutant mice and 5 wild type controls and were assessed by a pathologist without knowledge of genotype. Scale bars: 200 µm.
Mentions: A previously described Cbs mouse model of HCU incurs severe liver injury with approximately 90% of mice dying of liver failure in the first two weeks of life (Watanabe et al., 1995). Mice that survive the early neonatal period typically present with severe liver injury including panlobular microsteatosis, fibrosis, macrophage infiltration and severely elevated levels of plasma ALT (Maclean et al., 2010a). Previous work in our laboratory has indicated that elevated cystathionine acts to protect the liver of the HO mouse model of HCU and that this compound can exert significant protective effects against endoplasmic reticulum stress induced liver and kidney damage in WT mice (Maclean et al., 2012a, 2010b). The presence of similar levels of tHcy in the female Cgl mice to those observed in Cbs and HO HCU mice prompted a histological and immunohistochemical examination of male and female Cgl mouse livers. In this analysis, male Cgl mice exhibited no evidence of hepatic dysfunction with no detectable steatosis, fibrosis or inflammation (Fig. 7). ALT values for all male Cgl mice investigated were within the normal range. H&E staining revealed that female Cgl mice exhibit very low levels of hepatic steatosis. This finding was confirmed by staining for the cytoplasmic lipid droplet protein Plin2 (Fig. 7A). Masson trichrome staining of female Cgl mice revealed no evidence of hepatic fibrosis (Fig. 7B) and plasma ALT levels were within the normal range. Collectively, our data indicates that female Cgl mice incur minimal liver damage compared to Cbs mice with similar levels of tHcy and are consistent with a possible hepatoprotective role for elevated cystathionine against liver injury that merits further investigation.Fig. 7.

Bottom Line: In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide.Cgl mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls.Female Cgl mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

No MeSH data available.


Related in: MedlinePlus