Nonalcoholic steatohepatitis can be ameliorated by reactivating the CNC-bZIP transcription factor Nrf2

Fat in the liver typically develops when an individual consumes more fat and sugar than the body can handle. It is usually observed in people who are overweight or obese. If fat represents more than 5% of the liver mass, then it is a fatty liver. Whilst this condition probably does not cause any immediate harm, the extra fat may render the liver vulnerable to injury and inflammation that results in non-alcoholic steatohepatitis (NASH). The long-term outlook of people with NASH is not well understood, though emerging epidemiological evidence from Scottish National Health Service records indicates that NASH is a risk factor for cancer. At present, there is no proven effective medication for NASH. Since it is now a common health condition, NASH has raised considerable interest amongst scientists seeking to understand the pathophysiology of the disease.

Mechanistically, NASH has been linked to endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, lipotoxicity and iron overload, all of which can be countered by activation of the CNC-bZIP transcription factor NF-E2 p45-related factor 2 (Nrf2). Many studies have revealed Nrf2 to be a master regulator of gene expression that enables cells to adapt to the presence of a wide spectrum of electrophiles and oxidative stressors by upregulating proteins with antioxidant, detoxification, anti-inflammatory and mitochondrial metabolic functions. In a paper published in the peer-reviewed journal Free Radical Biology and Medicine, University of Dundee scientists Dr Boushra Bathish, Dr Holly Robertson, Professor John Dillon, Professor Albena Dinkova-Kostova, and Professor John Hayes have provided an expert opinion review of the various mechanisms that contribute to NASH, the molecular regulation of Nrf2 transcriptional activity and the biochemical actions of the genes controlled by Nrf2. Moreover, they have evaluated in vivo evidence that activation of Nrf2 can arrest, and possibly reverse, the development of NASH. It is noteworthy that Professor Hayes and colleagues are internationally recognized for their research into the molecular mechanisms that regulate Nrf2 and the potential of pharmacological manipulation of Nrf2 activity to treat NASH.

According to the authors, Nrf2-knockout mice are especially vulnerable to NASH, whilst genetic or pharmacological activation of Nrf2 boosts resistance to NASH. Importantly, they also discuss evidence that the development and progression of NASH is accompanied by downregulation of Nrf2, with the likelihood that Nrf2 downregulation represents an integral component of the pathogenesis of the disease. Recognition that Nrf2 downregulation accompanies NASH, suggests that restoring Nrf2 activity to its normal levels might provide a viable therapeutic strategy. Puzzlingly, during the early stages of the disease, diets that cause NASH appear to activate Nrf2. Such upregulation of Nrf2 activity during the initial onset of disease occurs because the oxidative stress and lipid peroxidation components, generated in the fatty liver, inactivate the Nrf2 repressor Keap1, which under non-stressed conditions continuously targets Nrf2 for proteasomal degradation by mediating its ubiquitylation. In the longer term however, persistent consumption of NASH-inducing diets results in a significant reduction in Nrf2 activity, under conditions when Keap1 is unlikely to repress Nrf2, suggesting that Nrf2 is subject to additional mechanisms of suppression that are poorly understood. The authors have detailed alternative mechanisms of Nrf2 suppression, such as ubiquitylation of Nrf2 directed by β-TrCP that is initiated by activation of MAPKs, or ubiquitylation of Nrf2 upon activation of Hrd1/SYVN1 by endoplasmic reticulum stress, and have proposed that these additional ways of ubiquitylating Nrf2 probably contribute to the progression of NASH.

An appealing and perhaps successful method for treating NASH is the activation of Nrf2, possibly in conjunction with other medications. In view of the broad cytoprotective effects of Nrf2 and its role in maintaining redox homeostasis, it is apparent that numerous pathways that contribute to the aetiology of NASH will probably become blunted when Nrf2 is activated. It is well recognized that soft electrophiles that block the ubiquitin ligase substrate adaptor function of Keap1 can induce the expression of Nrf2-target genes, making such compounds potential therapeutic agents for activating Nrf2 and treating NASH. It may also be necessary to use medications that oppose β-TrCP or inhibit MAPKs, and so restore Nrf2 activity to typical cytoprotective levels when MAPKs are activated and downregulate Nrf2. Other ways of treating NASH might include restoring normal homeostatic Nrf2 activity by inhibiting its ubiquitylation by Hrd1/SYVN1 or by preventing competition for the recruitment of coactivators to Nrf2 by ATF3 or by preventing the competition by Bach1 for the binding to Nrf2 recognition sites in gene promoters. Interestingly, some of the proteins that repress Nrf2 are activated by TGF-β signaling, which suggests that the progression of NASH is dictated by crosstalk between Nrf2 and TGF-β signaling.

In a nutshell, Professor Hayes and colleagues have summarized the molecular mechanisms that regulate Nrf2 activity and the pathways it controls, and have discussed the potential therapeutic applications of targeting Nrf2 in NASH. It is hoped in the future further studies to understand and explore the therapeutic impact of Nrf2 will improve the prognosis for NASH patients.