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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.

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NAFLD models in WT and KO mice were established by feeding with high-fat diet for eight consecutive weeks. Fresh sections were stained with H&E to demonstrate lipid accumulation. The sections were examined by light microscopy, and the liver images are displayed at 200× original magnification: (A) Nrf2+/+ mice on control diet; (B) Nrf2+/+ mice on high-fat diet; (C) Nrf2−/− mice on control diet; (D) Nrf2−/− mice on high-fat diet. The Nrf2+/+ and Nrf2−/− high-fat model groups liver sections exhibited severe hepatosteatosis consisting of mixed microvesicular and macrovesicular fat accumulation. The horizontal scale bar represents 100 μm.
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f0005: NAFLD models in WT and KO mice were established by feeding with high-fat diet for eight consecutive weeks. Fresh sections were stained with H&E to demonstrate lipid accumulation. The sections were examined by light microscopy, and the liver images are displayed at 200× original magnification: (A) Nrf2+/+ mice on control diet; (B) Nrf2+/+ mice on high-fat diet; (C) Nrf2−/− mice on control diet; (D) Nrf2−/− mice on high-fat diet. The Nrf2+/+ and Nrf2−/− high-fat model groups liver sections exhibited severe hepatosteatosis consisting of mixed microvesicular and macrovesicular fat accumulation. The horizontal scale bar represents 100 μm.

Mentions: All of the sections in the experimental groups exhibited diffuse hepatic steatosis (Fig. 1) under a light microscope, whereas no fatty liver was observed in the control group. The relative sizes of the hepatic cell nuclei were uneven. Hepatic steatosis (mostly microvesicular and macrovesicular mixed steatosis) was most obvious around the portal area and was accompanied by liver cell necrosis and inflammatory cell infiltration. The lobular and portal areas exhibited considerably more inflammatory cell infiltration in the experimental group than in the control group. The total histological scores of the livers in the model-group mice reached grade 2 or 3. Livers from WT-high-fat mice showed a minimal degree of microvesicular steatosis. Most significantly, livers from Nrf2 KO-high-fat mice exhibited severe macrovesicular steatosis and mild microvesicular steatosis, indicating that diffuse hepatic steatosis with moderate inflammation (NAFLD) had developed.


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 models in WT and KO mice were established by feeding with high-fat diet for eight consecutive weeks. Fresh sections were stained with H&E to demonstrate lipid accumulation. The sections were examined by light microscopy, and the liver images are displayed at 200× original magnification: (A) Nrf2+/+ mice on control diet; (B) Nrf2+/+ mice on high-fat diet; (C) Nrf2−/− mice on control diet; (D) Nrf2−/− mice on high-fat diet. The Nrf2+/+ and Nrf2−/− high-fat model groups liver sections exhibited severe hepatosteatosis consisting of mixed microvesicular and macrovesicular fat accumulation. The horizontal scale bar represents 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0005: NAFLD models in WT and KO mice were established by feeding with high-fat diet for eight consecutive weeks. Fresh sections were stained with H&E to demonstrate lipid accumulation. The sections were examined by light microscopy, and the liver images are displayed at 200× original magnification: (A) Nrf2+/+ mice on control diet; (B) Nrf2+/+ mice on high-fat diet; (C) Nrf2−/− mice on control diet; (D) Nrf2−/− mice on high-fat diet. The Nrf2+/+ and Nrf2−/− high-fat model groups liver sections exhibited severe hepatosteatosis consisting of mixed microvesicular and macrovesicular fat accumulation. The horizontal scale bar represents 100 μm.
Mentions: All of the sections in the experimental groups exhibited diffuse hepatic steatosis (Fig. 1) under a light microscope, whereas no fatty liver was observed in the control group. The relative sizes of the hepatic cell nuclei were uneven. Hepatic steatosis (mostly microvesicular and macrovesicular mixed steatosis) was most obvious around the portal area and was accompanied by liver cell necrosis and inflammatory cell infiltration. The lobular and portal areas exhibited considerably more inflammatory cell infiltration in the experimental group than in the control group. The total histological scores of the livers in the model-group mice reached grade 2 or 3. Livers from WT-high-fat mice showed a minimal degree of microvesicular steatosis. Most significantly, livers from Nrf2 KO-high-fat mice exhibited severe macrovesicular steatosis and mild microvesicular steatosis, indicating that diffuse hepatic steatosis with moderate inflammation (NAFLD) had developed.

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