Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2

Abstract

Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.