Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice.
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.
Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité -University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
Sebastian
http://orcid.org/0000-0002-6336-3939
S
Brachs
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Angelika F
AF
Winkel
Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité -University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
James
J
Polack
Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité -University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
Hui
H
Tang
Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité -University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
Maria
M
Brachs
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Daniel
D
Margerie
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Bodo
B
Brunner
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Kerstin
K
Jahn-Hofmann
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Hartmut
H
Ruetten
Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité -University School of Medicine, Berlin, Germany.|German Center for Cardiovascular Research, DZHK Partner site Berlin, Berlin, Germany.
Joachim
J
Spranger
Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany.
Dieter
D
Schmoll
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D005947:Glucose