Downregulation of Keap1 Confers Features of a Fasted Metabolic State

Elena V Knatko; Michael H Tatham; Ying Zhang; Cecilia Castro; Maureen Higgins; Sharadha Dayalan Naidu; Chiara Leonardi; Laureano de la Vega; Tadashi Honda; Julian L Griffin; Ronald T Hay; Albena T Dinkova-Kostova

doi:10.1016/j.isci.2020.101638

Downregulation of Keap1 Confers Features of a Fasted Metabolic State

iScience. 2020 Oct 6;23(10):101638. doi: 10.1016/j.isci.2020.101638. eCollection 2020 Oct 23.

Authors

Affiliations

¹ Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland DD1 9SY, UK.
² Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
³ Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1QW, UK.
⁴ Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
⁵ Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington, London SW7 2AZ, UK.
⁶ Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory, and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglyceride levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators.

Keywords: Human Metabolism; Molecular Biology; Omics.

Abstract

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