Limits...
Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation.

Cui Y, Wang Q, Li X, Zhang X - Redox Biol (2013)

Bottom Line: Livers of Nrf2 (-/-) mice on the high-fat diet exhibited more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in malondialdehyde.Furthermore, results in Nrf2-deficient mice showed that CYP2A5 expression was significantly attenuated in the absence of Nrf2, as was found with the conventional target genes of Nrf2.These findings suggest that the high-fat diet induced alteration in cellular redox status and induction of CYP2A5 was modulated through the redox-sensitive transcription Nrf2.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine, Northeast Agricultural University, No. 59 Mucai Street, Xiangfang District, Harbin 150030, Heilongjiang, China ; College of Animal Sciences and Technology, Heilongjiang Bayi Agricultural University, 2# Xinyang Road, New Development District, Daqing 163319, Heilongjiang, China.

ABSTRACT
Mouse cytochrome P450 2A5 (CYP2A5) is upregulated in various liver diseases and a putative common feature for all of these conditions is altered cellular redox status. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor that is post-translationally regulated by oxidative stress and controls the transcription of protective target genes. In the present study, we have characterized the regulation of CYP2A5 by Nrf2 and evaluated gene expression, protein content and activity of anti-oxidant enzymes in the Nrf2 (+/+) and Nrf2 (-/-) mice model of non-alcoholic fatty liver (NAFLD). After eight weeks of feeding on a high-fat diet, livers from Nrf2 (-/-) mice showed a substantial increase in macro and microvesicular steatosis and a massive increase in the number of neutrophil polymorphs, compared to livers from wild-type mice treated similarly. Livers of Nrf2 (-/-) mice on the high-fat diet exhibited more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in malondialdehyde. Furthermore, results in Nrf2-deficient mice showed that CYP2A5 expression was significantly attenuated in the absence of Nrf2, as was found with the conventional target genes of Nrf2. The treatment of wild-type mice with high-fat diet leaded to nuclear accumulation of Nrf2, and co-immunoprecipitation experiments showed that Nrf2 was bound to Cyp2a5. These findings suggest that the high-fat diet induced alteration in cellular redox status and induction of CYP2A5 was modulated through the redox-sensitive transcription Nrf2.

Show MeSH

Related in: MedlinePlus

NAFLD reduced mRNA expression of Nrf2 target genes in Nrf2−/−mice. CAT, catalase; GClC, glutamate cysteine ligase catalytic; γ-GCS, γ-glutamylcysteine synthetase; Nqo1, NAD(P)H:quinine oxidoreductase 1; GSTA1, glutathione S-transferase alpha 1 gene; HO-1, heme oxygense-1. The mRNA expressions of various genes were quantified by RT-PCR, using mRNA GAPDH as an internal control. The data are expressed as the mean±SD (n=3 per treatment group). †Statistically different from wild type on the same diet; ⁎statistical difference caused by the high-fat diet within each genotype.⁎P<0.05, ⁎⁎P<0.01; †P<0.05, ††P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3814957&req=5

f0015: NAFLD reduced mRNA expression of Nrf2 target genes in Nrf2−/−mice. CAT, catalase; GClC, glutamate cysteine ligase catalytic; γ-GCS, γ-glutamylcysteine synthetase; Nqo1, NAD(P)H:quinine oxidoreductase 1; GSTA1, glutathione S-transferase alpha 1 gene; HO-1, heme oxygense-1. The mRNA expressions of various genes were quantified by RT-PCR, using mRNA GAPDH as an internal control. The data are expressed as the mean±SD (n=3 per treatment group). †Statistically different from wild type on the same diet; ⁎statistical difference caused by the high-fat diet within each genotype.⁎P<0.05, ⁎⁎P<0.01; †P<0.05, ††P<0.01.

Mentions: Messenger RNA expression of several Nrf2 target genes is shown in Fig. 3. The expression of γ-GCS, Nqo1, GSTA1and HO-1 mRNA was induced by the high-fat diet in Nrf2+/+ and Nrf2−/−mice. However, no induction of CAT and GCLC was observed in KO mice fed with the high-fat diet. Furthermore, in KO mice fed with high-fat diet all of the Nrf2 target genes expression were significantly lower (P<0.05 or P<0.01) than the WT mice fed with high-fat diet.


Experimental nonalcoholic fatty liver disease in mice leads to cytochrome p450 2a5 upregulation through nuclear factor erythroid 2-like 2 translocation.

Cui Y, Wang Q, Li X, Zhang X - Redox Biol (2013)

NAFLD reduced mRNA expression of Nrf2 target genes in Nrf2−/−mice. CAT, catalase; GClC, glutamate cysteine ligase catalytic; γ-GCS, γ-glutamylcysteine synthetase; Nqo1, NAD(P)H:quinine oxidoreductase 1; GSTA1, glutathione S-transferase alpha 1 gene; HO-1, heme oxygense-1. The mRNA expressions of various genes were quantified by RT-PCR, using mRNA GAPDH as an internal control. The data are expressed as the mean±SD (n=3 per treatment group). †Statistically different from wild type on the same diet; ⁎statistical difference caused by the high-fat diet within each genotype.⁎P<0.05, ⁎⁎P<0.01; †P<0.05, ††P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814957&req=5

f0015: NAFLD reduced mRNA expression of Nrf2 target genes in Nrf2−/−mice. CAT, catalase; GClC, glutamate cysteine ligase catalytic; γ-GCS, γ-glutamylcysteine synthetase; Nqo1, NAD(P)H:quinine oxidoreductase 1; GSTA1, glutathione S-transferase alpha 1 gene; HO-1, heme oxygense-1. The mRNA expressions of various genes were quantified by RT-PCR, using mRNA GAPDH as an internal control. The data are expressed as the mean±SD (n=3 per treatment group). †Statistically different from wild type on the same diet; ⁎statistical difference caused by the high-fat diet within each genotype.⁎P<0.05, ⁎⁎P<0.01; †P<0.05, ††P<0.01.
Mentions: Messenger RNA expression of several Nrf2 target genes is shown in Fig. 3. The expression of γ-GCS, Nqo1, GSTA1and HO-1 mRNA was induced by the high-fat diet in Nrf2+/+ and Nrf2−/−mice. However, no induction of CAT and GCLC was observed in KO mice fed with the high-fat diet. Furthermore, in KO mice fed with high-fat diet all of the Nrf2 target genes expression were significantly lower (P<0.05 or P<0.01) than the WT mice fed with high-fat diet.

Bottom Line: Livers of Nrf2 (-/-) mice on the high-fat diet exhibited more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in malondialdehyde.Furthermore, results in Nrf2-deficient mice showed that CYP2A5 expression was significantly attenuated in the absence of Nrf2, as was found with the conventional target genes of Nrf2.These findings suggest that the high-fat diet induced alteration in cellular redox status and induction of CYP2A5 was modulated through the redox-sensitive transcription Nrf2.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine, Northeast Agricultural University, No. 59 Mucai Street, Xiangfang District, Harbin 150030, Heilongjiang, China ; College of Animal Sciences and Technology, Heilongjiang Bayi Agricultural University, 2# Xinyang Road, New Development District, Daqing 163319, Heilongjiang, China.

ABSTRACT
Mouse cytochrome P450 2A5 (CYP2A5) is upregulated in various liver diseases and a putative common feature for all of these conditions is altered cellular redox status. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor that is post-translationally regulated by oxidative stress and controls the transcription of protective target genes. In the present study, we have characterized the regulation of CYP2A5 by Nrf2 and evaluated gene expression, protein content and activity of anti-oxidant enzymes in the Nrf2 (+/+) and Nrf2 (-/-) mice model of non-alcoholic fatty liver (NAFLD). After eight weeks of feeding on a high-fat diet, livers from Nrf2 (-/-) mice showed a substantial increase in macro and microvesicular steatosis and a massive increase in the number of neutrophil polymorphs, compared to livers from wild-type mice treated similarly. Livers of Nrf2 (-/-) mice on the high-fat diet exhibited more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in malondialdehyde. Furthermore, results in Nrf2-deficient mice showed that CYP2A5 expression was significantly attenuated in the absence of Nrf2, as was found with the conventional target genes of Nrf2. The treatment of wild-type mice with high-fat diet leaded to nuclear accumulation of Nrf2, and co-immunoprecipitation experiments showed that Nrf2 was bound to Cyp2a5. These findings suggest that the high-fat diet induced alteration in cellular redox status and induction of CYP2A5 was modulated through the redox-sensitive transcription Nrf2.

Show MeSH
Related in: MedlinePlus