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
