New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders

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A longitudinal molecular model of the development and progression of nonalcoholic fatty liver disease (NAFLD) over time is lacking.We have recently validated a high fat/sugar water-induced animal (an isogenic strain of C57BL/6 J:129S1/SvImJ mice) model of NAFLD that closely mimics most aspects of human disease.The hepatic transcriptome of such mice with fatty liver (8 weeks), steatohepatitis with early fibrosis (16-24 weeks) and advanced fibrosis (52 weeks) after initiation of the diet was evaluated and compared to mice on chow diet.Fatty liver development was associated with transcriptional activation of lipogenesis, FXR-RXR, PPAR-α mediated lipid oxidation and oxidative stress pathways.With progression to steatohepatitis, metabolic pathway activation persisted with additional activation of IL-1/inhibition of RXR, granulocyte diapedesis/adhesion, Fc macrophage activation, prothrombin activation and hepatic stellate cell activation.Progression to advanced fibrosis was associated with dampening of metabolic, oxidative stress and cell stress related pathway activation but with further Fc macrophage activation, cell death and turnover and activation of cancer-related networks.The molecular progression of NAFLD involves a metabolic perturbation which triggers subsequent cell stress and inflammation driving cell death and turnover.Over time, inflammation and fibrogenic pathways become dominant while in advanced disease an inflammatory-oncogenic profile dominates.Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in the Western world and is rapidly increasing in prevalence globally 1 .It may manifest itself as nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH).While it was generally assumed that only NASH progressed to cirrhosis and end-stage liver disease, recent studies indicate that NAFL can also lead to progressive fibrosis 2-4 .A vast amount of literature has already accumulated documenting activation of specific cellular pathways in the genesis and evolution of NASH 5,6 .It is however not known if these pathways all get turned on and remain turned on throughout the course of the disease.The relevance of when specific pathways are activated during disease evolution to cirrhosis is also unknown.Current drug development is based on the assumption that the molecular target for a given drug is equally relevant for all patients with NASH; however the failure to achieve a therapeutic response in only 40-50% of treated patients despite similar drug compliance indicates that the population is heterogeneous with respect to treatment response.A potential explanation for this could be that different molecular pathways are differentially activated at various points in disease progression.While this is far from proven, longitudinal assessment of the transcriptome with evolution of the disease is a required first step to address this possibility and inform future Precision Medicine approaches for NASH.Indeed, such transcriptomic models have provided the foundational basis for Precision Medicine approaches for many cancers 7 .

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