Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure

• DOI: 10.1016/j.isci.2021.102552
• Publication Date: 2021-05-19T16:50:20Z
• Authors: Jose Meseguer-Rip...; Baltasar Lucendo-...; Carl Tucker; Sofia Ferreira-Go...; Natalie Homer; Yu Wang; Philip J. Starkey...; Enrique M Toledo; Esther Mellado-Gomez; Joanna Simpson; Oliver Flint; Himjyot Jaiswal; Nicola L. Beer; Allan E. Karlsen; Stuart J. Forbes; James W. Dear; Jeremy Hughes; David C. Hay
• Keywords: 0301 basic medicine; Cell biology; 03 medical and health sciences; Molecular biology; Science; Q; Toxicology; Transcriptomics; Article; 3. Good health

Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-β signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo. We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties.