Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity

Dionysios V. Chartoumpekis,Venetsana E. Kyriazopoulou,Ioannis G. Habeos,Apostolos Zaravinos,Panos G. Ziros,Gerasimos P. Sykiotis,Agathoklis I. Psyrogiannis,Ralitsa P. Iskrenova

doi:10.1155/2013/340731

Dionysios V. Chartoumpekis, Venetsana E. Kyriazopoulou + Show 6 more

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https://doi.org/10.1155/2013/340731

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Abstract

Introduction. The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf2 has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD-) induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT) versus Nrf2 knockout (Nrf2-KO) mice after a long-term HFD. Methods. WT and Nrf2-KO mice were fed an HFD for 180 days; total RNA was prepared from liver and used for microarray analysis and quantitative real-time RT-PCR (qRT-PCR). Results. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Selected genes, including ones known to be involved in metabolic regulation, were prioritized for verification by qRT-PCR: Cyp7a1 and Fabp5 were significantly overexpressed in Nrf2-KO mice; in contrast, Car, Cyp2b10, Lipocalin 13, Aquaporin 8, Cbr3, Me1, and Nqo1 were significantly underexpressed in Nrf2-KO mice. Conclusion. Transcriptome profiling after HFD-induced obesity confirms that Nrf2 is implicated in liver metabolic gene networks. The specific genes identified here may provide insights into Nrf2-dependent mechanisms of metabolic regulation.

Highlights

The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress
We described the phenotypic comparison of WT versus Nrf2KO mice under high-fat diet (HFD, 60 kcal% fat) or a control diet for 180 days [13]
The findings of our previous study that male Nrf2 knockout (Nrf2-KO) mice were at least partially protected from HFD-induced (60 kcal% fat) obesity and were more insulin sensitive and more glucose tolerant compared to their WT counterparts [13] are consistent with previous reports using comparable but different treatment parameters (40 kcal% fat diet or modified high-fat-diets) [14,15,16]

Summary

Introduction

The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD-) induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT) versus Nrf knockout (Nrf2-KO) mice after a long-term HFD. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Transcriptome profiling after HFD-induced obesity confirms that Nrf is implicated in liver metabolic gene networks. A transcription factor that has recently been implicated in obesity and metabolic dysregulation is Nrf (NFE2-related factor 2), encoded by NFE2L2 (nuclear erythroid factor 2-like 2) [5]. Upon exposure to oxidative and electrophilic stress, Nrf escapes Keap1-mediated degradation and accumulates in the nucleus where it binds to cis elements

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