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

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 (Lead / Corresponding author)

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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.

Original language	English
Article number	101638
Number of pages	48
Journal	iScience
Volume	23
Issue number	10
Early online date	5 Oct 2020
DOIs	https://doi.org/10.1016/j.isci.2020.101638
Publication status	Published - 23 Oct 2020

Keywords

Human Metabolism
Molecular Biology
Omics

ASJC Scopus subject areas

General

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10.1016/j.isci.2020.101638Licence: CC BY

Final Published VersionFinal published version, 13.5 MBLicence: CC BY

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title = "Downregulation of Keap1 confers features of a fasted metabolic state",

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",

author = "Knatko, {Elena V.} and Tatham, {Michael H.} and Ying Zhang and Cecilia Castro and Maureen Higgins and {Dayalan Naidu}, Sharadha and Chiara Leonardi and {de la Vega}, Laureano and Tadashi Honda and Griffin, {Julian L.} and Hay, {Ronald T.} and Dinkova-Kostova, {Albena T.}",

note = "Cancer Research UK Grant numbers: C20953/A18644, C434/A13067 and Wellcome Trust Grant numbers: 098391/Z/12/Z, 217196/Z/19/Z",

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language = "English",

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T1 - Downregulation of Keap1 confers features of a fasted metabolic state

AU - Knatko, Elena V.

AU - Tatham, Michael H.

AU - Zhang, Ying

AU - Castro, Cecilia

AU - Higgins, Maureen

AU - Dayalan Naidu, Sharadha

AU - Leonardi, Chiara

AU - de la Vega, Laureano

AU - Honda, Tadashi

AU - Griffin, Julian L.

AU - Hay, Ronald T.

AU - Dinkova-Kostova, Albena T.

N1 - Cancer Research UK Grant numbers: C20953/A18644, C434/A13067 and Wellcome Trust Grant numbers: 098391/Z/12/Z, 217196/Z/19/Z

PY - 2020/10/23

Y1 - 2020/10/23

N2 - 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.

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Downregulation of Keap1 confers features of a fasted metabolic state

Abstract

Keywords

ASJC Scopus subject areas

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Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

Dinkova-Kostova, Albena

Cite this

Downregulation of Keap1 confers features of a fasted metabolic state

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

Profiles

Dinkova-Kostova, Albena

Cite this