Downregulation of Keap1 Confers Features of a Fasted Metabolic State.

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

doi:10.1016/j.isci.2020.101638

Abstract

SummaryTranscription 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.

Highlights

Kelch-like ECH-associated protein 1 (Keap1) is the mammalian sensor for electrophiles and oxidants and the main negative regulator of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2, gene name NFE2L2)
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
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

Summary

Introduction

Kelch-like ECH-associated protein 1 (Keap1) is the mammalian sensor for electrophiles and oxidants and the main negative regulator of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf, gene name NFE2L2). Keap and Nrf form a tightly coupled sensor/transducer system that orchestrates the expression of a large network of genes encoding proteins, which are essential for adaptation and survival under conditions of oxidative, electrophilic, and inflammatory stress (Yamamoto et al, 2018). Keap acts as a substrate adapter of a Cullin RING E3-ubiquitin Ligase (CRL), containing Cul and Rbx, which continuously targets Nrf for ubiquitination and proteasomal degradation (Cullinan et al, 2004; Kobayashi et al, 2004; Zhang et al, 2004). Nuclear Nrf coordinately activates transcription of nearly 500 genes (Malhotra et al, 2010), the protein products of which are extraordinarily versatile and, by a range of mechanisms—including direct antioxidant activity, obligatory 2-electron reduction reactions, conjugation with endogenous ligands, recognition, repair and removal of damaged proteins— serve as critical cytoprotective defenses to eliminate a wide variety of potentially damaging agents and to restore redox balance

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