title: Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet.
abstract: The Keap1/Nrf2 pathway, known to regulate the expression of a series of cytoprotective and antioxidant genes, has been studied in the context of obesity and type 2 diabetes; diseases that are characterized by chronic oxidative stress. There is increasing evidence, however, that the transcription factor Nrf2 can crosstalk with pathways not directly related to cytoprotection. Our present work focuses on the effect of Nrf2 on hepatic gluconeogenesis and lipogenesis, two metabolic processes which are dysregulated in the obese/diabetic state. To this end, a genetic mouse model of Nrf2 pathway activation was used (Keap1-hypo; both Keap1 alleles are hypomorphic) and was exposed to a 3-month high-fat diet along with the relevant control wild-type mice. The Keap1-hypo mice were partially protected from obesity, had lower fasting glucose and insulin levels and developed less liver steatosis compared to the wild-type. Key gluconeogenic and lipogenic enzymes were repressed in the Keap1-hypo livers with concomitant activated Ampk signaling. Primary Keap1-hypo hepatocyte cultures also show increased Ampk signaling and repressed glucose production. In conclusion, increased Keap1/Nrf2 signaling in the liver is accompanied by repressed gluconeogenesis and lipogenesis that can, at least partially, explain the ameliorated diabetic phenotype in the Keap1-hypo mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Slocum
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Skoko
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nobunao
authors.initials: N
authors.lastname: Wakabayashi
authors.affiliation: The Center for Metabolism and Obesity Research, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dic16@pitt.edu.
authors.forename: Dionysios V
authors.initials: DV
authors.lastname: Chartoumpekis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000379:methods; D004041:Dietary Fats / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004041:Dietary Fats; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse
keywords: Ampk; Diabetes; Gluconeogenesis; Keap1; Lipogenesis; Nrf2