The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation

Abstract

Purpose of review: The vertebrate cap'n'collar family transcription factor Nrf2 and its invertebrate homologues SKN-1 (in worms) and CncC (in flies) function as master mediators of antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls gene expression programs that defend various tissues against diverse electrophilic stressors and oxidative insults, thus protecting the organism from disorders that are caused or exacerbated by such stresses. Moreover, studies on model organisms implicate the Nrf2 pathway in the prevention of aging-related diseases and suggest that SKN-1-regulated and CncC-regulated gene expression can promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article discusses another aspect of the Nrf2 pathway's function that has not yet received the same degree of attention, but emerges as a topic of increasing interest and potential clinical impact: its role in metabolic regulation and its interaction with central signaling systems that respond to nutritional inputs.

Recent findings: Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects of caloric restriction. Nrf2 signaling also crosstalks with metabolic signaling systems such as the insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role in models of diabetic nephropathy.

Summary: The emerging role of Nrf2 as an effector of metabolic and longevity signals offers new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2 signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.

Figure 1. Schematic model of Nrf2 activation

In basal conditions the protein levels of Nrf2 are kept low due to the rapid proteasome-mediated turn-over facilitated by the Kelch family protein Keap1 which acts as a Nrf2-specific E3 ligase adaptor protein. In response to various extracellular signals the inhibitory effect of Keap1 on Nrf2 is interrupted, such that Nrf2 is stabilized and accumulates in the nucleus. There it dimerizes with a small Maf protein, binds to AREs (Antioxidant Response Elements) in the regulatory regions of its target genes and modulates their transcription.

Figure 2. Model: Nrf2 as a convergence point for stress, metabolic, and longevity signals

Nrf2 can be activated by various types of oxidative and electrophile stress. Recent evidence reviewed in this article shows that Nrf2 function can also respond to Lipid Me metabolic and longevity signals such as CR, low levels of IIS, and lipid metabolites. We suggest that the transcriptome changes that occur in these conditions include different, but overlapping sets of Nrf2 target genes. The resulting Nrf2-induced genetic programs can contribute to stress protection, longevity, or changes in metabolism. A scientific challenge, or opportunity, arising from this model is to evaluate pharmacological options to evoke longevity programs, possibly by using Nrf2-activating drugs that have originally been identified as cancer chemopreventive agents.