Abstract
The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 7 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated successful knock-down of Keap1 expression and induction of Nrf2-dependent genes involved in anti-oxidative stress defense and biotransformation, proving the activation of Nrf2 by the siRNAs against Keap1. Neither the expression of fatty acid- nor carbohydrate-handling proteins was regulated by Keap1 knock-down. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance. The data indicate that hepatic Keap1/Nrf2 is not a major regulator of glucose or lipid metabolism in mice.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Carbohydrate Metabolism / physiology*
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Cytoskeletal Proteins / metabolism
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Fatty Acids / metabolism*
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Glucose / metabolism*
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Intracellular Signaling Peptides and Proteins / metabolism
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Kelch-Like ECH-Associated Protein 1 / metabolism
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Lipid Metabolism / physiology*
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Male
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Mice
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Mice, Inbred C57BL
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NF-E2-Related Factor 2 / metabolism*
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Oxidative Stress / physiology
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Signal Transduction / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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Fatty Acids
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Intracellular Signaling Peptides and Proteins
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Glucose
Grants and funding
This work was supported by a collaboration between Charité and Sanofi-Aventis Deutschland GmbH and SB, JP, HT, MB and JS were supported by the DZHK (BMBF). Sanofi-Aventis Deutschland GmbH provided support in the form of salaries for authors [AFW, DM, BB, KJ-H, HR, and DS] and a research grant to SB and JS. DS was involved in study design and experiments were partially carried out in the labs of Sanofi-Aventis Deutschland GmbH. The specific roles of the authors are articulated in the ‘author contributions’ section. However Sanofi-Aventis Deutschland GmbH as funding organization did not have any further role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder did not directly benefit from the study and the study did not involve a product the funder sells. JS is PI of the German Center for Cardiovascular Research (DZHK) and this study was supported by resources of the DZHK. The DZHK provided salaries for authors [HT, MB], but the DZHK did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.